The word ‘crisis’ has a wide range of meanings and it’s well used in the media to catch the reader’s attention. Lately, the terms ‘political crisis’, financial ‘crisis’ and ‘constitutional crisis’ appear almost daily in media headlines. In a previous life, the term ‘crisis management’ was used daily in the work I was undertaking as I went from problem to problem, dampening or putting out fires (….. that’s a metaphor!).  Thinking back, my adrenaline (epinephrine), norepinephrine, and cortisol must have been very busy! 

However, in the world of Neuroendocrine Tumours (NETs), ‘crisis’ has a very significant meaning, and its very mention will make ears prick up.  The word ‘crisis’ is normally spoken or written using the term ‘Carcinoid Crisis’ given it is normally associated with those who have carcinoid syndrome.  One might assume it only involves patients with tumours in locations previously described using the ancient term “carcinoid“.  Perhaps this is another knock-on effect caused by the historical use of the word ‘Carcinoid‘ to incorrectly refer to all NETs. However, I’ve studied and researched and it would appear that some form of ‘crisis’ might apply to at least one other NET – Pheochromocytoma/Paraganglioma – a catecholamine-secreting group of tumours (see more below).  Although this is a different variant of crisis situation, maybe there should be a more generic NETs wide term? 

What is (so-called) ‘Carcinoid Crisis’?

In the simplest of terms, it is a dangerous change in blood pressure, heart rate, and breathing (technical term – cardiopulmonary hemodynamic instability).  On an operating table under anaesthetics or an invasive procedure such as liver embolization, this can be an event that could worry both patient and doctor.  Incidentally, this happens with many other types of conditions (…… hormones and peptides do exist in other illnesses). However, with a patient already oversecreting these hormones and peptides, it could be a risky affair. 

What is the difference between carcinoid crisis and carcinoid syndrome?

A carcinoid crisis is said to be a situation where nearly all of the possible symptoms of carcinoid syndrome come at the same time and in some severity. Carcinoid crisis is a serious and life-threatening complication of carcinoid syndrome and is generally found in people who already have carcinoid syndrome. The crisis may occur suddenly, or it can be associated with stress, or a reaction to treatment, but it is mainly a result of the use of anaesthesia. There is probably a thin line between a severe bout of carcinoid syndrome and carcinoid crisis but generally, it can be characterized by an abrupt flushing of face and sometimes upper body, usually severe falls in blood pressure and even bronchospasm with wheezing can infrequently occur. The attack may look like a severe allergic reaction.

It is said by one very well-known NET expert to “not to be something which happens randomly to all patients, it is usually linked to a medical procedure of some sort when you are having anaesthesia”.  Dr Eric Liu also said, “Luckily it is relatively uncommon”.

Why does it happen to some NET Patients?

NETs can release a variety of ‘vasoactive peptides’ (hormones) in excess (e.g. serotonin, catecholamines, histamine).  Under normal circumstances, these would just present as routine syndromes which may need to be controlled in most cases with somatostatin analogue treatment (Octreotide/Lanreotide).

Excess amounts of these vasoactive substances can cause both hypertension and hypotension (high and low blood pressure respectively). In extreme cases, this can lead to what is known as a crisis situation.

How is the risk managed?

Most people are effectively managed on monthly injections of Octreotide/Lanreotide but some people still need ‘rescue shots’ (top-ups) when they are experiencing breakthrough symptoms.  When I was symptomatic (syndromic), I would regularly flush in stressful situations but that was definitely syndrome rather than crisis. Check out my video explaining how I felt.  It’s worth reading something called the 5 E’s of Carcinoid Syndrome, probably useful to other types of NETs as I’m sure there is some overlap (again the ‘carcinoid’ term is unintentionally used as a catch-all).

If you research this plus perhaps from your own experience, you will know there are different ideas and ‘protocols’.  However, they all mostly involve some pre-procedure infusion of a somatostatin analogue (normally Octreotide) – although I’d love to hear from anyone who has had Lanreotide as an alternative.  Some doctors or hospitals are known to have their own ‘protocols’ and I’ve uploaded the one from the ISI NET book page 215 (Wang, Boudreaux, O’Dorisio, Vinik, Woltering, et al). Click here.  Please note this is an example rather than a recommendation as this is something the (then) NOLA team has developed for their own centre. 

UKINETS guidance has a rather nice graphical guidance sheet click here

In all the big procedures I’ve had in my local NET Centre, I have always been admitted the day before to receive what they describe as an ‘Octreotide Soak’.  The link below is an example of the UK standard for pre and peri-operative protection (please note your NET team may be working to a slightly different protocol based on their own version of best practice, just to emphasise that this is an example and not advice).

I did not have protection for some procedures prior to diagnosis (even when in hindsight I had carcinoid syndrome), and after my diagnosis.  Additionally, I don’t need anything special for dental procedures involving epinephrine.  There have been no incidents. 

What about minor procedures?

Patients are always asking about the risk and requirements for smaller procedures such as an Endoscopy.  There does not seem to be common guidance on this but Dr Woltering who is always forthcoming with advice suggests 200 micrograms of Octreotide before the procedure commences.  Looking at the UKINETS guidance click here, there appears to be a less risk-averse approach by considering whether patients are symptomatic or not (syndromic or not).

The Dentist

A frequently answered question and nothing is contained in any national guidelines (to me that says there is not a huge connection).  Epinephrine is one of the so called “5 Es of carcinoid syndrome” (so technically should only affect those with serotonin secreting NETs).  The only advice on this comes from known specialist Dr Woltering and everything is contained in my blog about the 5 Es of Carcinoid Syndrome. Additionally, in that blog there is also info for users of ‘Epi Pens’. You may need to de-risk those situations.

What about other types of NETs

The ISI Book Link above (here for convenience), does state “regardless of tumor type, all NETs should be pre-treated with Octreotide for protection against crisis“.  The omission of the word ‘carcinoid’ indicates a suggestion that it’s not just ‘carcinoid’ (also indicating the name needs changing!). However, the new study I linked above would appear to take another view. 

I know that NET patients other than those with ‘Carcinoid Syndrome causing tumours’ are also treated with somatostatin analogues, as they too can be subject to the effects of excess secretion of certain vasoactive peptides. Once again, the word ‘Carcinoid’ causes confusion.  There are many types of NET that were never called ‘Carcinoid’ and this had led to great confusion.  We need to call it something like Hormonal Crisis to avoid this confusion. I did note that Novartis (AAA) actually call it that in the Lutathera instructions – well done them! 

Why is the issue relative to Pheochromocytoma/Paraganglioma? 

Pheochromocytomas and paragangliomas are catecholamine-producing neoplasms that can cause life-threatening hemodynamic instability, particularly intraoperatively, when the tumor is manipulated.  In some ways, their version of ‘crisis’ is more complex and dangerous than the issues with ‘carcinoid crisis’ above.  There needs to be significant pre-operative preparation in addition to peri-operative measures, in fact with this type of tumour, post-surgical treatment and monitoring is also required.

I recently read an article about a person with Pheochromocytoma. The person had what was described as an ‘Intraoperative Hypertensive Crisis‘ that appeared to be caused by her tumour type rather than the sort of incident that might occur in standard surgery.  Hypertension (high blood pressure) can be a symptom of Pheochromocytoma so you can see the problem with surgery and other procedures. An interesting issue with this type of NET is that after surgery, the patient is at risk for hypotension (low blood pressure) from venous dilation caused by the sudden withdrawal of catecholamines. Read more here.

Summary

I highly suspect there are many examples from the NET world beyond what was once called the ‘carcinoid‘ subtype of NETs and I’ve already given you at least one above.  I’ll update this post as I discover other examples.  In the meantime, make sure you ask your medical team about ‘crisis protection’ if you are to undergo any surgical or invasive medical procedure. Minor procedures should also be assessed. 

Do we need to rename the term Carcinoid Crisis to Neuroendocrine Crisis or Hormonal Crisis?  Absolutely right we do