Anesthesiology

Anesthesia for Breast Biopsy and Lumpectomy

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What the Anesthesiologist Should Know before the Operative Procedure

About one in eight (12%) of American women will develop breast cancer in their lifetime. Breast cancer is the second leading cause of cancer death in women, exceeded only by lung cancer. The chance that breast cancer will be responsible for a woman’s death is about 1 in 36 (about 3%). Death rates from breast cancer have been declining since about 1989, with larger decreases in women younger than 50. These decreases are believed to be the result of earlier detection through screening and increased awareness, as well as improved treatment.

According to Tumor, Nodes, Metastases (TNM) staging, 5-year relative survival rates by stage for patients presenting with stage I, IIA, IIB, IIIA, IIIB, and IV disease are 95, 85, 70, 52, 48, and 18 percent, respectively. Both age under 35 as well as age over 65 at diagnosis are associated with less favorable prognosis

The widespread use of mammography has resulted in early detection, as over 20% of newly diagnosed malignancies are in situ. Randomized clinical trials have demonstrated a 30% reduction in breast cancer mortality in women aged 50 to 69 years who are screened annually or biennially with mammograms.

The most recent U.S. Preventive Services Task Force (USPSTF) recommendation statement on screening for breast cancer in the general population (2009) recommends against routine screening mammography in women aged 40 to 49 years. The decision to start regular, biennial screening mammography before the age of 50 years should be an individual one and it should take into account patient context. The USPSTF does however recommend biennial screening mammography for women between the ages of 50 and 74. They state that current evidence is insufficient to assess the additional benefits and harms of screening mammography in women 75 years or older. Evidence is also insufficient to assess the benefits and harms of clinical breast examination in women 40 years or older, as well as digital mammography or magnetic resonance imaging as opposed to film mammography for screening purposes.

Guidelines from major groups (including the National Comprehensive Cancer Network [NCCN] and the American Cancer Society) recommend a combination of annual mammography and breast MRI for breast cancer surveillance in women who are BRCA mutation carriers or those with a significantly elevated risk of developing breast cancer.

Breast cancer risk factors

Genetics: A first-degree relative with breast cancer before the age of 50 increases the patient’s odds of having the disease by as much as four-fold. Despite the lower rates for young, premenopausal women, those whose cancer is diagnosed before age 35 are more likely to be carriers of breast cancer susceptibility genes BRCA1 and BRCA2 and to experience a more biologically aggressive form of the disease, which results in decreased disease-free and overall survival rates.

Age: Breast cancer is most frequently diagnosed among women aged 55-64 with the median age at diagnosis being 61.

Race/ethnicity: Overall rates are highest for Caucasian woman, lowest for Native American and Korean women, and intermediate for African American as well as other Asian and Hispanic women.

Hormonal risk factors: Prolonged exposure to estrogen (early menarche, late menopause, nulliparity) is a risk factor.

Diet and body weight: Multiple studies have shown association between breast cancer and both dietary fat and total caloric intake. Body weight has been positively correlated with both breast cancer incidence and mortality in postmenopausal women. Data have shown a dose-response relationship between alcohol consumption and breast cancer risk.

Radiation exposure: The risk is greatest among women exposed during puberty and occurs after a latent period of 10 to 20 years.

Benign breast disease: Lobular carcinoma in situ (LCIS) is the most common benign lesion, which increases the risk of subsequent breast cancer in either breast. This lesion is more appropriately termed lobular neoplasia. It is not known to be a premalignant lesion, but rather a marker that identifies women at an increased risk for subsequent development of invasive breast cancer. This risk remains elevated even beyond 2 decades, and most of the subsequent cancers are ductal rather than lobular. LCIS is usually multicentric and is frequently bilateral.

Most women with LCIS have disease that can be managed without additional local therapy after biopsy. No evidence is available that re-excision to obtain clear margins is required. The use of tamoxifen has decreased the risk of developing breast cancer in women with LCIS and should be considered in the routine management of these women.

Surgical procedures

Many surgical procedures have been developed with the goals of early cancer detection, and preservation of breast tissue when possible.

Lumpectomy is the excision of a breast lesion whether palpable or nonpalpable for histopathologic diagnosis.

The gold standard for initial assessment of breast lesions is minimally invasive breast biopsy under radiographic guidance. Minimally invasive breast biopsy includes fine needle aspiration and core-needle biopsies with or without image guidance and/or vacuum assistance. Minimally invasive breast biopsy is as accurate as open biopsy for the diagnosis of malignancy, particularly when combined with image guidance and vacuum assistance. Although at least one study showed that despite an increase in the use of minimally invasive breast biopsy over time, its use (at least in the region studied) was lower than recommended by the National Cancer Center Network. Open biopsies might still be required or preferred in certain situations, the 2009 Consensus Statement and NCCN have set target rates of <5% to 10% for these more invasive procedures.

The term “excisional biopsy” usually refers to removal of a benign lesion such as fibroadenoma, whereas lumpectomy is a removal of a benign or cancerous lesion with cancer-free surrounding margins. Ductoscopy can be used to excise intraductal lesions (which are most commonly benign). Smaller needle aspirations can be performed in the office and may be done under radiographic guidance. These are generally presurgical diagnostic studies performed under minimal local anesthesia and will not be covered in this chapter. Nonpalpable lesions have likely been picked up on routine mammography and are typically seen as calcifications or distorted anatomy. Needle localization by the radiologist may be needed before the surgical procedure, especially for nonpalpable lesions. A hook wire is inserted under local anesthesia and radiographic guidance is used to localize the lesion.

For cancerous lesions, clinically pathologic lymph nodes are excised. Sentinel node excision is performed in the absence of such nodes and is thought to be a perfectly adequate replacement for the more invasive Level I and II lymph node dissection. The sentinel node is the first draining node of a breast cancer and is likely in the axilla but may be in the internal mammary chain. Subsequent axillary node dissection is performed on patients with tumor-positive sentinel nodes and larger than 0.2-mm metastasis. A frozen section is typically performed intraoperatively to decide on the extent of node dissection.

To identify a sentinel node, a blue dye is typically injected around the lesion by the surgeon. The most commonly used dye is methylene blue. Other dyes include 1% isosulfan blue and 99m-technetium–labeled sulfur colloid. The latter is a radioactive agent injected typically in nuclear medicine and does not require special handling. An intraoperative gamma probe senses the lesion. Many surgeons combine both color and nuclear dyes. Many of the color dyes interfere with pulse oximetry as discussed below. Careful monitoring and possible arterial blood gas analysis are warranted.

1. What is the urgency of the surgery?

What is the risk of delay in order to obtain additional preoperative information?

One study showed that breast tumor growth varied considerably between subjects with 5% of tumors taking less than 1.2 months to grow from 10 mm to 20 mm in diameter, and another 5% taking longer than 6.3 years. The mean time a tumor needed to grow from 10 mm to 20 mm in diameter was estimated as 1.7 years, increasing with age. Studies showed that patients with delays prior to presentation and/or treatment of 12 to 26 weeks had significantly worse survival rates than those with delays of less than 12 weeks. Ten years after the onset of symptoms, survival was 52% for women with delays less than 12 weeks and 47% for those with longer delays. At 20 years the survival rates were 34% and 24%, respectively (p = .003).

In summary, it is generally accepted that total delays of 3 to 6 months are associated with lower survival and every effort to intervene at 12 weeks or sooner should be made.

Breast cancer in adolescent and young adult women (ages 15-39) constitutes 5% to 6% of all breast cancer cases in the United States however it has a worse prognosis than in older women. Five-year survival rates are lowest for adolescent and young adult women, and those with a longer treatment delay time have significantly decreased survival time compared with those with a shorter treatment delay time. This adverse impact on survival was shown to be more pronounced in African American women, those with public or no insurance, and those with low socioeconomic status.

2. Preoperative evaluation

Patient anxiety associated with breast cancer and altered body image can be quite significant. Anesthesia preoperative evaluation programs that provide patient and family perioperative education can increase the patient’s understanding of options for treatment while decreasing anxiety and fears. A randomized clinical trial of a brief presurgery hypnosis session showed decreased incidence and severity of pain, nausea, fatigue, discomfort, emotional upset at discharge, and institutional cost. Administration of preoperative midazolam may be indicated for the anxious patient.

One recent multicenter prospective cohort study investigated psychological, sociodemographic, and surgical risk factors, adjusted for intraoperative nerve handling, on painful adverse outcomes captured at multiple time points after resectional surgery for primary breast cancer. They provide insights into those at risk of persistent adverse outcomes, namely younger women and those with psychological vulnerability, axillary clearance surgery, and more severe acute postoperative pain.

Larger tumors, lymph node involvement, and the lack of estrogen and progesterone receptors are associated with poorer prognosis. The most common site of metastases is bone, then lung, liver, and brain. Patients should be evaluated for signs and symptoms of these metastases.

The association between cancer and venous thromboembolism is well known. Occasionally, the thromboembolic event occurs before the diagnosis of cancer and may be a predictor of the subsequent diagnosis of cancer.

The sequence of radiation, chemotherapy, surgery, and endocrine therapy has generated long-standing controversy. Some studies showed an advantage for preoperative endocrine therapy by reducing metastatic potential of cells released by surgery on estrogen receptor–positive tumors. Tamoxifen, often used in hormonal chemotherapy in breast tumors responsive to estrogen binding, can result in preoperative nausea, vomiting, dehydration, skin rash, pruritus, and, rarely, myelosuppression.

Previous radiation therapy may be associated with chest wall nerve damage, pneumonitis, pulmonary fibrosis, and cardiac injury. It is also associated with an increased incidence of lung cancer.

3. What are the implications of co-existing disease on perioperative care?

Patients may present with a variety of diseases that are unrelated to their breast etiology. Careful history taking and planning are always indicated.

Selected patients may undergo chemotherapy preoperatively to shrink the tumor and enhance breast preservation. Primary tumor downsizing with neoadjuvant chemotherapy can improve lumpectomy eligibility. In such cases, careful attention should be paid to the regimen used and its toxicity and side effects on the various systems as noted.

a. Cardiovascular

Anthracycline (doxorubicin)-based regimens produce a clinically significant form of heart failure in up to 1% of cases. The incidence of cardiac dysfunction increases dramatically when the cumulative dose of doxorubicin exceeds 450 mg/m2. Dexrazodane is an iron chelator shown to decrease the cardiotoxic effect of doxorubicin. The incidence of cardiomyopathy is significantly higher when doxorubicin was combined with Herceptin (trastuzumab).

b. Pulmonary

Radiation-induced lung injury typically presents with two distinct, subsequent clinical phases: pneumonitis and fibrosis. Radiation pneumonitis occurs 4-12 weeks after completion of radiation therapy, and radiation pneumonitis can regress to complete restitution or evolve into fibrosis when present with a more severe grade. Clinical symptoms of pulmonary injury are nonspecific and can include pleuritic chest pain, fever, dyspnea, and a nonproductive cough.

Concurrent chemotherapy - Several chemotherapeutic agents are known sensitizers to radiotherapy, including doxorubicin, taxanes, dactinomycin, bleomycin, cyclophosphamide, vincristine, mitomycin, gemcitabine, recombinant interferon-alpha, and bevacizumab. Patients receiving these drugs are at a higher risk of developing radiation-induced lung injury (RILI). In addition, several of the drugs themselves are associated with lung injury. By contrast, other drugs may sensitize tumor cells to the effects of radiation without an increase in lung injury.

It is likely that sequential administration of paclitaxel and radiation therapy (RT) diminishes the risk of radiation pneumonitis as compared to concurrent treatment. However, women who receive taxanes as a component of their adjuvant therapy for breast cancer may also need to have a smaller volume of lung included in the radiation field.

C. Renal

Cyclophosphamide can cause hemorrhagic cystitis when given in high doses or if proper hydration was not maintained.

d. GI

Nausea and vomiting are the most common gastrointestinal (GI) toxicities. Stomatitis and diarrhea can occur when chemotherapy causes damage to the GI mucosa.

e. Neurologic

Paclitaxel can cause neurologictoxicity in the form of sensory peripheral neuropathy. Often theneuropathy is reversible with discontinuation of the drug but may becomepermanent if not recognized early. The vinca alkaloids can also causeperipheral neuropathy and autonomic dysfunction, which may produceconstipation or ileus.

f. Endocrine

Chemotherapy has long been shown to cause ovarian ablation and premature menopause. Patients are prone to all the health issues associated with lack of estrogen including osteoporosis and the risk of cardiac disease.

g. Additional systems/conditions which may be of concern in a patient undergoing this procedure and are relevant for the anesthetic plan (eg. musculoskeletal in orthopedic procedures, hematologic in a cancer patient)

Dermatologic: Many chemotherapeutic agents can cause rashes or photosensitivity. Hair loss usually begins 2 to 3 weeks after initiation of chemotherapy, and regrowth starts approximately 1 month after discontinuation of chemotherapy treatment.

Secondary malignancies: Many cytotoxic chemotherapeutic agents are known carcinogens. Alkylating agents (cyclophosphamide), in particular, are associated with an increased risk of acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS).

Myelosuppression: Leukopenia generally occurs by days 7 to 14 after chemotherapy is given and usually reverts by days 21 to 28. Thrombocytopenia can occur within 1 to 2 weeks after chemotherapy. The hemoglobin level may gradually decrease, causing significant fatigue and other associated symptoms.

4. What are the patient’s medications and how should they be managed in the perioperative period?

Patients may continue most of their regular medications. Medications held prior to surgery include diuretics and oral hypoglycemics. Medications, stopped well in advance of surgery include antiplatelet agents, such as clopidogrel, consistent with accepted national guidelines.

For thromboprophylaxis in the surgical patient, either low-dose heparin or low-molecular-weight (LMWH) heparin is effective and safe. For patients receiving chemotherapy in advanced breast cancer, low-dose warfarin is effective.

There has been speculation among several authors regarding a direct antitumor effect of LMWH during anticancer therapy, which may confer survival benefit to patients with cancer. Other authors have suggested that the antitumor effect of LMWH was incidental and independent of the anticoagulant effect. The effect of LWMH on tumor progression in patients with malignant disease remains to be fully elucidated.

a. Are there medications commonly seen in patients undergoing this procedure and for which should there be greater concern?

Many patients diagnosed with breast cancer are using over-the-counter herbal medicines. Anesthesiologists should ask their patient about the use of herbal products and consider the possibility of herbal–drug interactions. Herbal medications should be stopped at least 7 days before surgery, owing to the uncertainty over their actual content.

Estrogen replacement and tamoxifen should be discontinued several days before surgery due to prolonged risk of thromboembolism. Tamoxifen therapy, although unlikely at this stage, may cause a higher incidence of deep venous thrombosis and pulmonary embolism.

One study examined the relationship between the duration of tamoxifen use in female patients with breast cancer and the risk of venous thromboembolism in a large population-based setting and found that in their study population initiation of tamoxifen coincided with initial clustering of venous thromboembolism, with risks due specifically to tamoxifen and increasing during continued exposure. Evidence suggested that the venous thromboembolism clustering occurred in high risk individuals at initiation of tamoxifen therapy. They conclude that careful selection of patients for whom tamoxifen therapy is appropriate based on susceptibility to venous thromboembolism is thus required prior to initiation of therapy.

Hernandez et al showed in a cohort study that the 5-year risk of DVT/PE was 1.2% for women receiving tamoxifen and 0.5% for women not receiving tamoxifen. Women treated with tamoxifen were at a higher risk for DVT/PE during the first 2 years after exposure. Risk of DVT/PE on tamoxifen was higher in women aged 55 years or older in women with a body mass index of 25 kg/m2 or greater, an elevated blood pressure, a total cholesterol of 250 mg/dL or higher, current smoking, and a family history of coronary artery disease. Transdermal estrogen therapy concomitant with tamoxifen does not appear to be associated with any excess of DVT/PE.

b. What should be recommended with regard to continuation of medications taken chronically?

See earlier comments.

c. How to modify care for patients with known allergies -

N/A

d. Latex allergy- If the patient has a sensitivity to latex (eg. rash from gloves, underwear, etc.) versus anaphylactic reaction, prepare the operating room with latex-free products.

N/A

e. Does the patient have any antibiotic allergies? (common antibiotic allergies and alternative antibiotics)

Antibiotic prophylaxis with cefazolin is warranted for breast cancer procedures and clean procedures in patients with other risk factors for infection. Clindamycin and vancomycin are acceptable alternatives for patients with beta-lactam hypersensitivity; in the setting of risk for SSI due to gram-negative pathogens, an additional agent may be warranted (such as an aminoglycoside, aztreonam, or a fluoroquinolone).

The most common organisms are S. aureus, other staphylococci, and streptococci. A higher rate of infection due to gram-negative organisms occurs in the setting of procedures involving macerated, moist environments (such as under the axilla of an obese individual), and among patients with diabetes.

One review of seven randomized trials including nearly 2000 patients undergoing breast cancer procedures without reconstruction noted that prophylactic antibiotics significantly reduced the incidence of SSI (relative risk 0.66; 95% CI 0.48-0.89).

f. Does the patient have a history of allergy to anesthesia?

Local anesthetics/muscle relaxants: Clear communication between anesthesiologist and surgeon about local anesthetic allergies is needed, as the anesthesiologist may be able to shed better light on the different groups of local anesthetics and the lack of cross reactivity. Most commonly patients suffer from a reaction to the PABA group, which is a byproduct of the degradation of the ester variety of local anesthetics and is not a contraindication to the administration of an amide (such as lidocaine or bupivacaine). Note that some multidose lidocaine vials include PABA-producing preservatives (methylparaben).

5. What laboratory tests should be obtained and has everything been reviewed?

In healthy women of menstruating age who are not surgically sterile, a pregnancy test should be offered. Electrocardiogram, CBC, serum electrolytes, coagulation panel, and other studies may be ordered as appropriate given the patient’s past medical history and current treatment (including recent chemotherapy). Serum alkaline phosphatase elevation preoperatively may suggest metastatic bone invasion. Echocardiography is warranted in case of doxorubicin-induced cardiomyopathy.

Intraoperative Management: What are the options for anesthetic management and how to determine the best technique?

Lumpectomy may be performed under local anesthesia alone or with monitored anesthesia care (MAC) or regional or general anesthesia. The decision should involve the anesthesiologist, the surgeon, and, most importantly, the patient. Typically, the patient had just presented with a suspicion of a breast mass warranting excision and the anxiety component of this information cannot be discounted. Patients may also have fear of deformity to their breast and fears about anesthesia. With extreme cases, this will warrant general anesthesia even when not otherwise clinically indicated.

Special care should be taken in placing an IV line. An arm with signs of lymphedema should be avoided so as to not exacerbate the lymphedema and cause potential infection. It is also important to protect that arm from compression (from operating room equipment or blood pressure cuff) and heat exposure. Positioning for breast procedures is usually supine with the ipsilateral arm sometimes abducted to facilitate lymph node sampling. The anesthesiologist should pay special attention to excessive extension of the brachial plexus. No monitors or intravenous access should be placed on the ipsilateral arm. Tilting of the surgical table is often necessary to improve surgical exposure. All pressure points should be checked and padded.

Since most of these procedures are performed on an outpatient basis, the choice of anesthetic should provide fast recovery and adequate postoperative pain control. General anesthesia remains the most commonly used technique for all breast procedures. There has been a growing interest in performing these procedures in the office by the surgeon under local anesthesia with the aim of reducing cost. This approach is best suited for T1N0 tumors (size <1.5 cm in diameter, negative nodes). A sentinel lymph node biopsy may be performed prior to the definitive excision under local anesthesia alone or with MAC. This is occasionally done to reduce the dependence on the less accurate frozen sections in the diagnosis. There is minimal morbidity from repeated operations as the sentinel node histopathologic analysis would yield higher accuracy than a frozen section well before undertaking a major procedure under general anesthesia.

There has been growing interest in the effect of anesthetic choice on cancer survival. A multitude of in vitro and animal studies have reported on the topic of breast cancer tumor growth and metastasis in the context of anesthetic choice including general anesthesia, local anesthetics, and opioids.

In 2006, Exydaktylos et al. published a retrospective review of 129 patients undergoing breast cancer surgery under general anesthesia and receiving either opioids or paravertebral blocks for pain management. At 36 months follow up, 94% of those receiving regional anesthesia remained cancer free while only 77% of those receiving opioids remained cancer free. As pointed out by Durieux, this article started a strong and sustained interest in the possibility that choices in perioperative anesthetic management may influence cancer surgery outcome.

Ecimovic et al. showed that in an in vitro model of breast cancer cell function, sevoflurane increased proliferation, migration, and invasion in ER-positive breast cancer cells and increased proliferation and migration but not invasion in ER-negative cells, although the observed effect size was small and not dose-dependent. The same group showed that propofol reduced NET1 expression and cell migration in both ER-positive and -negative cells, which was reversed by silencing NET1, implying a role for NET1 in mediating the effect of propofol on breast cancer cell function in vitro. Another group found that clinically relevant concentrations of propofol reduced the level of matrix metalloproteinases in breast cancer by inhibition of NF-kB pathways subsequently restraining migration and invasion of breast cancer cells. Further in vitro and clinical studies are needed.

Available data on the role of opioids in cancer are conflicting. Long-term opioid administration in subanalgesic doses in mice without surgery suggests that morphine promotes cancer growth and metastasis, largely by inducing mitogenesis and angiogenesis. In contrast, mouse models resembling the perioperative setting, using analgesic doses of opioid, suggest either a protective effect of opioids for cancer or no effect.

Morphine does not appear to stimulate tumour initiation, and there is currently no evidence that morphine analgesia causes cancer. Whether opioid administration augments the risk of recurrence or metastasis after cancer surgery remains unclear. Currently, available research data are insufficient to indicate a change of clinical practice.

Other studies focused on inflammation as a causative event in many cancers and showed that intraoperative administration of non-steroidal anti-inflammatory drugs, especially ketorolac, was associated with longer recurrence-free survival in a set of 327 breast cancer patients. Cyclooxygenase inhibitors may also prevent some of the opioid-induced effects on tumor growth. For example, celecoxib blocks morphine-induced tumor angiogenesis, resulting in greatly reduced tumor outgrowth in animal models. This might explain the observed benefit of intraoperative ketorolac.

Sessler and colleagues continue to investigate the relationship between anesthestic technique and cancer recurrence. They have emphasized that the primary defense against new cancers and cancer recurrence is natural killer cells. Natural killer cell function is impaired by the surgical stress response, volatile anesthetics, and by opioids, whereas regional analgesia reduces the surgical stress response and decreases the need for volatile anesthetics and opioids. Intravenous lidocaine as well as COX-2 inhibitors are anti-inflammatory and appear to enhance natural killer cell function.

In addition, lidocaine and bupivacaine induced apoptosis of breast tumor cells at clinically relevant concentrations. It is noteworthy that the apoptotic action of local anesthetics was more pronounced in malignant breast cancer cells than in mammary epithelial cells. Furthermore, this group’s results suggest that the in vitro apoptotic effects of local anesthetics are reproducible in vivo in their xenograft tumor model.

Studies have been performed comparing serum of patients given propofol-paravertebral anesthesia versus sevoflurane anesthesia on breast cancer cell function. Looney reported that a propofol-paravertebral anesthetic (PPA) technique attenuated postoperative changes in endothelial growth factor C and transforming growth factor β concentrations to a greater extent than balanced general anesthesia and morphine analgesia in women undergoing surgery for primary breast cancer.

Prospective studies of the effect of anesthetic choice on breast cancer survival are currently underway. Hiller urges that while we await these prospective studies, future studies should be scrutinized for factors such as cancer type, staging, and lymphovacular space invasion which would have a greater magnitude of impact on cancer outcomes.

Notwithstanding these investigations, a recent consensus statement by leading researchers underscored that there is currently insufficient evidence to support any change in clinical practice.

a. Regional anesthesia

Regional anesthesia is a viable alternative to general anesthesia or MAC. Multiple studies confirmed that it can be safely offered to most patients undergoing breast surgery. The benefits of regional anesthesia include lower cancer recurrence and improved metastasis-free survival, low rates of postoperative nausea and vomiting (PONV), excellent pain control, quicker time to discharge, and fewer unplanned admissions compared with general anesthesia.

Neuraxial

More case reports than blinded randomized trials are available for thoracic and cervical epidural use, but evidence suggests better pain control postoperatively and reduction in PONV to be the likely advantages. A few studies, mostly in breast augmentation/reconstruction patients, show earlier discharge from the PACU and hospital.

Paravertebral blocks

There has been a growing interest with this technique with the hope of providing better pain control and less PONV for patients.

Paravertebral block (PVB) provides the added advantage of unilateral block of spinal nerves and sympathetic chain. An intense blockade of pain stimuli is achieved with minimal sympathectomy.

Ultrasound imaging makes thoracic paravertebral block easier to perform and helps to avoid inadvertent pleural puncture. The ultrasound probe may be used to identify the structures, followed by a more traditional landmark guided approach to the thoracic paravertebral space. This is generally referred to as an “ultrasound-assisted approach”.

The “ultrasound-guided approach” paravertebral blocks could performed with the probe in a transverse position, a paramedian longitudinal position, or in an oblique plain. The needle may be inserted in an in-plane or out-of-plane fashion. The patient is positioned in the sitting or lateral decubitus position. One study concluded that the risk/benefit ratio of PVB does not favor routine use for minor breast surgery. After cleaning the skin with an antiseptic solution the ultrasound probe is placed over a T4 spinous process in the midline in a longitudinal fashion. The probe is then moved laterally to visualize the transverse process, the superior costo-transverse ligament, and the pleura.

When performing an ultrasound assisted block, the practitioner measures the depth of the transverse process, the depth of the superior costo-transverse ligament, and the depth of the pleura. The point at which the transverse process and the rib intersects represent the lateral aspect of paravertebral space and is generally 2.5-3cm from the midline. The ultrasound probe is then put aside and the thoracic paravertebral block is performed using a traditional landmark technique. An 18-20 gauge blunt tipped block needle is introduced into paravertebral space in a cephalad direction. With ultrasound-guided technique the tip of the needle is advanced under direct visualization until it pierces the superior costo-transverse ligament. If the superior costo-transverse ligament is not easily seen, the needle is advanced until it is directly above the pleura. When the needle tip is located immediately above the pleura, the needle is aspirated to confirm the absence of blood or air. After that, 10-15 cc of Ropivacaine 0.5% is injected in 3-4 cc increments. Spread of local anesthetic with depression of pleura is visualized with the ultrasound probe. PVBs can be done as a single-shot technique or as a continuous catheter placement.

A meta-analysis of 11 studies (close to 800 patients) reported the most common adverse event of a PVB was Horner’s syndrome, resolving within 8 to 10 hours spontaneously. Major complications, including extensive epidural or intrathecal spread (1%), accidental pleural puncture (0.8%), and pneumothorax (0.5%), were observed rarely after a PVB. These studies did not employ ultrasound technology. Only recently, Abdallah et al. reported that by using ultrasound guidance, quality of recovery was improved in 64 women randomized to multilevel paravertebral blocks and total intravenous anesthesia for breast tumor resection compared with general anesthesia with sevoflurane and morphine.

Severe neurologic complications associated with a PVB have been reported only on rare occasions. It is possible that these complications can be further reduced with ultrasound techniques, and further outcome data are needed. This safety profile makes PVB an alternative method for patients with significant comorbidities. The decrease in pain scores after PVB for breast surgery may lead to a reduction in surgical stays, increase in rate of ambulatory surgeries, and a significant cost saving. Studies also suggest earlier return to normal diet following this technique.

b. General anesthesia

Various general anesthesia techniques have been compared. Studies found better pain scores with propofol infusion compared with sevoflurane-based anesthesia after high-dose remifentanil maintenance. Moreover, hyperalgesia did not occur after low-dose remifentanil-based anesthesia. One recent study examined PONV in low- and high-dose remifentanil regimens for total intravenous anesthesia (TIVA) in adult female patients, ASA Class I undergoing local breast excision and found that TIVA with high-dose remifentanil did not aggravate PONV with similar postoperative pain, compared with low-dose remifentanil.

General anesthesia can be achieved with an endotracheal tube or laryngeal ask airway (LMA). Hohlrieder et al. showed that the frequency of PONV, airway morbidity, and analgesic requirements is lower for the LMA than the tracheal tube in females undergoing breast surgery. Studies are ongoing to determine the impact of general anesthesia on cancer recurrence.

c. Monitored anesthesia care

MAC may be ideal for excisional biopsies of simple superficial lesions such as fibroadenomas. This may be achieved by propofol infusion (typically 25 to 100 μg/kg/min). A bolus of remifentanil of 0.5 to 1 μg/kg may be given before local anesthetic administration by the surgeon.

Alternatively, midazolam alone or in combination with an opioid agent may be used and may allow for better communication with the patient and less likelihood of obstruction of breathing or reduction in breathing effort when properly dosed. MAC also facilitates more expeditious start of the procedure and turnover of the operating room.

An occasional need to convert to general anesthesia may arise either because the patient does not tolerate the procedure or because the depth of sedation intensifies requiring airway control.

6. What is the author’s preferred method of anesthesia technique and why?

Local anesthesia could be chosen for a patient without severe anxiety component for a small mass excision (<1.5 cm) with negative lymph nodes. Anxious patients presenting with simple superficial lesions for excisional biopsies may undergo MAC with sedation.

The majority of patients are good candidates for PVBs. The blocks could be used as primary anesthetics, as an adjunct to general anesthesia or for postoperative pain control. Both ultrasound-assisted and ultrasound-guided techniques are effective. PVBs can be done as a single-shot technique or as a continuous catheter placement.

General anesthesia can be offered to patients with significant anxiety or uncooperative patients. Patients with larger lesions, and/or patients undergoing lymph nodes dissection may benefit from thoracic paravertebral blocks combined with general anesthesia. LMA would be a good choice for patients when full stomach precautions are not needed. As females are particularly susceptible to PONV, triggering agents such as narcotics should be administered with caution and preemptive antiemetics should be given before the end of the procedure (e.g., 5-HT3 antagonists, NK-1 antagonists, dexamethasone, or transdermal scopolamine). Use of non opioid analgesics is strongly encouraged, and should be administered intraoperatively to provide smooth transition to postoperative phase. IV acetaminophen, ibuprofen or ketorolac are suggested.

It is prudent to avoid hypothermia, hypotension, anemia, and blood transfusions, which could affect various immune functions.

Blue dye usually causes a transient decrease in the pulse oximeter reading of 2% to 5%. Larger reductions have been reported and the pulse oximetry reading may not return to normal until up to 6 hours post injection. In this case, an ABG is warranted to verify adequacy of oxygenation. Patients will have blue-tinged urine, stool, or emesis and may have a blue tinge to their skin color for several hours postoperatively. Allergic reactions as severe as shock have been reported following the injection of isosulfan blue. Methylene blue has a lower incidence of allergic reactions but can cause skin necrosis if injected intradermally without prior dilution. Lymphedema is a potential complication of the nodal resection.

Seromas are a very common surgical complication, followed by hematoma (<10%)and infection (1% to 2%). An exceedingly rare complication of wire migration into the chest may arise from the needle localization.

a. If the patient is intubated, are there any special criteria for extubation?

N/A

b. Postoperative management

Pain in the postoperative period may be exacerbated by the patient’s psychological state and the uncertainty of the diagnosis. Therefore, the ideal approach for pain control should be multimodal. Regional anesthesia provides the best postoperative pain control but carries the risks discussed earlier. It also decreases the consumption of narcotics.

Various studies showed none to some benefit from surgical infiltration of local anesthetics or irrigation with local anesthetics. Evidence is emerging that following mastectomy, adding a multiple-day, ambulatory, continuous ropivacaine infusion to a single-injection ropivacaine paravertebral nerve block in the immediate postoperative period may result in improved analgesia and less functional deficit.

Wound infiltration with ropivacaine was found to reduce postoperative pain for the first 90 min after surgery in women underoing breast cancer surgery, but did not reduce the incidence or severity of pain 3-12 months later.

Indwelling catheters that inject local anesthetic in a preprogrammed manner may be used with good results. A multimodal approach that includes gabapentin and local anesthetic along with the traditional NSAIDs and narcotics appears to be beneficial for both acute and chronic pain after breast surgery.

In addition, Mohamed et al. demonstrated that adding adjunctive analgesic agents, such as dexmedetomidine to the paravertebral anesthetic solution lowered analgesic consumption, significantly reduced pain scores, and shortened the time needed to resume daily activity.

PONV in this vulnerable population (young female ± nonsmoker) should be promptly treated with ondansetron (±dexamethasone in the absence of contraindications). Reports suggest a decrease in PONV in patients receiving preemptive ondansetron before the end of the procedure in this population.

Summary

As more evidence emerges over the next few years substantiating regional techniques with better outcomes and less recurrence, the use of general anesthesia is likely to decrease. Decreasing postoperative opioid requirements by regional techniques, and by adopting a multimodal analgesic approach making maximum use of non-opioid adjuvants, including cyclooxygenase inhibitors has many benefits. These approaches will limit volatile anesthetic requirements and reduce surgical stress response, two factors implicated in recurrence.

More procedures will be conducted outside the operating room, such as MRI-guided biopsies, and will likely be done under local anesthesia or, if necessary, MAC by an anesthesiologist.

Alternative methods of pain control such as transcutaneous electric acupoint stimulation as suggested by Zhang et al. may significantly improve the quality of recovery and decrease the incidence of anaesthesia-related side-effects for patients undergoing ambulatory surgery in the future.

Over the past decade, both breast and axillary surgery have become less invasive. Patients are more likely to have breast-conserving surgery and also sentinel node biopsy or axillary sampling rather than axillary clearance. These procedures are potentially very suitable for day surgery, the safety and benefits for elective operations of which have been increasingly recognized.

What’s the Evidence?

http://www.cancer.org/Cancer/BreastCancer/.

(Resource for updated breast cancer epidemiology.)

Newman, LA. "Epidemiology of locally advanced breast cancer". Semin Radiat Oncol. vol. 19. 2009. pp. 195-203.

(States 5-year relative survival rates by stage.)

Bastiaannet, E, Liefers, GJ, de Craen, AJ. "Breast cancer in elderly compared to younger patients in the Netherlands: stage at diagnosis, treatment and survival in 127, 805 unselected patients". Breast Cancer Res Treat. vol. 124. 2010. pp. 801-807.

(Shows less favorable prognosis in older and younger women.)

van de Water, W, Markopoulos, C, van de Velde, CJ. "Association between age at diagnosis and disease-specific mortality among postmenopausal women with hormone receptor-positive breast cancer". JAMA. vol. 307. 2012. pp. 590-597.

(Shows less favorable prognosis in older and younger women.)

"National Comprehensive Cancer Network (NCCN)". NCCN Clinical practice guidelines in oncology. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp.

(Resource for recommendations for mammography and breast MRI.)

Breast Cancer Early Detection 2014. http://www.cancer.org/acs/groups/cid/documents/webcontent/003165-pdf.pdf.

(Resource for recommendations for mammography and breast MRI.)

http://seer.cancer.gov/statfacts/html/breast.html.

(Resource for updated breast cancer epidemiology.)

Zimmermann, CJ, Sheffield, KM, Duncan, CB. "Time trends and geographic variation in use of minimally invasive breast biopsy". J Am Coll Surg. vol. 216. 2013. pp. 814-824.

(Showed that despite an increase in the use of minimally invasive breast biopsy over time its use (at least in rural Texas) was lower than recommended by the NCCN.)

Silverstein, MJ, Recht, A, Lagios, MD. "Special report: consensus conference III. Image-detected breast cancer: state-of-the-art diagnosis and treatment". J Am JColl Surg. vol. 209. 2009. pp. 504-520.

(Describes target rates for invasive breast procedures.)

Bevers, TB, Anderson, BO, Bonaccio, E. "NCCN clinical practice guidelines in oncology: breast cancer screening and diagnosis". J Natl Compr Canc Netw. vol. 7. 2009. pp. 1060-1096.

(Describes what breast procedures are indicated for each type of lesion.)

Weedon-Fekjær, H, Lindqvist, BH, Vatten, LJ. "Breast cancer tumor growth estimated through mammography screening data". Breast Cancer Res Treat. vol. 10. 2008. pp. R41.

(Shows that the mean time a tumor needed to grow from 10mm to 20mm in diameter was estimated asat 1.7 years increasing with age.)

Richards, MA, Smith, P, Ramirez, AJ. "The influence on survival of delay in the presentation and treatment of symptomatic breast cancer". Br J Cancer. vol. 79. 1999. pp. 858-864.

(Shows correlation between increased delay time and worse survival rates.)

Smith, EC, Ziogas, A, Anton-Culver, H. "Delay in surgical treatment and survival after breast cancer diagnosis in young women by race". JAMA Surg. vol. 24. 2013. pp. 1-8.

(African American women, those with public or no insurance and those with low socioeconomic status had pronounced adverse impacts of treatment delay.)

Bruce, J, Thornton, AJ, Powell, R. "Psychological, surgical, and sociodemographic predictors of pain outcomes after breast cancer surgery: a population-based cohort study". Pain. vol. 155. 2014. pp. 232-243.

(Shows that younger women, those with psychological vulnerability, axillary clearance surgery, and more severe acute post-operative pain had the highest level of painful adverse outcomes at multiple time points.)

Moding, EJ, Kastan, MB, Kirsch, DG. "Strategies for Optimizing the Response of Cancer and Normal Tissues to Radiation". Nature Reviews Drug discovery. vol. 12. 2013. pp. 526-542.

(Some drugs may sensitize tumor cells to the effects of radiation without an increase in lung injury.)

Lazo-Langner, A, Goss, GD, Spaans, JN. "The effect of low-molecular-weight heparin on cancer survival. A systematic review and meta-analysis of randomized trials". J Thromb Haemost. vol. 5. 2007. pp. 729-737.

(Shows improved survival in cancer patients with LMWH.)

Nagy, Z, Turcsik, V, Blaskó, G. "The effect of LMWH (Nadroparin) on tumor progression". Pathol Oncol Res. vol. 15. 2009. pp. 689-692.

(Suggests that the antitumor effect of LMWH was incidental and independent of the anticoagulant effect.)

Onitilo, AA, Doi, SAR, Engel, JM. "Clustering of venous thrombosis events at the start of tamoxifen therapy in breast cancer. A population-based experience". Thromb Res. vol. 130. 2012. pp. 27-31.

(Careful selection of patients for whom tamoxifen therapy is appropriate should be assessed prior to initiation based on susceptibility to venous thromboembolism.)

Hernandez, RK, Sørensen, HT, Pedersen, L. "Tamoxifen treatment and risk of deep venous thrombosis and pulmonary embolism: a Danish population-based cohort study". Cancer. vol. 115. 2009. pp. 4442-4449.

(Discusses risk of DVT/PE in women receiving and not receiving tamoxifen based on time exposed, age, BMI, blood pressure, total cholesterol, smoking status, family history of CAD, and concomitant transdermal estrogen therapy.)

Jones, DJ, Bunn, F, Bell-Syer, SV. "Prophylactic antibiotics to prevent surgical site infection after breast cancer surgery". Cochrane Database Syst Rev. vol. 3. 2014.

(Shows that in nearly 2000 patients undergoing breast cancer procedures without reconstruction, prophylactic antibiotics significantly reduced incidence of surgical site infection.)

Exadaktylos, AK, Buggy, DJ, Moriarty, DC. "Can anesthetic technique for primary breast cancer surgery affect recurrence or metastasis?". Anesthesiology. vol. 105. 2006. pp. 660-664.

(First article to suggest the possible relationship between anesthetic technique for primary breast cancer surgery and recurrence.)

"Durieux M. Anesthesia and cancer recurrence: improved understanding, but no reason for change". Anesth Analg. vol. 118. 2014. pp. 8-9.

(Points out that the Exydaktylos 2006 article started a strong and sustained interest in the possibility that anesthestic choice could influence cancer outcome.)

Ecimovic, P, McHugh, B, Murray, D. "Effects of sevoflurane on breast cancer cell function in vitro". Anticancer Res. vol. 33. 2013. pp. 4255-4260.

(In this in vitro model of breast cancer cell function, sevoflurane increased proliferation, migration, and invasion in ER-positive MCF7 cells and increased proliferation, and migration but not invasion in ER-negative cells. However, the observed effect size was small and not dose-dependent.)

Ecimovic, P, Murray, D, Doran, P. "Propofol and bupivacaine in breast cancer cell function in vitro - role of the NET1 gene". Anticancer Res. vol. 34. 2014. pp. 1321-1331.

(Propofol reduced NET1 expression and cell migration in both ER-positive and -negative cells, which was reversed by silencing NET1, implying a role for NET1 in mediating the effect of propofol on breast cancer cell function in vitro.)

Li, Q, Zhang, L, Han, Y. "Propofol reduces MMPs expression by inhibiting NF-κB activity in human MDA-MB-231 cells". Biomed Pharmacother. vol. 66. 2012. pp. 52-56.

(Clinically relevant concentrations of propofol reduced the level of MMPs in breast cancer by inhibition of NF-B pathways subsequently restraining migration and invasion of breast cancer cells.)

Jaura, A, Flood, G, Gallagher, HC. "Differential effects of serum from patients administered distinct anaesthetic techniques on apoptosis in breast cancer cells in vitro: a pilot study". Br J Anaesth. vol. 113. 2014. pp. 163-67.

(Serum from patients given sevoflurane anaesthesia and opioids for primary breast cancer surgery reduces apoptosis in ER-negative breast cancer cells to a greater extent than serum from patients given propofol-paravertebral anaesthesia.)

Gupta, K, Kshirsagar, S, Chang, L. "Morphine stimulates angiogenesis by activating proangiogenic and survival-promoting signalling and promotes breast tumor growth". Cancer Res. vol. 62. 2002. pp. 4491-4498.

(Shows that morphine, in a concentration typical of that observed in patients’ blood, stimulates human microvascular endothelial cell proliferation and angiogenesis in vitro and in vivo. In addition it promotes tumor neovascularization in a human breast tumor xenograft model in mice leading to increased tumor progression.)

Ecimovic, P, Murray, D, Doran, P. "Direct effect of morphine on breast cancer cell function in vitro: role of the NET1 gene". Br J Anaesth. vol. 107. 2011. pp. 916-923.

(The NET1 gene, but not opioid receptors, is expressed in breast adenocarcinoma cells and may facilitate their migration. Morphine increased both expression of NET1 and cell migration but not when NET1 was silenced, implying that NET1 contributes to mediating the direct effect of morphine on breast cancer cell migration.)

Forget, P, Vandenhende, J, Berliere, M. "Do intraoperative analgesics influence breast cancer recurrence after mastectomy? A retrospective analysis". Anesth Analg. vol. 110. 2010. pp. 1630-1635.

(This retrospective analysis suggests that intraoperative administration of ketorolac decreases the risk of breast cancer relapse compared with other analgesícs.)

"Link Between Anesthetic Agents, Technique and Cancer Outcomes Need Research". Anesthesiology News. 2014.

(Newspaper article announcing the imminent consensus statement on possible link of anesthestic technique/agents and risk for cancer and cancer recurrence.)

Buggy, DJ, Borgeat, A, Cata, J. "Consensus statement from the BJA Workshop on Cancer and Anaesthesia". Br J Anaesth. vol. 114. 2015. pp. 2-3.

(Recently released BJA workship consensus statement on the relationship between anesthetic/analgesic technique and cancer outcomes stating that there is currently insufficient evidence to support any change in clinical practice.)

Muñoz, M, Rosso, M, Casinello, F. "Paravertebral anesthesia: how substance P and the NK-1 receptor could be involved in regional block and breast cancer recurrence". Breast Cancer Res Treat. vol. 122. 2010. pp. 601-603.

(Shows that SP and NK-1 receptors play a key role in tumor growth and proliferation. Regional anesthesia and analgesia may help to preserve immune function by attenuating the surgical stress response that inhibits immune function and diminishing the need for opioids, which are also known to inhibit both cellular and humoral immune function.)

Chang, Y, Liu, CL, Chen, MJ. "Local anesthetics induce apoptosis in human breast tumor cells". Anesth Analg. vol. 118. 2014. pp. 116-124.

(Lidocaine and bupivacaine induce apoptosis of breast tumor cells at clinically relevant concentrations.)

Looney, M, Doran, P, Buggy, DJ. "Effect of anesthetic technique on serum vascular endothelial growth factor C and transforming growth factor β in women undergoing anesthesia and surgery for breast cancer". Anesthesiology. vol. 11. 2010. pp. 1118-1125.

(Anesthetic technique influences serum concentrations of factors associated with angiogenesis in primary breast cancer surgery.)

Hiller, J, Ismail, H, Riedel, B. "Improved quality of anesthesia and cancer recurrence studies". Anesth Analg. vol. 119. 2014. pp. 751-752.

(Expresses concern that retrospective studies examining variations in anesthesia practice on cancer outcomes do not include factors like cancer type, staging, and lymphovascular space invasion.)

Marhofer, P, Kettner, SC, Hajbok, L. "Lateral ultrasound-guided paravertebral blockade: an anatomical-based description of a new technique". BJA. vol. 105. 2010. pp. 526-532.

(Technique description.)

Schnabel, A, Reichl, SU, Kranke, P. "Efficacy and safety of paravertebral blocks in breast surgery: a meta-analysis of randomized controlled trials". Br J Anaesth. vol. 105. 2010. pp. 842-852.

(Meta-analysis reporting that the most common adverse effect of a PVB was Horner’s syndrome which resolved within 8-10 hours spontaneously.)

Naja, Z, Lonnqvist, PA. "Somatic paravertebral nerve blockade. Incidence of failed block and complications". Anaesthesia. vol. 56. 2001. pp. 1184-1188.

(Earlier study that outlines the potential major complications of PVB and their incidence.)

Abdallah, FW, Morgan, PJ, Cil, T. "Ultrasound-guided multilevel paravertebral blocks and total intravenous anesthesia improve the quality of recovery after ambulatory breast tumor resection". Anesthesiology. vol. 120. 2014. pp. 703-713.

(Combining multilevel PVBs with total intravenous anesthesia provides reliable anesthesia, improves postoperative analgesia, enhances quality of recovery, and expedites discharge compared with inhalational gas- and opioid-based general anesthesia for ambulatory breast tumor resection.)

Kim, SH, Oh, CS, Yoon, TG. "Total intravenous anaesthesia with high-dose remifentanil does not aggravate postoperative nausea and vomiting and pain, compared with low-dose remifentanil: a double-blind and randomized trial". Scientific World Journal. vol. 2014. 2014. pp. 724-753.

(Compares TIVA with low versus high dose remifentanil.)

Hohlrieder, M, Brimacombe, J, von Goedecke, A. "Postoperative nausea, vomiting, airway morbidity, and analgesic requirements are lower for the ProSeal laryngeal mask airway than the tracheal tube in females undergoing breast and gynaecological surgery". Br J Anaesth. vol. 99. 2007. pp. 576-580.

(Compares the LMA with endotracheal tube for breast surgery.)

Ilfeld, BM, Madison, SJ, Suresh, PJ. "Treatment of postmastectomy pain with ambulatory continuous paravertebral nerve blocks: a randomized, triple-masked, placebo-controlled study". Reg Anesth Pain Med. vol. 39. 2014. pp. 89-96.

(After mastectomy, adding a multiple-day, ambulatory, continuous ropivacaine infusion to a single-injection ropivacaine paravertebral nerve block results in improved analgesia and less functional deficit during the infusion. However, no benefits were identified after infusion discontinuation.)

Albi-Feldzer, A, Mouret-Fourme, E, Hamouda, S. "A double-blind randomized trial of wound and intercostal space infiltration with ropivacaine during breast cancer surgery: effects on chronic postoperative pain". Anesthesiology. vol. 118. 2013. pp. 318-326.

(This multicenter, prospective study shows that ropivacaine wound infiltration after breast cancer surgery decreased immediate postoperative pain but did not decrease chronic pain at 3, 6, and 12 months postoperatively.)

Mohamed, SA, Fares, KM, Mohamed, AA. "Dexmedetomidine as an adjunctive analgesic with bupivacaine in paravertebral analgesia for breast cancer surgery". Pain Physician. vol. 17. 2014. pp. E589-598.

(The addition of dexmedetomidine 1 µg/kg to bupivacaine 0.25% in thoracic PVB in patients undergoing modified radical mastectomy improves the quality and the duration of analgesia and also provides an analgesic sparing effect with no serious side effects.)

Zhang, Q, Gao, Z, Wang, H. "The effect of pre-treatment with transcutaneous electrical acupoint stimulation on the quality of recovery after ambulatory breast surgery: a prospective, randomised controlled trial". Anaesthesia. vol. 69. 2014. pp. 832-839.

(Concluded that transcutaneous electric acupoint stimulation can significantly improve the quality of recovery and decrease the incidence of anaesthesia-related side-effects for patients undergoing ambulatory surgery.)
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