New Requests for Old Diseases

This post is a written version of a talk by Dr Andrew Weatherall delivered at the South African Society of Anaesthesiologists Congress in 2017. The organising committee extended the invite and covered travel, accommodation and registration costs. 

We’re all pretty used to dealing with requests from surgeons. Changes in bed position. A dose of antibiotics to cover their disgusting operations. A switch in the playlist to cover versions of all the greatest hits from The Rolling Stones arranged for mandolin and recorder. Easy.

There are some requests we’d probably reject of course. Anything that involves accounting for someone else’s whereabouts or handling fake passports I guess. Actually I’d probably reject that playlist request too.

But every now and then a surgeon comes with a request to take on a new challenge. Which is what happened in the case of J.

An Introduction

J is a 16 year old and he has presented with a Wilms’ tumour. It is not the first time.

At the age of 3 he first came to know the hospital with a primary tumour. The treatment at that stage included tumour resection, a left nephrectomy, chemotherapy and external beam radiotherapy. It was a long year.

He returned at the age of 14 with a recurrence in his abdominal wall. Another round of surgery, chemotherapy and radiotherapy followed. This time he has returned with this…

Mass

When the anaesthetist can spot the angry looking mass above the white lake of the tumour it is probably big.

J has already rolled past fourth line chemotherapy. He has reached the maximum permissible lifetime dose of external beam radiotherapy. A grim outlook would be the summary for the initial conversations.

Then the combined teams approach him with a different offer. The conversation must have been something like “We’ve come up with an alternative. We’ll go back to surgery and take out everything that looks tumour all over the peritoneum. Then we’ll insert small guides to allow us to feed a radiation source right down to the tumour bed. We’ll do that intermittently for 3 days. Then we’ll go back to the operating theatre, take out the guides and bathe your insides in chemotherapy.” 

And now they are requesting anaesthesia to come to the party.

Where do you go?

So when faced with a challenging picture, of any sort really, where do you go? We figured we’d do that thing that should be in more superhero movies… we went to the library and we looked for paediatric information on all three phases they were talking about – cytoreductive surgery (CRS), brachytherapy and heated intraperitoneal chemotherapy (HIPEC).

And we found nothing. Nothing paediatric anyway.

So we started by trying to understand a little bit more about what they were planning and turned to the adults to see if they could teach us anything.

Cytoreductive Surgery (CRS)

CRS aims to do everything surgically necessary to remove all macroscopic tumour within the peritoneum. That will mean some primary resection but potentially removal of large areas of peritoneum and even resection of intra-abdominal organs. The end goal is to leave only nodules < 2.5 mm in size. Why 2.5 mm? Well …

Heated Intraperitoneal Chemotherapy (HIPEC)

In adult practice this generally follows immediately on from the CRS. It involves delivery of topical chemotherapy in the peritoneal cavity but the drug in its carrier is also heated to somewhere between 410C-430C. It’s left to circulate for 60-120 minutes. The heating serves a couple of purposes:

  • It maximises penetration of the agent into the residual tumour (which is already hopefully optimised by decreasing the size of those nodules).
  • It slows down the absorption into the bloodstream, hopefully meaning renal clearance can stay on top of things.

Brachytherapy

Brachytherapy is sort of a different way of harnessing the principles that work with radiotherapy. The difference is that the radiation source (in the form of a little bead) is delivered into the tissue. In some settings you might leave behind the little source of radiation to just do its work in the tissues. For other set-ups, as in this case, you deliver the radiation source to the area briefly with the aid of a special system.

And why???

It sounds like a lot of trouble doesn’t it? And can this really help when we’re at the end of the line?

Well there is some surgical literature out there, mostly from Hayes-Jordan et al out of Texas. They have some work out there showing that in desmoplastic small round cell tumour (which is impressively rare) 1 year survival can be improved to around 89% (from the 30-55% range in other publications).

They’ve also published a series describing patients with ovarian carcinoma and disseminated peritoneal disease with 5 of 8 patients still alive 2-6 years after treatment. More recently they’ve published a report on 50 patients (2 of whom had Wilms’ tumours) and in those patients where complete cytoreduction was managed the median survival was 31.4 months (compared to 7.1 months where there was inadequate cytoreduction).

So it looks like there may be benefits to some patients. Some patients and their families will take that option.

But what about J?

Well they want to take this option. He comes into it with mild renal impairment in that one kidney (with a Cr of 175 micromol/L) and mild LV dysfunction (with fractional shortening of 28%). On catching up with him prior most of the conversation centred on how anxious he was about this operation (well, all operations really). He’s using oxycodone 5 mg  when he needs it for pain.

Making a Plan

What adult practice can offer us is an idea of what the key considerations are for each part of the operation.

1. CRS

With all the resection of tissue involved it’s not surprising that the key component of this part is to be ready for significant fluid shifts and potential blood loss. In a publication looking at practice in 29 adult centres Bell et al found that most centres used invasive arterial pressures and central venous catheters as part of their routine.

You can find different ranges of fluid loss described but Schmidt et al quantified the median fluid requirement as 11.9 mL/kg/hour. No particular fluid choice seems to be recommended, even where there is a significant component of albumin loss. It is fluids that matter the most to the kidneys though as, sort of unsurprisingly, maintaining urine output with frusemide or dopamine doesn’t seem to help. I know, astonishing that those approaches which seem to work nowhere also don’t work here but still get discussed in the literature.

2. Brachytherapy

The set up in kids seems likely to be different to adults where patients would often be awake. There is some theoretical advantage to minimising fluid in cases only involving brachytherapy in adults as there is a theory that swelling in the implantation area might get in the way of the planned positioning. That doesn’t really fit well with the CRS bit though.

Once the guides are in place for cases like this (see the picture below), it is important not to allow movement of those guides, particularly once the position of them has been recorded in scanning.

Oh, I should mention that. The plan once the guides were in was a trip to MRI and the radiation oncology CT scanner to map the positions of these guides and plan the commencement of therapy. That’s a few patient moves and some logistics to consider.

Last point is that there is a remote but theoretical risk that the system that delivers the radioactive bead down the guides could get stuck with that bead still in the patient. If someone mentions this possibility that has never been reported worldwide (so the radiation oncologists tell me) there is a chance someone in your hospital will ask for a worked contingency plan for how you’ll rapidly get it out before it causes damage to the patient.

Of course a quick laparotomy in the radiation oncology suite won’t necessarily be the easiest. And everyone in the room will potentially get exposed to that source. And near as I can tell being exposed to radiation only makes you stronger in comic books. But it’s there as a risk in theory so you may want to have that chat.

3. HIPEC 

This bit is the real insult to the patient. You combine the toxicity of whichever agent you choose, the risks of hyperthermia and the hyperdynamic state all at the same time. Unchecked hyperthermia could lead to consumptive coagulopathy, kidney and liver injuries, peripheral neuropathies, seizures and arrhythmias.

That hyperdynamic phase is associated with an increase in heart rate, cardiac index and oxygen consumption too. Vasopressor or inotropic support might well be required.

And the toxicity extends beyond the simple consideration of the kidneys. Cisplatin for example can cause cardiotoxicity as well as selective renal magnesium loss along with QT interval changes. An exploration of the toxicities of the planned agent is worth undertaking prior.

Which is not to say the kidneys don’t matter. Dysfunction rates are anywhere up to 10% in the adult literature thanks to the potent mix of the agents, the fluid state and, depending on the technique for instilling the agent to the peritoneal cavity, raised intra-abdominal pressures.

Last but not least there’s that whole issue with flinging chemotherapy around the operating room. One solution to minimise the risk of exposure is to leave the abdomen closed while the agent is instilled via tubing. The problem with this is that the circulation of the agent is probably less effective and the pressures in the abdomen will rise at least a bit.

The preferred option is therefore to set up an open well or “coliseum” to contain any agent. A specialised system can then circulate the agent while monitoring in multiple spots to make sure the temperature is even throughout the peritoneal cavity.

It does make it particular important to educate theatre staff in safe practices around chemotherapy agents and brief a spill plan in advance though.

Crunch Time

The plan in this case was simple then. A good go at premedication. A plan to be ready for fluid shifts and blood loss with good venous access and an invasive arterial pressure. Analgesia via thoracic epidural (after all the guides were small so why not extubate the patient?) and plans to start the brachytherapy the next day and finish up with the HIPEC procedure 4 days after the first operation. Easy.

And it sort of was. The first procedure took a total of 11 hours and the blood loss wasn’t huge. And then the radiation oncologists mentioned that their art and craft work to create the set-up for the guides was a bit more extensive than planned. They did this …

CT_SAG_BRACHYTHERAPY_1.CT.0003.0020.2016.08.05.15.45.07.932863.19390780

The anaesthetist can still spot it. Another big thing.

And on the outside that meant that maybe closing the abdomen was ambitious. So a new plan was made – stay intubated and avoid full closure of the abdomen to ensure intra-abdominal pressures around that single kidney didn’t rise.

IMG_0718a-2

That’s quite the construction. Each numbered plastic guide hooks up to the radiation oncology machine that will deliver the bead down the guide to the tip placed in the spot where the tumour used to sit.

Brachytherapy proceeded without issue though and the patient returned for HIPEC on the Friday. And that stage went well too. There were no hiccups with the coliseum and the patient’s temperature never hit 39.

Col Edited copy

If you look carefully you can see four temperature probes monitoring agent circulation as well as the tubing for the actual recirculation system.

Pack it up and go home then. Extubate the patient the next day (tick, done) and it’s all wrapped up, yes?

Better Efforts

Of course there are always things you could do better and there are things to learn for the next time. Except when will a next time come? Should we just let adult places do it seeing as they’ll be doing it more anyway.

Yeah, nah.

The thing is we know that in situations where adult caseloads are higher, paeds centres seem to provide better outcomes for kids in trauma, appendicitis management, leukaemia and even management of interhospital transports. There’s even stuff out there suggesting kids do better around a Whipples’ procedure in a paediatric centre despite the fact paediatric surgeons almost never do these.

So keep them with the paeds centres.

But if we’re going to do them are there choices the anaesthetists can make to influence outcomes more?

Well there is some retrospective research suggesting that techniques where you utilise regional analgesia might be associated with less recurrence in breast cancer, ovarian cancer, prostate cancer and colon cancer. There is also some work suggesting that TIVA might be associated with better survival in breast, colon, rectal and bladder cancer.

So why would that even make sense?

Well the theory goes that it’s about the immune system and the inflammatory milieu. Finally. I squeeze milieu into something.

We know that to metastasise the tumour cells need to get into the circulation and dodge detection and elimination by the immune system (things like Natural Killer cells) We also know that surgery will release some of the cells. And right at that moment we suppress the patient’s immune system.

Serum from those given sevoflurane/opioid combinations appears to create a serum “mix of the many things” that supports metastatic behaviour of cancer cells in a dish. We know that regional techniques might help maintain NK function.

But we also know that the research is not at all conclusive. The question then becomes what do you lose by using TIVA and regionals more. Probably not much. TIVA is a nice technique and regionals work well. So given the choice again I think that’s what I’d reach for.

Something that does make sense is to minimise transfusion. We know that transfusions lead to an immunomodulatory effect with alterations in circulating lymphocytes T-helper cells and other cell-mediated processes. Transfusion is associated with lower survival rates in at least colorectal and gastric cancer though programs to reduce transfusion rates haven’t been shown to alter outcomes just yet. Still, avoiding more transfusions has plenty of bonuses.

What about that next time then, Gadget?

I’d still give the premed. I’d probably use regional and TIVA by preference. And I’d try to do better.

There’s more to this story though.

IMG_1218

So many more words

In the recovery phase a tubulopathy did develop and the kidney took a while to get happier again. J did develop superior mesenteric artery syndrome though which declared itself with feed intolerance and ended up taking 8 weeks to resolve. Unsurprisingly abdominal pain also required some input from the pain service.

What was way more of an issue was the anxiety. Psychological services ended up being almost the most important team during recovery.

We could have been ready for that. It makes sense that would flare up, particularly if there were some concerns prior. We pride ourselves on supporting all the stuff around the kids better than adult centres and yet we weren’t quite ready here. Those techniques are sort of the oldest part of our kit, and we kind of forgot to be completely switched on for that. We can do better.

So next time a new request comes in how will I tackle it?

I’ll research the new thing, and remember the old things we already do well. And hopefully deliver on our task of making sure the kids can get past all the grey and find some colour.

Street Martin Whatson

 

Notes:

The case described here has been cleared for educational purposes and publication by the patient and family. Deep thanks to colleagues Dr Jonathan Karpelowsky and Dr Jennifer Chard for the education they’ve offered around the surgery and radiation oncology.

We have published a special interest article triggered by this case in Pediatric Anesthesia in the hope that the next people who have to look will have an easier way in. You can find it here:

Weatherall AD, Bennett TR, Lovell M, Fung W, de Lima J. Staged intraperitoneal brachytherapy and hyperthermic intraperitoneal chemotherapy in an adolescent: novel anesthetic challenges for pediatric anesthetists. Pediatr. Anesth. 2017;27:338-45. 

The papers from Hayes-Jordan and team are here:

Hayes-Jordan A, et al. Novel treatment for desmoplastic small round cell tumour: hyperthermia intraperitoneal perfusion. J Pediatr Surg. 2010;45:1000-6.

Hayes-Jordan A, et al. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in pediatric ovarian tutors: a novel treatment approach. Pediatr. Surg. Int. 2015;32:71-73.

Hayes-Jordan A, et al. Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for Children, Adolescents, and Young Adults: The First 50 Cases. Ann Surg Once. 2015;22:1726-32.

Now here are some of the adult papers that were kind of useful:

Bell JC, et al. Perioperative Management of Patients Undergoing Cytoreductive Surgery Combined with Heated Intraperitoneal Chemotherapy for Peritoneal Surface Malignancy: A Multi-Institutional Experience. Ann Surg Once. 2012;19:4244-51. 

Schmidt C, et al. Peri-operative anaesthetic management of cytoreductive surgery with hyperthermia intraperitoneal chemotherapy. Anaesthesia. 2008;63:389-95.

Here’s some stuff on paeds specialty care vs adult or non-specialist care:

… in trauma

Walther AE, et al. Pediatric and adult trauma centers differ in evaluation, treatment, and outcomes for severely injured adolescents. J Pediatr Surg. 2016;51:1346-50. 

… in appendicitis

Whisker L, et al. Appendicitis in children: a comparative study between a specialist paediatric centre and a district general hospital. J Pediatr Surg. 2009;44:362-7. 

… in leukaemia

Klein-Geltik J, et al. Use of paediatric versus adult oncology treatment centres by adolescents 15-19 years old: the Canadian Childhood Cancer Surveillance and Control Program. Eur J Cancer. 205;41:404-10. 

… in retrieval

Ramnarayan P, et al. Effect of specialist retrieval teams on outcomes in children admitted to paediatric intensive care units in England and Wales: a retrospective cohort study. Lancet. 2010;376:698-704. 

On anaesthesia technique, transfusion and outcomes you could start by reading in these spots (there is heaps out there):

Cakmakkaya OS, et al. Anaesthetic techniques for risk of malignant tumour recurrence. Cochrane Database of Systematic Reviews. 2014;11: doi:10.1002/14651858.CD008877.pub2

Heaney A, Buggy DJ. Can anaesthetic and analgesic techniques affect cancer recurrence or metastasis? BJA. 2012;109(S1);i17-i28. 

Xu, YJ, et al. Effects of anaesthesia on proliferation, invasion and apoptosis of LoVo colon cancer cells in vitro. Anaesthesia. 2015;71:147-54.

Then here’s the paper looking at the drop in transfusion rates with a program that didn’t show a drop in recurrence (which covers the background pretty well):

van Osdol MD, et al. Long-term outcomes of an integrated transfusion reduction initiative in patients undergoing resection for colorectal cancer. Amer J Surg. 2015;210:990-5. 

Oh and that painting of the kid pulling back the grey was picked up via a fantastic website that shares all sorts of art called thisiscolossal.com which I drop by a couple of times a week for inspiration.

 

 

 

 

One response to “New Requests for Old Diseases

  1. Pingback: New requests for old diseases | Prehospital and Retrieval Medicine - THE PHARM dedicated to the memory of Dr John Hinds·

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