Carcinoid tumours are uncommon, slow-growing, mostly asymptomatic neuroendocrine tumours of enterochromaffin cells.1 The incidence of carcinoid tumours is estimated to be 3.8-5.2/100,000 people.1,2 These tumours secrete hormones, including serotonin, bradykinin, histamine, and other vasoactive peptides that are metabolized quickly by the liver after being released into the portal circulation.3,4 Tumours of the small intestine are most likely to metastasize to the liver, allowing the hormones to escape hepatic metabolism and be released into the systemic circulation.4,5 These hormones may lead to symptoms such as diarrhea, flushing, tachycardia, and bronchoconstriction, collectively known as carcinoid syndrome.6 Only 10% of patients with carcinoid tumours will ever experience these symptoms.7

When a large number of hormones are released at once, these symptoms become life-threatening and precipitate an event known as a carcinoid crisis.8 A carcinoid crisis is a medical emergency that involves extreme hypo- or hypertension and sometimes includes flushing, bronchoconstriction, tachycardia, or coma.6 This is known to happen when patients undergo anesthesia or tumour manipulation, or it may occur spontaneously.8-10 Serotonin, histamine, bradykinin, kallikrein, and catecholamines are thought to be the main mediators of carcinoid crises.6 Currently, there are no known indicators to allow clinicians to predict which patients will develop a carcinoid crisis.11

Somatostatin is known to inhibit the production of gastric acid, gastrointestinal tract motility, and secretion of bile, colonic fluid, insulin, glucagon, secretin, serotonin, and vasoactive intestinal peptides.7,12 Octreotide is a somatostatin analogue that acts both to block the release of hormones and to stabilize blood pressure directly.9 Octreotide administered subcutaneously in doses of 50-1,500 μg·day−1 is effective for treating symptoms of carcinoid syndrome.Footnote 1 For carcinoid crises, octreotide is typically administered in bolus doses or hourly infusion rates of 100-500 μg iv.6,13,14 Due to the apparent low risk-to-benefit profile, much higher doses are sometimes used for patients with complicated conditions in urgent situations. Octreotide is also recommended as a prophylaxis against carcinoid crises when patients with carcinoid tumours undergo surgery.6 The decisions around the doses of octreotide for prophylaxis and treatment are often left to the anesthesiologist managing the surgical case.

The objective of this study was to assess the state of evidence to inform clinicians on the use of octreotide in doses greater than 1,500 μg iv or infusion rates exceeding 1,500 μg·hr−1 for the treatment of carcinoid crisis. We chose a 1,500 μg dose as the upper limit, as this is the highest recommended dose of octreotide for any of its labelled indications.A Furthermore, we attempted to identify risk factors to predict a need for these high doses and examined adverse effects of octreotide in the treatment of carcinoid crisis. In this systematic review, we examined the dose of intravenous octreotide administered for the treatment of carcinoid crisis. This is invaluable information for anesthesiologists and other clinicians who must make incisive critical decisions when presented with this rare life-threatening condition.

Methods

We conducted this systematic review following pre-specified protocols influenced by the guidelines for Meta-analysis Of Observational Studies in Epidemiology and Systematic Reviews of Observational Studies,15 and we presented this systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses: the PRISMA statement.16 The protocol was determined a priori by one of the authors (S.C.S.).

Eligibility criteria

Studies were eligible for inclusion if they included patients who received octreotide intravenously during an episode of suspected or confirmed carcinoid crisis. We sought to compare the outcomes of patients who received an octreotide bolus exceeding 1,500 μg or an infusion at a rate in excess of 1,500 μg·hr−1 iv with outcomes of all patients who received a lower dose of octreotide. Inclusion criteria comprised articles that directly identified a carcinoid crisis as well as articles that described patients with carcinoid tumours who experienced perioperative life-threatening hyper/hypotension for which no other cause could be identified and for which octreotide was used. As no randomized controlled trials were identified, our search criteria were expanded to include non-randomized study designs, such as case reports and case series.

Studies were excluded if there was an inadequate description of the octreotide dose or if octreotide was not administered for the treatment of a crisis. Studies that reported subcutaneous octreotide were also excluded because intravenous octreotide is the current standard of care recommended for carcinoid crisis.7,17

Resolution of carcinoid crisis symptoms was the primary outcome. Secondary outcomes included death, length of stay in the intensive care unit (ICU), and total length of stay in hospital.

Search strategy

One reviewer (S.C.S.) systematically searched MEDLINE, Experta Medica (EMBASE), and Cochrane library from the inception of each source until March 2006. A second reviewer (N.S.) updated the search in October 2010 and June 2011 to identify any new articles.

The search strategy was tailored to the functions of each database and included the terms “carcinoid syndrome” or “malignant carcinoid syndrome” AND “octreotide”. The MeSH function was used for both terms when searching MEDLINE. The search conducted with EMBASE was limited to articles containing “octreotide” and “carcinoid syndrome” as keywords. The search strategy was developed by a pharmacist with previous experience in systematic reviews (S.C.S.). Carcinoid syndrome was chosen as a broad search term in order to be comprehensive and not to miss any cases that were not directly labelled as crises.

The reference lists of all relevant reviews and included articles were evaluated to identify additional articles meeting our inclusion criteria. All citations were downloaded into RefWorks software.Footnote 2

Study selection

One reviewer (S.C.S.) evaluated the eligibility of the articles identified in March 2006. The second reviewer (N.S.) evaluated the eligibility of articles identified in March 2006, October 2010, and June 2011. Conflicts were resolved by consensus between both authors.

Data abstraction

Data from the 2006 search were independently abstracted by two reviewers using a pre-specified electronic form. Data from articles identified in subsequent searches were abstracted by a single reviewer (N.S.). Data extracted from each included paper are described in Table 1. Communication was attempted with authors in order to confirm reported values and obtain additional information. When authors of included articles used the terms hypertension, hypotension, bronchoconstriction, and flushing in relation to carcinoid crisis, we considered these as symptoms of carcinoid crisis. Similarly, when authors of included articles described elevated or decreased blood pressure requiring intervention, difficulty breathing, or skin colour abnormalities associated with a carcinoid crisis, these symptoms were considered attributable to carcinoid crisis. We recorded presence of hypertension, hypotension, bronchoconstriction, and flushing when directly stated by the authors to be present and related to carcinoid crisis or when elevated or decreased blood pressure requiring intervention, difficulty breathing, or skin colour abnormalities were stated by the authors as being present and related to carcinoid crisis. We defined resolution of crisis as per the definitions assigned by the authors, and we also accepted any and all adverse events categorized by the authors of the included papers. We collected patient age, sex, tumour location, presence of carcinoid heart disease, prior octreotide use, and carcinoid crisis symptoms in order to evaluate these as possible risk factors for requiring higher doses of octreotide.

Table 1 Characteristics of patients, octreotide dose, and carcinoid crisis
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Results

Study selection

Our electronic search identified 679 articles, and we identified an additional 15 articles by hand searching relevant articles. After screening titles and abstracts, we retrieved 148 articles for further review. Eighteen publications met inclusion criteria after full-text review. Refer to the Figure for selection of studies.

Figure
figure 1

Flow diagram - selection of studies

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Study characteristics

Seventeen of the included articles are case reports involving 18 patients experiencing a carcinoid crisis.9,13,18-32 One publication is a retrospective chart review describing 89 patients experiencing a carcinoid crisis.33 Some patients experienced more than one crisis.25,32 Study characteristics, octreotide dose characteristics, and crisis symptoms of all case reports are shown in Table 1. All studies were published between 1985 and 2010. Seven authors of eight articles kindly provided additional unpublished information.20-25,28,33

Octreotide dose and outcomes

Octreotide was effective at treating carcinoid crises at intravenous doses of 25–500 mcg and intravenous infusions at a rate of 50–150 mcg/h in the included case reports that described patient outcomes. Some carcinoid crises were acute and responded fully within one hour of octreotide administration 9,13,18-21,23-27,30-32 while other crises involved persistent hormone secretion requiring an octreotide infusion until symptoms eventually subsided.22,28,29 Table 2 describes the range of octreotide doses used in the case reports where symptoms resolved within an hour of octreotide administration. One paper describes the use of 50 μg boluses but does not clearly state the number of times these were administered.31

Table 2 Summary of octreotide bolus doses used in case reports
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Three patients had crises that lasted more than 24 hr.22,28,29 The infusion doses used for these patients are summarized in Table 3. The first case involved a male patient with an atypical carcinoid tumour of the lung with liver metastases.28 He had previously received long-acting release (LAR) octreotide 20 mg per month intramuscularly. This patient experienced a carcinoid crisis after administration of his second round of radionuclide therapy. The authors suggested that the 90Y-DOTA-D-Phe(1)-Tyr(3)-octreotide (90Y-DOTATOC) radionuclide therapy caused this crisis. The patient had one prior and one subsequent uncomplicated radionuclide treatment with a lower exposure to 90Y-DOTATOC. According to personal communications with the author, the infusion of 50 μg·hr−1 octreotide was performed for three days when the crisis was most severe, and then it was gradually reduced in the next two days as symptoms improved. The patient’s length of stay was one week. After one week, the crisis had completely resolved, and during this time, the patient was switched to subcutaneous octreotide in addition to LAR octreotide 30 mg every 28 days. The author also disclosed that this patient had previously experienced a less severe crisis not requiring hospital admission. The second case of prolonged crisis involved an 80-yr-old male patient with a carcinoid tumour of unreported origin and hepatic metastases.22 This patient experienced a carcinoid crisis that presented as flushing and profound hypotension 24 hr after bland embolization of the main right hepatic lobe. This patient had previous exposure to monthly LAR octreotide 20 mg intramuscularly and received no octreotide as surgical prophylaxis (unpublished information). According to information provided by the author, the patient’s crisis was treated with an octreotide infusion at a rate of 50 μg·hr−1 iv for two days, then 150 μg·hr−1 for eight hours. The third case regarding a prolonged crisis involved a 59-yr-old male with a well-differentiated primary midgut carcinoid tumour with metastases and carcinoid heart disease.29 The use of LAR octreotide was not reported in this patient who experienced a crisis on the second day after hepatic artery embolization. This patient received octreotide 100 μg prior to the procedure and octreotide 100 μg·hr−1 iv for 24 hr after embolization. Crisis symptoms included flushing, profound hypotension, tachycardia, and dyspnoea. The crisis eventually resolved after treatment with an octreotide infusion at a rate of 100 μg·hr−1 and oral cyproheptadine for four days along with dobutamine and digoxin to treat acute right ventricular dysfunction (including prolonged symptoms of hypotension) thought to be secondary to carcinoid crisis.

Table 3 Description of octreotide infusion rates used in case reports
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No patient died during crisis, although three patients described in separate case reports died from other complications more than 36 hr post-crisis. The first was a 79-yr-old female with a metastatic carcinoid tumour of the liver. This patient died of bradykinin shock involving intense edema and hypotension 36 hr post-hemicolectomy.23 An 80-yr-old male with metastatic hepatic carcinoid disease died of hydropneumothorax with complete collapse of the right lung 18 days post-bland embolization of the main right hepatic lobe.22 Finally, a 57-yr-old male with extensive metastatic carcinoid disease and concomitant psychosis died of respiratory insufficiency and cachexia due to carcinoid tumour progression more than five months after experiencing a carcinoid crisis.20,21

Length of stay in hospital and length of stay in the ICU were neither consistently nor uniformly reported, so we were unable to evaluate these outcomes.

Risk factors for higher octreotide doses

Octreotide exposure

Amongst patients described in case reports, those receiving octreotide as maintenance therapy to manage carcinoid syndrome symptoms appeared to receive higher doses of octreotide to manage carcinoid crisis than patients who had no history of octreotide use. In patients who were receiving octreotide maintenance therapy as outpatients, the highest dose of octreotide given to treat a carcinoid crisis was 200 μg. The available data were not comprehensive enough to facilitate quantitative statistical analyses.

One patient experienced seven carcinoid crises during surgery and three carcinoid crises postoperatively. The initial crises responded to octreotide boluses of 20-50 μg, while all later crises slowly responded to and resolved with octreotide boluses of 100-200 μg.25 This may be an example of tachyphylaxis to octreotide; however, increasing severity of carcinoid crisis could not be ruled out as the need for higher doses.

Carcinoid heart disease

In a retrospective chart review of 100 patients with carcinoid heart disease undergoing surgery, 89 patients were reported to have experienced a carcinoid crisis.33 According to our communications with the author, a crisis was defined by the investigator as the need for octreotide administration intraoperatively. In many cases, reported changes in blood pressure did not appear to be life-threatening; therefore, we are uncertain whether these patients were actually experiencing a carcinoid crisis (unpublished data). The median octreotide dose was 1,500 μg, although no description of carcinoid crisis symptoms or resolution was available (unpublished data). Carcinoid heart disease may be an independent predictor of complications during surgery and may also signal the need for higher doses of octreotide to treat a crisis.33

Consequences of octreotide in the treatment of carcinoid crisis

Adverse effects were not well reported in any study. No outcomes were reported for those patients receiving octreotide doses greater than 1,500 μg iv.

Discussion

Octreotide doses ranging from 25-500 μg iv and infusions at rates of 50-150 μg·hr−1 iv were effective for reversing carcinoid crises. Patients with prior exposure to octreotide for the management of carcinoid syndrome received slightly higher doses of octreotide to manage crises than those patients who had no history of octreotide use. During perioperative assessment, anesthesiologists may find that a patient’s previous use of octreotide is a predictive tool to estimate the dose of octreotide necessary to treat potential intraoperative carcinoid crises. This is corroborated by two studies in which the use of higher doses of octreotide to manage carcinoid syndrome was correlated with the need for higher octreotide doses to manage intraoperative carcinoid symptoms.30,33 Due to limited evidence, we cannot make causal statements regarding octreotide and the development of tachyphylaxis. Tachyphylaxis has been shown to develop after months or years of treatment in nearly all patients and is initially overcome by increasing the dose of octreotide.34 A decreased response to octreotide may involve down-regulation of receptors and/or various types of resistance to octreotide, including gene mutations.35 In our review, one patient experiencing seven carcinoid crises required increasing doses of octreotide with each subsequent crisis.25

Carcinoid heart disease is typically a late manifestation of carcinoid tumours, and patients with carcinoid heart disease may have an increased risk of perioperative complications.14,36 This was supported in a study by Weingarten et al where a high proportion of patients with carcinoid heart disease were reported to have experienced a carcinoid crisis.33 This study also presents the possibility that patients with carcinoid heart disease may require higher doses of octreotide should a crisis occur.33

Side effects of subcutaneous octreotide therapy are minimal and can include fat malabsorption, pain at the injection site, rash, nausea and vomiting, abdominal discomfort, dizziness, cholestasis, and headache.37 Octreotide is also known to cause hyperglycemia through suppression of insulin.30,38 In a case series, octreotide-induced hyperglycemia has been shown whereby patients receiving higher doses of octreotide for surgical prophylaxis experienced elevated blood glucose and required insulin administration.30 Somatostatin inhibits many other hormones, including growth hormone and thyroid stimulating hormone.39 Since octreotide is a somatostatin analogue, inhibition of these same hormones could lead to adverse effects. Furthermore, since octreotide can be immediately effective for reversing life-threatening carcinoid crises, side effects are likely to go unnoticed or are imperceptible compared with the trauma of the crisis and surgery themselves.

Each tumour secretes a unique cocktail of hormones, which makes each carcinoid crisis different and leads to discrepancy regarding the definition, symptoms, and treatment of carcinoid crisis. In addition, the unpredictability and urgency of carcinoid crisis makes it very difficult to research the underlying process. There is still much to learn about the physiology of carcinoid tumours, carcinoid crises, and the mechanism of octreotide in the treatment of carcinoid crisis. Understanding risk factors could be valuable to anesthesiologists in the prophylactic management (i.e., perioperative) and incidental treatment (i.e., intraoperative) of carcinoid crisis.

This systematic review included extensive searches across multiple databases and incorporated best available evidence for the clinical question.16 The heterogeneity in the definition of carcinoid crisis, the incomplete reporting of outcomes of interest, and the small sample size limit the ability to make causal inferences. The objective of this review was to assess the state of the evidence to support the use of octreotide boluses or hourly infusion rates in doses greater than 1,500 μg iv for the management of carcinoid crisis. The results of the review clearly show the lack of evidence on this important clinical question. Nevertheless, the paucity of reported safety concerns may encourage clinicians to utilize higher doses of octreotide when efficacy is the major concern in the presence of this life-threatening event. More research is needed before we can support or refute the necessity, side effects, and outcomes of octreotide doses greater than 1,500 μg iv and infusion rates in excess of 1,500 μg·hr−1. In particular, guidelines should be established to identify which patients, if any, may benefit from such large doses. In light of the urgent and unpredictable nature of carcinoid crisis, the information presented should provide anesthesiologists and other clinicians with guidance to make the proper preoperative preparations for patients at risk.