Anaesthesia for retroperitoneal lymph node dissection in the treatment of testicular cancer

Learning objectives.

By reading this article you should be able to:

• •Describe the surgical techniques involved in retroperitoneal lymph node dissection surgery.
• •Recognise the lifelong association between bleomycin, oxygen, and pulmonary toxicity.
• •Explain the cardiovascular complications of chemotherapy.
• •Discuss the anaesthetic implications of prolonged surgery.

Key points.

• •Testicular cancer is sensitive to chemotherapy and relatively few patients require retroperitoneal lymph node dissection surgery.
• •This surgery should be performed in specialist centres.
• •Chemotherapy with bleomycin can cause bleomycin-induced pneumonitis; there is a lifelong adverse association between oxygen therapy and previous bleomycin exposure.
• •Chemotherapeutic agents can accelerate cardiovascular disease.
• •Retroperitoneal lymph node dissection is an extensive surgery with potential for major haemorrhage.

Retroperitoneal lymph node dissection (RPLND) is an operation that is integral to the management of metastatic germ cell cancer. It is performed for those 18–35% of patients with a non-seminomatous germ cell tumour who still have residual disease after orchidectomy and chemotherapy/radiotherapy. It is technically challenging surgery, with potential for involvement of the great vessels, and a concomitant nephrectomy rate of around 11%.¹ Patients will have recently undergone platinum-based chemotherapy, which can result in significant cardiovascular and respiratory compromise, despite the young age of the patients. The extensive nature of the surgery, its duration and complexity require a well-planned and nuanced anaesthetic technique, and it is recommended that the cases are performed in specialist centres catering for high volumes of patients.²

Testicular cancer

Testicular cancer remains rare. There are around 2300 new diagnoses of testicular cancer a year, most of them in men under 35 yrs old.³ Of these, 95% are germ cell tumours of which there are two types, seminomas and non-seminomas. Prognosis, even in advanced disease, is excellent, with 98% of men surviving 10 yrs after diagnosis. A multimodal approach with orchidectomy, chemotherapy, surgical resection of residual disease, and in some instances radiotherapy, has contributed to the success of the treatment.

RPLND is most often performed in those patients where residual disease is evident after chemotherapy. It also has a role in the salvage of the patient who has already been heavily treated with chemotherapy; surgery remains a fundamental tool to achieve durable complete remissions in up to 20% of patients, particularly if there is an isolated raised alpha-fetoprotein.4, 5 The resection of non-responsive or progressive (e.g. rising markers) disease after salvage chemotherapy or growing teratoma syndrome, can be particularly challenging for both surgeon and anaesthetist. When the disease is resectable, a significant proportion of these patients may be rendered disease-free in the long term. The disease bulk itself can consist of viable cancer (10%), mature teratoma (50%), or necrotic-fibrotic tissue (40%), which if left, can dedifferentiate and undergo malignant transformation.

Clinical presentation

Testicular cancer typically presents with a lump, a feeling of scrotal ‘heaviness’ or pain/discomfort in the scrotum. Less common symptoms include back or abdominal pain and respiratory symptoms secondary to metastases.

Before orchidectomy, it is important to perform a chest X-ray, as the presence of pulmonary metastases indicates advanced disease, in which case orchidectomy should be postponed and chemotherapy instituted immediately.

Chemotherapy and anaesthesia

In the 1970s, platinum-based chemotherapeutic agents heralded a new age of treatment for testicular cancer. In addition, prompt diagnosis, multidisciplinary working, and meticulous follow up with regular assessment of tumour markers and cross-sectional imaging have significantly reduced mortality from testicular cancer. This advance is not without cost, however, as the agents primarily used, bleomycin, etoposide, and cisplatin (BEP), all cause significant toxicity that can have lifelong consequences.

Bleomycin is known for its acute pulmonary toxicity with reported rates of bleomycin-induced pneumonitis of between 2% and 42%. Risk factors for acute pulmonary toxicity include high total bleomycin dose (>300 U), impaired renal function, use of granulocyte-colony stimulating factor, cigarette smoking and older age.⁶ In patients who have been treated with bleomycin, it is recommended that they wear a medical alert bracelet or carry a medical alert card.

Bleomycin binds to DNA, producing breaks in single- and double-stranded DNA via free radical formation in the presence of oxygen and iron. Bleomycin hydrolase is present in many tissues in the body, but significantly, not in the lungs or skin. It is excreted renally.

Bleomycin causes damage in a cytokine and free radical-mediated process. Endothelial damage stimulates further inflammatory mediators, fibroblast activation, oedema, and collagen deposition.

The association between bleomycin and acute respiratory distress syndrome (ARDS) after surgery was reported in 1978 shortly after the introduction of bleomycin as a chemotherapy agent.⁷ There were five deaths from ARDS attributed to oxygen toxicity and notably, to the liberal use of crystalloids. The same authors subsequently described a prospective case series that did not demonstrate such dramatic mortality after instituting a reduced Fio₂ and preference for colloids (described as 5% protein fraction or fresh frozen plasma) over crystalloids.

More recent papers have questioned the lifelong association of oxygen therapy and bleomycin exposure, particularly in the advent of restrictive fluid strategies and lung protective ventilation. One study in particular studied the use of 3 min preoxygenation then a limit for Fio₂ of 0.3 in patients undergoing RPLND after bleomycin treatment and had much lower than expected postoperative respiratory complications.⁸ During anaesthesia, adjustments to the concentration of oxygen administered can be guided by Spo₂ and measurement of Pao_2. The aim is to deliver as low a concentration of oxygen as is possible to maintain an Spo₂ ≥92% and a Pao₂ ≥8 kPa.

While the concerns regarding bleomycin are well established and relatively well known, the improvements in cancer survival generally mean we are beginning to understand the long-term effects of other chemotherapeutic agents on the body. There is an increasing amount of published evidence on the cardiovascular effects of newer agents on long-term cardiovascular morbidity. The underlying mechanisms relate to impaired endothelial function, oxidative stress, thrombosis, and direct vascular and renal damage. The morbidity is so significant that there are calls for more awareness in offsetting cardiovascular risk in patients receiving chemotherapy. Indeed, this has resulted in cardio-oncology emerging as a subspecialty in its own right. Cisplatin in particular has a high incidence of post-chemotherapy hypertension, one paper reporting as high as 53% in those treated with higher doses, and a 9% rate of thromboembolism. An ECG and echocardiography may be required in those patients treated with cisplatin who are exhibiting signs and symptoms suggestive of chemotherapy-induced cardiotoxicity.

In patients treated with cisplatin for testicular cancer, there is a reported 6% rate of major cardiac events in one paper with a 14-yr follow up. This is discussed in more detail in a review of anticancer therapy and cardiovascular morbidity by Cameron and colleagues.⁹ Cisplatin-induced peripheral neuropathy (CIPN) is another well-known adverse effect. It is dose-dependent, and while many patients will have a gradual decline in the severity of symptoms, some 20–40% will have a permanent deficit. Therefore, these patients are at a higher risk of nerve injury as they may have undiagnosed sensory neuropathy. Finally, cisplatin is one of the most ototoxic drugs available. There is some degree of sensorineural hearing loss in 20–75% of patients. In cumulative doses >600 mg m⁻², this nears 60%.¹⁰

Etoposide is the third chemotherapeutic agent used in this regimen; its main adverse effect is myelosuppression and treatment therefore requires monitoring. This effect only lasts during its acute treatment and does not persist after chemotherapy has ended.

Surgical technique

In order to access the retroperitoneum, the surgical procedure involves a large midline incision. In the UK, 93% of these cases are performed with an open technique.² Although laparoscopic and even robotic techniques can offer a reduced length of stay, the nature of this type of surgery does not lend itself to these techniques. The thoracoabdominal approach can be useful for concomitant resection of ipsilateral retrocrural disease and lung metastases.

The lymphatic drainage of the testis is to areas adjacent to the great vessels. These lymph nodes are divided into the paracaval, interaortocaval and the para-aortic regions. The surgical approach has evolved to describe a bilateral infrahilar template (Fig. 1), the boundaries of which include bilateral renal veins superiorly, nodal tissue laterally, between both ureters and inferiorly, to the bifurcation of common iliac arteries (Fig. 2). The most common complication remains retrograde ejaculation.³ In order to try and prevent this and the consequent infertility, surgical techniques have developed specifically to preserve paravertebral sympathetic ganglia, postganglionic sympathetic fibres from T12-L4 and the hypogastric plexus. This is described as a ‘nerve-sparing’ technique.

Fig 1.

Anatomical diagrams of the right (a) and left (b) hilar templates. Reproduced with permission from Ernstoff and colleagues.²⁴

Fig 2.

Dissection illustration of the hilar template with both great vessels visible.

These are long operations, with the potential for sudden catastrophic bleeding, with 5% of cases in the UK reporting vascular reconstruction and an 11% nephrectomy rate.¹

Anaesthesia for RPLND

Preoperative assessment

The usual history should be noted. Often there is a recent orchidectomy and a prior anaesthetic chart available. It is important to note the type of chemotherapy used and as a result, any reduction in exercise tolerance. BEP chemotherapy is most commonly used in these cases, however, there are instances where it has been deemed too toxic to the cardiorespiratory systems, or a patient may have experienced pronounced adverse effects. As such, some patients may have had surveillance pulmonary function tests before and after chemotherapy.

Standard preliminary investigations should be noted, including ferritin and iron studies if the patient is anaemic. Iron deficiency anaemia should be treated before surgery, with i.v. preparations if necessary, to expedite surgery. While there is no specific literature pertaining to patients undergoing RPLND, active management of iron replacement has been recommended in many national anaesthetic and surgical guidelines.11, 12

Cardiovascular disease

As discussed earlier, chemotherapy can have significant effects on the cardiovascular system despite the relatively young age of these patients. As such, an ECG is required and less often, an echocardiogram. Of particular note, cisplatin can prolong the QT interval and thus cause torsade de pointes. As a minimum, four units of blood should be cross-matched. When blood loss occurs it can be sudden and of large volume. More blood may be required when there is predicted involvement of the great vessels.

Respiratory disease

Chemotherapy can also have a harmful effect on the lungs, with bleomycin-induced lung injury affecting a significant portion of patients. In addition, there could be a considerable history of smoking (including cannabis) in these patients, so pulmonary function tests can be useful. Bleomycin can cause a reduction in the diffusing capacity of the lung for carbon monoxide. Doses are reduced or even withheld when pulmonary function deteriorates during treatment. However, the most significant sign in predicting the presence of bleomycin-induced lung damage is cough.¹³

Cardiopulmonary exercise testing

Cardiopulmonary exercise testing has become a standard test in many centres for preoperative assessment in patients undergoing high-risk or major surgery. While there are still some discrepancies in which variables are reported, recent guidelines should clarify these issues.¹⁴ Cardiopulmonary exercise testing can be used to assess preoperative fitness and to determine whether the limitation is respiratory or cardiac in nature.¹⁴

We know that chemotherapy causes functional deconditioning and a reduction in $\dot{V}$o_2max. Evidence is emerging that exercise training while undergoing BEP chemotherapy is both feasible and can prevent a reduction in $\dot{V}$o_2max.¹⁵ We also know that BEP chemotherapy reduces muscle mass by 2.5 kg and decreases isometric strength by 10%.¹⁶ There is a paucity of data on the effectiveness of exercise training before surgery and during chemotherapy. This is an area of current scientific interest.

Perioperative management

Monitoring

Both non-invasive and invasive monitoring are required because the surgery often involves repeated compression of the inferior vena cava (IVC) and even cross-clamping of the aorta. Unless otherwise indicated, the invasive lines can be placed after induction of anaesthesia. Continuous temperature monitoring is also required.

In patients where there is planned vascular involvement, it can be useful to place a rapid infusion cannula in addition to standard central venous and arterial catheters. There are different types of devices available, all of which use the Hagen–Poiseuille principle that a shorter, wider diameter tube is best suited to rapid fluid administration. A vascath is one such device that can be used for rapid infusion and has the benefit, if required, of being available to use for postoperative renal replacement therapy. This is particularly useful in those patients who undergo concomitant nephrectomy.

Induction

In patients who have received bleomycin, few anaesthetists perform preoxygenation of the lungs as there is a concern that hyperoxaemia can lead to acute lung injury in bleomycin-treated patients.

When preoxygenation is not performed, meticulous attention must be paid to positioning for tracheal intubation, in order to minimise the time to intubation. In patients who are obese, the use of an Oxford pillow conjunction with a McGrath videolaryngoscope is a very useful technique. If a patient is predicted to have a difficult airway, it would be prudent to consider an awake fibreoptic intubation in this situation.

A patient whose lungs have not been preoxygenated is likely to become hypoxic during intubation, and desaturations to the mid 70–80s are not uncommon, although usually do not last longer than 30–45 s.

During maintenance of anaesthesia, Fio₂ of 0.21 is delivered but can be increased to 0.3 if required. The Fio₂ limit of 0.3 is also ideally used both during and after surgery. Low oxygen saturations would be tolerated as long as the Pao₂ was >8 kPa; the Fio₂ would be increased if necessary only if the patient was demonstrably hypoxic on arterial blood gas analysis.

Because of the duration of surgery, a remifentanil and desflurane anaesthetic technique can be used. For most cases, the postoperative destination is the high dependency unit rather than intensive care, and a rapid wake-up and recovery from anaesthesia is desirable.

Positioning for surgery

As these patients may have subclinical sensory nerve damage related to chemotherapy, the nerves are vulnerable to further insult. Other predisposing factors are diabetes, hypertension, and smoking. Careful positioning is crucial, to manage pressure areas. We use a sheepskin base, with arms abducted to around 70 degrees, with a bent elbow and hands resting in pronation (Fig. 3). All pressure points should be padded to avoid pressure ischaemia of vulnerable areas such as the heels. The position often favoured by surgeons involves significant hyperextension of the back in order to gain better surgical access (Fig. 4).

Fig 3.

Optimal arm position to minimise further nerve injury after chemotherapy.

Fig 4.

Hyperextension of the patient on the operating table to maximise surgical access.

It is important to flex the joints (including the head) regularly and move the Spo₂ probe to avoid pressure necrosis. Intermittent pneumatic compression devices are not used because of the higher incidence for venous bleeding in this type of surgery.

Analgesia

Analgesia can be provided with epidural analgesia or with intrathecal opioids as part of a multimodal technique for postoperative pain management. If an intrathecal opioid technique is used, the choice of opioid will differ depending on the institution, but one regimen would be to administer preservative-free intrathecal morphine 5 μg kg⁻¹ before induction of anaesthesia. Intrathecal local anaesthetic is not required and the intrathecal opioid can be delivered in sterile saline. Benefits of this technique include reliable analgesia, quicker postoperative mobilisation, and less intraoperative hypotension.

After administration of intrathecal opioids, our next step for analgesia is to use a high volume, low concentration rectus sheath injection. This is performed before placement of the surgical retractor. In our institution, the surgeon will inject levobupivacaine 2 mg kg⁻¹ diluted up to a volume of 100 ml with saline, into the posterior rectus sheath. This is performed using a regional block needle (Fig. 5). At the end of surgery, rectus sheath catheters are inserted under direct vision by the surgeons and 20 ml levobupivacaine 0.25% is administered to each side. These can be used for up to 3 days after surgery with top-ups administered every 6 h. Finally, a small dose of morphine (around 0.1 mg kg⁻¹) is given toward the end of the procedure and a PCA device is provided for additional postoperative pain control.

Fig 5.

Rectus sheath injection before placement of the surgical retractor.

If choosing epidural analgesia, this would need to be at the low thoracic level in order to reach the level of the xiphisternum. Working epidural analgesia provides excellent pain relief and should result in a reduction in opioid consumption and related adverse effects. Given the large incision across multiple dermatomes, adequate spread of local anaesthetic can be a problem. A failure rate of 24.8% has been quoted in the literature for epidural analgesia in patients undergoing major elective abdominal surgery for cancer.¹⁷

Fluid management

This type of surgery is unusual as there can be profound, but relatively short-lived hypotension relating to direct IVC compression. Therefore, it is important to be aware of the progress of surgery and communicate well with the surgeon, as hypotension may not always be attributable to IVC compression. Occasionally there is vascular injury, which results in rapid blood loss.

Short periods of profound hypotension relating to surgical compression of the IVC are to be expected and to a certain extent tolerated, but if necessary, the surgeon may need to release pressure on the IVC and restore preload.

These patients can be very fluid responsive, and they will require i.v. fluid boluses, with the most recent evidence suggesting that liberal fluid strategies in major abdominal surgery are safer.¹⁸ In order to judge fluid responsiveness it can be useful to use dynamic indices and the basic physiological variables of HR and BP. Systolic pressure variation and pulse pressure variation are examples of dynamic indices and can be used in patients in sinus rhythm. The original evidence required patients to be ventilated mechanically at tidal volumes of 8–10 ml kg⁻¹. This is perhaps not in keeping with a modern lung-protective strategy, but as long as one understands the caveats associated with their use, these devices can be useful. Values of >20% would clearly suggest intravascular depletion. When values are around 9–13% then there exists a ‘grey zone’ where interpretation can be more difficult. Interpreting the response to a fluid challenge is also key.¹⁹

Whether or not the use of perioperative invasive cardiac output monitoring is useful in practice is an area of debate, and use often depends on local and individual preferences.

Blood management

Haemoglobin should be optimised before surgery if necessary and blood should be available perioperatively (minimum four units). Often there is insufficient time before surgery for oral iron therapy (i.e. less than 6 weeks); therefore, if the patient is iron deficient, this should be replaced with i.v. preparations. Fluid warmers and forced air warming devices should also be used as standard, as there is a large exposed body surface area through which heat will be lost continuously. Temperature homeostasis is crucial to normal clotting and therefore warrants continual monitoring.

Currently, the use of cell salvage for primary urological malignancies is approved by the National Institute for Health and Care Excellence (NICE).²⁰ It is recommended that leukodepletion filters should be used before reinfusion to filter malignant cells; further elimination of malignant cells can be achieved by irradiation. However, the manufacturers of cell salvage equipment do not advise its use in oncological surgery when there is already secondary spread of tumour and therefore cell salvage is not commonly used.

Tranexamic acid is not used in these cases as there is research to suggest an interaction with bleomycin that can increase the risk of thromboembolism. This research concerned coadministration in mice, and the mechanism is thought to be via a reduction in plasmin activation. It is not known whether this effect persists and so tranexamic acid is generally avoided.²¹

The majority of cases will not require perioperative blood transfusion and the average blood loss is around 500 ml. However, in those cases with vascular involvement, the blood loss can be much larger. Often the cases where there is potential for major haemorrhage will be anticipated based on preoperative imaging. Preoperative autologous blood transfusion is usually not appropriate as the patients have recently had chemotherapy and are recovering from the after-effects of marrow suppression.

There has been a move towards using a 1:1:1 (red cells, fresh frozen plasma and platelets) resuscitation strategy in major haemorrhage. The evidence for this has come from the management of major trauma. A recent study has highlighted the sparse evidence for this outside the setting of trauma.²² The approach taken is likely to reflect local policies for the management of major haemorrhage and be guided by the local haematology department. Threshold-based transfusion triggers are not appropriate for managing ongoing major haemorrhage. Estimated blood loss and haemodynamic status should be used to guide transfusion. It is also worth reinforcing the importance of maintaining an adequate serum calcium concentration. It can decrease during transfusion and it is an important factor in coagulation.

After surgery, NICE guidance states a conservative target of >7 g L⁻¹ would be appropriate in the absence of acute coronary syndrome.²³

Thromboprophylaxis

Intraoperative compression devices are contraindicated in RPLND as they can increase venous bleeding. Low molecular weight heparin is usually commenced within 24 h after surgery.

Postoperative management

High-dependency care is required because of the extensive nature of the surgery, the use of high-dose intrathecal opioids, the presence of either epidural or wound catheters, and to closely monitor the use of supplemental oxygen, which may involve repeated blood gas testing at least initially. Institutional experience is useful in the postoperative management of these patients, and we use ‘end of bed’ signs as reminders to be wary of excessive use of oxygen. Oxygen therapy is guided by oxygen saturations and the Pao₂, aiming to use only enough oxygen as is necessary to achieve a value of 8 kPa or greater.

Rarely, if there has been massive blood transfusion and metabolic derangement, then admission to intensive care is required.

In summary, RPLND surgery is an interesting, challenging operation requiring a team-based approach and an understanding of the long-term complications of chemotherapy.

Declaration of interest

The authors declare that they have no conflicts of interest.

MCQs

The associated MCQs (to support CME/CPD activity) will be accessible at www.bjaed.org/cme/home by subscribers to BJA Education.

Biographies

Miriam Stephens FRCA is a consultant anaesthetist at Wishaw General Hospital. She is lead consultant for preoperative assessment and has established a preoperative anaemia clinic. She developed an interest in anaesthesia for RPLND when working as a specialist trainee at the Queen Elizabeth University Hospital in Glasgow.

Therese Murphy FCA RCSI is a consultant anaesthetist at the Queen Elizabeth University Hospital. Her major clinical interests are anaesthesia for RPLND and obstetric anaesthesia.

David Hendry BSc FRCS FRCS (urol) is a consultant urologist at the Queen Elizabeth University Hospital. He is lead consultant for the RPLND service in Scotland and also has an interest in penile cancer.

Matrix codes: 1A02, 2A07, 3A03