Neuroblastoma

What the Anesthesiologist Should Know before the Operative Procedure

Critical issues related to surgical excision of neuroblastomas (NBs) are directly related to (1) the location of the tumor, (2) the extension of the tumor and compression or involvement of adjacent structures and (3) the ability of the tumor to produce catecholamines.

(1) NBs have origin on neural crest cells. They can arise anywhere within the sympathetic nervous system (mainly paravertebral), adrenal medulla and around the preaortic retroperitoneal paraganglia.

Nevertheless, the most frequent location is abdominal (68%) and in most cases (66%) from adrenal origin. The second most common location is mediastinum, followed by retroperitoneum. Some tumors are localized and amenable to complete resection, while others are large, grow rapidly and are invasive. In the latter, biopsy for diagnosis may be followed by chemotherapy with tumor resection after several cycles of chemotherapy.

NBs were traditionally classified using the International Neuroblastoma Staging System (INSS) based on the extent of surgical resection. Stage 1 are completely resected tumors, stages 2 and 3 are partially resected tumors with or without nodal involvement and stage 4 tumors with distant nodal or hematogenous spread of the disease.

An additional stage (4s) is used to describe tumors with dissemination limited to skin, liver and minimal bone marrow involvement (in infants <1 year of age) which have potential for spontaneous regression.

In 2009 the International Neuroblastoma Risk Group (INRG) developed a new clinical staging system based on tumor imaging. The primary reason for this new system was to allow pretreatment staging and risk assessment prior to surgical excision of the primary tumor. This staging system includes stages L1/L2 (loco-regional disease with specific image-defined risk factors); stage M (disseminated disease) analogous to INSS stage 4; and stage MS similar to INSS stage 4s.The INRG also developed a pre-treatment risk algorithm based on seven prognostic factors: INRG stage, age (with better prognosis in children less than 18 months of age), histopathology of the tumor (including histologic category and tumor differentiation) and genetic factors (ploidy, 11qAberration and amplification of MYCN oncogene).

Based on these factors, patients are classified as low-, intermediate- or high-risk disease. Low- and intermediate-risk disease patients have excellent outcomes with 5-year survival rates higher than 90%. Patients with high-risk disease have lower survival rates, less than 50%. For high risk patients, multiple clinical trials are currently underway using molecular therapeutic target agents. Including radiopharmaceutical targeted therapies (iodine-131 plus metaiodobenzylguanidine I-MIBG), immunotherapy (anti GD2 antibodies and chimeric 14.18) and antiangiogenic approaches.

Most thoracic NBs are located in the posterior mediastinum and only in rare cases are associated with airway compression. Between 2% and 4% of NBs are associated with airway compression documented by CT and with associated symptoms (wheezing).

(2) Extension of the tumor and involvement of adjacent structures should be carefully evaluated, especially if involvement of vascular structures (rare) or other organs (kidneys more frequently) is suspected. Nephrectomy is the most common intraoperative complication. Additionally, these tumors can be very large and cause mechanical problems in their resection by interfering with blood flow to adjacent organs such as intestines or kidneys during manipulation to resect. This can result in significant swelling/third spacing that may not allow primary closure of abdominal incisions.

(3) Because of its origin from neural crest tissue, neuroblastomas have the potential to synthesize and release catecholamines. Although uncommon, at only 3%, patients can experience elevated blood pressures and tachycardia intraoperatively.

Other considerations are related to the phase of treatment at the time of surgery. Currently most patients receive chemotherapy prior to surgery to resect the main tumor, in order to reduce the size and vascularity of the tumor. Hematologic findings secondary to the chemotherapy may include anemia, thrombocytopenia and neutropenia. Cardiac involvement should be assessed if anthracyclines were used, due to their potential to induce cardiomyopathy and heart failure.

Another consideration related to chemotherapy for neuroblastoma, is severe pain secondary to targeted immunotherapy with anti GD2 monoclonal antibodies (ch14.18) for patients with high-risk neuroblastoma. Up to 87% of patients report severe pain during immunotherapy infusion, especially during the initial cycles. Pain is usually reported in the abdomen, back and extremities or in some patients as whole body allodynia. Most patients are treated with opioids, but there are reports of successful pain treatment with lidocaine and hydromorphone and dexmedetomidine infusions.

1. What is the urgency of the surgery?

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

Most surgeries for resection of NBs are elective. Therefore, adequate preanesthetic evaluation and patient optimization should be the rule. Some of the few exceptions include emergent surgery for treatment of cord compression in intraspinal tumors and treatment for increased intracranial pressure due to primary (rare) or metastatic (more common) intracranial tumors.

2. Preoperative evaluation

Most common medical conditions to evaluate for this procedure, regardless of the location of the tumor, are hematologic and neuroendocrine abnormalities. Other conditions are directly related to the location of the tumor, the extension and compression of vital organs. Some examples include compression of great vessels, compression of the airway, ventilatory impairment and involvement of other organs, most frequently, the kidneys.

One medically unstable condition warranting further evaluation is hypertensive crises due to production and release of catecholamines by tumor cells, which has been described in 3.5% of patients.

Patients with secreting tumors can present with episodes of flushing, diaphoresis and tachycardia as well as episodes of hypertension. If a secretory tumor is suspected, blood and urine levels of catecholamines and metabolites should be measured and treatment with beta- and/or alpha-blockers should be initiated. Alpha-blockade should be established first to avoid exacerbation of hypertension by enhanced vasoconstriction if beta-blockade is begun before alpha-blockade. Then beta-blockade can be added for heart rate control. Since secreting tumors lead to volume constriction, this also allows time to return to normovolemia.

Delaying surgery may be indicated if there is inadequate control of the hypertensive crises.

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

Availability of intensive care unit admission and mechanical ventilation for postoperative care should be done for the majority of these cases especially with large tumors. For children who have undergone chemotherapy before the tumor resection, evaluation of hematologic parameters and clotting is warranted so arrangements can be made for blood and blood product support if needed.

Similarly, assessment of cardiac function if anthracyclines have been used will help decide if inotropic infusions should be prepared for intraoperative use. For the rare patient with a secreting tumor, preoperative planning needs to include assessment of the adequacy of alpha- and beta-blockade and preparation of sympathetic blocking agents as well as adrenergic support medications if needed during tumor manipulation and after tumor resection.

b. Cardiovascular system

A thorough cardiovascular exam to rule out signs of myocardial insufficiency secondary to cardiomyopathy in patients who had anthracyclines as part of their chemotherapy is necessary. All of these patients must have an echocardiogram with evaluation of ejection fraction. Also look specifically for hypertension and/or tachycardia at the time of exam.

All patients who at the time of surgery are receiving alpha- and/or beta-blockers should continue them. Be prepared for episodes of tachycardia and hypertension at the time of tumor manipulation and to use short-acting antihypertensive agents intraoperatively if needed. Volume resuscitation after tumor removal is frequently needed so vascular access to allow rapid infusion is necessary.

c. Pulmonary

If the tumor is located in the thorax, look for stridor, wheezing and signs and symptoms of pleural effusion. Look for signs of airway obstruction in the physical exam and in diagnostic images. Be prepared for difficult airway and/or ventilation if any of the above is present. Also, if the tumor is located in the abdomen and the mass is large, anticipate ventilatory difficulties due to restriction of diaphragmatic motion.

d. Renal-GI:

An important number of NBs are derived from adrenal tissue. Therefore, it is not uncommon to see tumor growth into renal tissue or vascular beds. Some patients can have hypertension secondary to increase of renin production due to renal artery compression.

e. Neurologic:

Some NBs, especially paravertebral ones, can present with spinal compression. If this is the case, a thorough neurologic exam to document any preexisting deficits should be performed. If intraoperative spinal cord monitoring is planned, anesthesia with intravenous agents may be required. Baseline neurologic function assessment also holds true for primary or metastatic intracranial NBs. For the latter, evaluation of increased intracranial pressure should be done, usually with imaging studies.

f. Endocrine:

Three percent of NBs release catecholamines. Most of them are diagnosed and treated before surgery and patients come to surgery on alpha-adrenergic and/or beta-adrenergic blockers with adequate control of blood pressure and heart rate. Despite adequate preoperative control, some patients can still present with increased release of catecholamines intraoperatively due to surgical manipulation.

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)

N/A

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

Chemotherapy courses usually have been completed 1-3 weeks before the scheduled resection unless there is an urgent reason to proceed such as airway impingement. As mentioned before, alpha- and beta-blocker medicines should continue in the preoperative period.

Chronic pain medications are also frequently used in these patients. Opioids, if chronically used, should be continued. Additionally, analgesic regimens should be modified according to the extent of surgery and the use of regional techniques for postoperative pain treatment.

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

N/A

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

N/A

j. How To modify care for patients with known allergies –

N/A

k. 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

l. Does the patient have any antibiotic allergies- [Tier 2- Common antibiotic allergies and alternative antibiotics]

N/A

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

N/A

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

Hemoglobin, hematocrit, platelet count.

Coagulation panel.

Electrolytes.

Renal function tests: creatinine and blood urea nitrogen (BUN).

Bloodand urine catecholamine and metabolite levels if clinical signswarrant. Reference ranges: Plasma levels [epinephrine supine <110pg/mL, standing <140; norepinephrine supine 70-750 pg/mL, standing200-1700 pg/mL; dopamine supine <30 pg/mL (no postural change)].

Urine24 hours [epinephrine children <1 y 0-2.5 mcg/24 h increase with agereaching adult values 0-20 mcg/24 h between 10-15 y; norepinephrinechildren <1 y 0-10 mcg/24 h increase with age reaching adult values15-80 mcg/24 h at 10 y; dopamine children <1 y 0-85 mcg/24 h reachingadult values 65-400 mcg/24 h at 4 y].

Imaging studies (MRI, CAT scans) to evaluate the size and the tumor’s extension.

Echocardiogram if anthracyclines were used as part of the chemotherapy regimen.

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

General anesthesia with or without a regional technique is the technique used in these children. The use of a regional technique in combination with general anesthesia is optimal for postoperative pain control. However, careful consideration of the risk of blood loss with hypotension and potential coagulopathy with its risk implication for central neuroaxial techniques and hemostasis should be balanced against the benefits of regional techniques for postoperative pain control.

Invasive monitoring with an arterial catheter is highly recommended for continuous monitoring of hemodynamic stability and frequent blood sampling. A central venous catheter is used if there are concerns of cardiac involvement or if there is inadequate venous access. Most of these patients will have indwelling central venous access if preresection chemotherapy has been used. Central venous access to allow rapid transfusion of fluids and/or blood may be necessary during this surgery.

a. Regional anesthesia –

N/A

b. General Anesthesia

N/A

c. Monitored Anesthesia Care

N/A

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

Our preference is general anesthesia with invasive monitoring with arterial catheters and central venous access, which is usually in-situ at the time of surgery. Additional venous access to allow transfusion is placed, usually after induction and should ideally be in upper extremities to avoid any issue of inferior vena caval compression limiting response to fluid resuscitation. Since central venous access is present most children receive iv premedication with midazolam to facilitate parental separation, then iv induction and intubation.

Anesthesia maintenance with volatile agents (most commonly sevoflurane but isoflurane may also be used) and opiate infusions (remifentanil or fentanyl) are our common approach. With spinal cord impingement total intravenous techniques may be mandated to allow spinal cord evoked potential monitoring.

Blood should be typed and crossed and present before beginning surgery. Additional blood products should be easily ordered and available in a short time if needed. Availability of laboratory or point of care blood testing should be present for serial evaluation of hemoglobin and clotting studies as well as electrolytes with large tumors.

We decide on the use of epidural catheters based on discussion with the surgeons as to surgical plans, tumor size and any anticipated difficulty with the resection due to size or location of tumor. Some of these tumors, if not too large or involved in major vascular structures, have been resected laparoscopically or thoracoscopically.

Fluid resuscitation may be needed during tumor manipulation and after tumor removal since intravascular volume depletion is common. Intensive care admission is often a planned part of the postoperative care with large tumors or the rare secreting tumor. Informing family that continuing mechanical ventilation into the immediate postoperative period may be needed helps them be prepared if this is necessary. Careful sign out to intensive care staff is very important to assure all aspects of care continue in an optimal manner.

a. Neurologic:

N/A

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

N/A

c. Postoperative management

N/A

What's the Evidence?

Canete, A. J Pediatr Surg. vol. 33. 1998. pp. 1526-30. (Retrospective cohort study of 78 patients who underwent surgical resection of NB. It describes surgical complications.)

Haberkern, CM. Anesth Analg. vol. 75. 1992. pp. 854-58. (Retrospective review of a cohort of 127 NB patients. This article describes preoperative and intraoperative anesthetic management of surgical resection of NB, with emphasis on cardiovascular instability due to catecholamine release.)

Kain, ZN. J Clin Anesth. vol. 5. 1993. pp. 486-91. (Retrospective cohort study of 57 NB patients, describing clinical presentation, and intraoperative course of surgical resection of NB. This study highlights potential anesthetic risks such as airway.)

Lacreuse, I. J Pediatr Surg. vol. 42. 2007. pp. 1725-28. (Retrospective cohort study of 21 patients. This study describes the feasibility and intraoperative and postoperative course of thoracoscopic surgical resection of neuroblastomas.)

Monclair, T. J Clin Oncol. vol. 27. 2009. pp. 298-303. (Task force report from the International Neuroblastoma Risk Group, describing the new staging system for pretreatment risk classification.)

Park, J. Pediatr Clin N Am. vol. 55. 2008. pp. 97-120. (Review article; discuss the biology, clinical presentation, prognosis and treatment of neuroblastomas.)

Kako, H, Taghon, T, Veneziano, G, Aldrink, J, Ayoob, R, Tobias, J. “Severe intraoperative hypertension after induction of anesthesia in a child with a neuroblastoma”. J Anesth. vol. 27. 2013. pp. 464-467.

Gorges, M. Pediatr Blood Cancer. vol. 62. 2015. pp. 29-34. (Case series of 6 patients with high risk neuroblastoma receiving hydromorphone and dexmedetomidine for pain secondary to immunotherapy.)

Pinto, NR. J Clin Oncol. vol. 33. 2015. pp. 3009-3017. (Review article; discuss advances of risk classification and treatment strategies fro neuroblastoma.)

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