Beta-blockers and the thyrotoxic patient for thyroid and non-thyroid surgery : a clinical review

Abstract Introduction Thyrotoxic patients presenting for surgery should ideally be biochemically and clinically euthyroid. This is conventionally achieved through the use of anti-thyroid drugs, beta-blocker therapy and iodine. However, there are some circumstances where antithyroid drugs may not be a viable option. The implications of this scenario are not widely reported in the literature. This clinical review looks at the evidence on the safety of beta-blocker therapy without the use of antithyroid drugs in the preparation of the thyrotoxic patient for surgery. We also highlight key points in the pathophysiology of thyrotoxicosis and the management goals of these patients. Conclusion In circumstances where the use of anti-thyroid drugs is not possible in the preoperative management of patients for thyroid or non-thyroid surgery, the use of beta-blockers has been shown to be safe and effective. Safety can be increased by using iodine with or without corticosteroids up to the day of surgery in the rapid preoperative preparation of a severely thyrotoxic patient.


Introduction
A thyrotoxic patient undergoing surgery should ideally be rendered biochemically and clinically euthyroid prior to surgery 1 .This is through a combination of anti-thyroid drugs (ATD) and beta-blockers.However, in some circumstances, patients can be adequately managed with betablockers and potassium iodide 1 .The question remains though, how safe is this therapy compared with the conventional use of ATDs and betablockers?There have been several studies in the past that have suggested a role for sole beta-blocker therapy in the preoperative management of thyrotoxic patients.This paper aims to review the current literature to evaluate the safety of this practice.

Discussion
Thyrotoxicosis is a hypermetabolic syndrome secondary to elevated levels of thyroid hormones.The most common causes of thyrotoxicosis are Graves' disease, toxic multinodular goitre and toxic adenoma 1,2 .These diseases cause hyperthyroidism or an increase in both the synthesis and secretion of thyroid hormones by the thyroid.Other causes of thyrotoxicosis include thyroiditis or iatrogenesis.These causes do not increase the synthesis of thyroid hormones, and the use of ATDs is therefore contraindicated.
The symptoms of thyrotoxicosis are due to an excess of beta-adrenergic activity, and include hyperactivity, nervousness, tremor, weight loss and sweating [3][4][5][6] .Relevant to anaesthesia, an excess of thyroid hormones can affect cardiovascular physiology as shown in Figure 1.Importantly, these cardiovascular effects predispose a patient to develop supraventricular arrhythmias.In patients with pre-existing cardiac disease, ischaemia or failure may be precipitated 7 .Thyroid storm is a life-threatening complication of uncontrolled and severe thyrotoxicosis that can be triggered by various insults such as surgery, anaesthesia, manipulation of the thyroid or sepsis.It carries a high mortality rate of 10%-30% 8,9 .Its incidence, however, is rare due to the widespread use of ATDs and beta-blockers [1][2][3][4][5][6]9 .
Patients presenting for surgery with thyrotoxicosis can be divided into those requiring emergent care unrelated to thyroid, or those that are thyroid-related.The indications for thyroid-related surgery are are not available in many countries 1 .Use of iodine should be restricted in the preoperative period for no longer than 10 days.This is because of an "escape phenomenon" where an excess of iodine incorporates into new thyroid hormones, leading to a secondary rise in thyroid hormones and worsening of the thyrotoxic state.This occurs after 10-14 days of therapy 15,21,22 .
Several clinical features of thyrotoxicosis are due to sympatheticmediated stimulation relating to increased beta-adrenoreceptor upregulation and sensitization to catecholamines 3,15,23 .Since the 1960s, propranolol has been the agent of choice to attenuate the heightened beta-adrenoreceptor-mediated effects of thyrotoxicosis 2,24,25 .Other beta-blockers have become available since then, including more beta-1 selective agents (metoprolol), longacting agents (atenolol) and very short-acting agents (esmolol).Each has their own advantages and disadvantages in managing a thyrotoxic patient.However, the main limitation with all beta-blockers is that they do not alter the underlying hypermetabolic state.Therefore, longterm sole beta-blocker therapy is not recommended 15,26 .
Rare side effects include agranulocytosis and hepatotoxicity 1,5,17 .Common side effects include fever, arthralgia, rash and urticaria 1,5,17 .Since ATDs have no effect on the release of preformed thyroid hormones, it takes several weeks of therapy to render a patient euthryoid 5,16,17 .This regimen, however, has been reported to result in a larger, more vascular and friable gland due to thyrotropin (TSH) stimulation of the thyroid in response to ATD-induced hypothyroidism 15,13 .This unwanted effect can be lessened by increasing the duration of treatment 13,18 or through the use of iodine 1 .
In supra-physiological doses, Lugol's iodine inhibits thyroid hormone synthesis via the Wolff-Chaikov effect, and the release of preformed hormones 3,15 .The anti-thyroid effects are seen within the first 24 hours and maximally at 10 days of therapy 15,19 .Iodine has also been reported to reduce vascularity and friability of the thyroid gland, thereby possibly lowering surgical bleeding risk 19,20 .Oral iodinated radiographic contrast agents such as ipodate and iopanoic acid can also be used.It has the additional beneficial effect of reducing peripheral conversion of T 4 to T 3 15 .Unfortunately, these agents summarized in Table 1 1,10 .There are currently three major forms of treatment: medical therapy (ATD), 131 I and surgery 1,11 .All are safe and equally as successful when comparing longterm quality of life 12 , but each with their own advantages and disadvantages.Choice of treatment must take into account numerous factors-patient age, sex, desire to have children, underlying comorbidities and the personal "philosophies" of both the patient and physician or surgeon 13 .

Current preoperative preparation of a thyrotoxic patient
Preoperative optimization of the thyrotoxic patient depends on its aetiology.Targets for action are pathways in thyroid hormone synthesis, secretion and its peripheral action 1,14,15 .The aim is to reduce the risk of perioperative thyroid storm.For thyrotoxic patients secondary to hyperthyroidism (not thyroiditis or iatrogenesis), elective surgery should be postponed for 3-6 weeks so that a euthyroid state can be achieved with an ATD and beta-blockers as indicated for symptomatic relief and cardioprotection 1,2,16 .With emergent surgery, there is insufficient time to allow ATDs to achieve euthyroid state.Therefore, a combination of beta-blockers, iodine and high-dose steroids is given to rapidly facilitate safe surgery.
Thionamides are a class of ATD that include propylthiouracil (PTU), carbimazole and its active metabolite methimazole 15 .They act by halting thyroid hormone synthesis by blocking organification of iodine and coupling of iodotyrosines.PTU additionally inhibits peripheral deiodination of thyroxine (T 4 ) to triiodotyrosine (T 3 ) 6,15 .Carbimazole or methimazole, however, are generally preferred as they have the benefit of once-a-day administration and reduced side effects compared to PTU 1 .The exception is during the first trimester of pregnancy where PTU is not considered to be teratogenic 1 .supervision is required, especially in the first 24 hours post-surgery.Also, instead of weaning beta-blockers immediately after surgery like one would do if a patient were conventionally prepared with ATDs, they should be continued for 5-7 days post-operatively to prevent hyperthyroid symptoms and avert the risk of thyroid storm.This is because the biological half-lives of the excess circulating T 3 is 1-2 days and T 4 is 3-4 days in hyperthyroidism 46 .

Rapid correction of thyrotoxic state
There have been several small retrospective case series which have reported the occurrence of thyroid crisis in patients undergoing surgery following sole preparation with propranolol 24,45,[47][48][49][50] .This is in contrast to the prospective studies shown in Table 2.The circumstances in which thyroid storm occurred were either the dosage of propranolol being too low (160 mg/day or less) or the response to beta-blocker therapy not iodine in the preoperative treatment and stabilization of the thyrotoxic patient.These results are summarized in Table 2 [31][32][33][34][35][36][37][38][39][40][41][42][43][44][45] .They show that this regime can safely provide rapid control of the peripheral manifestations of hyperthyroidism, producing a clinically euthyroid patient in a relatively short period of time.
Given that beta-blockers do not interfere with the release of thyroid hormone, the fear remains that a clinically euthyroid patient treated with beta-blockers only remains exposed to high levels of circulating thyroid hormone.This then increases the risk of perioperative thyroid storm.It has been reported that the incidence of post-operative hyperthyroid symptoms occurs in 5%-20% of patients prepared with beta-blocker therapy alone 13,[40][41][42][43][44] .Many of these cases may be attributed to the short half-life of propranolol and the need for regular administration.Therefore, close Finally, high doses of dexamethasone, hydrocortisone or betamethasone are used as adjunct therapy when a severely thyrotoxic patient needs to be rapidly prepared for surgery 27 .They inhibit secretion of thyroid hormone and peripheral conversion of T 4 to T 3 3,17,28 .

Safety of beta-blockers as sole therapy
The use of ATDs may not be possible in patients undergoing emergency surgery, non-compliant patients and patients that are refractory to ATDs 16,29,30 .In view of the established safety of conventionally prepared thyrotoxic patients for surgery, it is essential that any deviation from this is comparably safe and effective 31 .
During the 1970s to the mid-1990s, numerous studies were performed with results advocating the use of beta-blockers, in particular propranolol, alone or in combination with No intolerance or side effects to these medications were noted, and surgery was performed without complication.While the use of these long-acting beta-blockers is less studied than propranolol, existing evidence demonstrates their safety and efficacy in the preparation of the hyperthyroid patient for surgery.
Esmolol is a very short-acting cardioselective beta-blocker that is given as a continuous intravenous infusion 52 .It is used primarily in the intensive care setting to treat severe and uncontrolled thyrotoxicosis, and also to control haemodynamics intra-operatively 1 .Compared with other beta-blockers, this agent has a faster onset and offset of action and is much easier to titrate due to its short half-life.This is advantageous in controlling severe thyrotoxicosis or storm, which are dynamic clinical situations 1 .

Conclusion
In circumstances where the use of ATDs is not possible in the preoperative management of patient presenting for thyroid or non-thyroid surgery, the use of beta-blockers has been shown to be safe and effective.However, to increase safety, we recommend the use of iodine with or without corticosteroids up to the day of surgery in the rapid preoperative preparation of the severely thyrotoxic patient.This should not be continued for longer than 10 days.The choice of beta-blocker is clinician-dependent and should be titrated to ideally achieve a heart rate of <90 beats per minute and the absence of symptomatic thyrotoxicosis prior to proceeding to surgery.If this Clinical evidence for specific betablockers Propranolol is the most commonly used beta-blocker to treat thyrotoxicosis and has been the mainstay betablocker therapy to prepare thyrotoxic patients for surgery 21,22,[32][33][34][35][36][37][38][39][40]42,44,45 . An advanage of propranolol compared to other beta-blockers is that it blocks peripheral conversion of T 4 to T 3 at high doses.Intravenous propranolol can also be given in the event oral intake is limited post-operatively 39 .A disadvantage is its short half-life requiring high doses and frequent administration of up to four times daily to maintain therapeutic plasma levels.This can limit medication compliance and increases the risk of perioperative thyroid storm or hyperthyroid symptoms if doses are missed or inadequate doses are prescribed 10 .It also has a wide interindividual variation range 40 .Being a non-selective beta-blocker, it is contraindicated in patients with reversible obstructive airways disease 4 .
Difficulties surrounding the use of propranolol led to a number of studies of other beta-blockers, in particular, more cardioselective agents such as metoprolol 4 .In a doubleblind crossover trial by Murchison in 1979, 51 each patient received 4 weeks of treatment with propranolol and 4 weeks with metoprolol.All showed improvement in clinical symptoms and signs.These results suggest that metoprolol is as effective as propranolol.Furthermore, there is also a stronger association between plasma metoprolol levels and clinical efficacy than with propranolol.These findings are supported by Adlerberth 1987 43 and Vickers in 1990. 44Metoprolol also offers a simpler twice-daily dosing regimen and can be given intravenously when oral administration is limited.
Nadolol and atenolol, long-acting beta-blockers, have also been suggested as possible alternatives to propranolol 26,41 .Peden in 1982 41 reported the use of daily nadolol and being adequately assessed prior to the commencement of surgery.This is important as there is large individual variability in response to propranolol 40,41,51 .Therefore, targets of heart rates <90 beats per minute and absence of symptomatic thyrotoxicosis should be used as end points prior to proceeding to surgery.
A biochemically euthyroid state is generally considered mandatory prior to surgery because of the concern that surgical manipulation of the hyperactive tissue may precipitate the release of thyroid hormone into the circulation giving rise to a thyroid storm 44 .Hermann et al. in 1994 reported a study of 23 patients with severe hyperthyroidism (defined as free T 3 or T 4 levels at least 300% the maximum normal value) prepared with propranolol alone 44 .Hormone levels were measured perioperatively-including from the middle thyroid vein before and after surgical manipulation of the gland, and from the cubital vein after removal of the thyroid lobes.There were no episodes of thyroid storm, and levels of free T 4 and T 3 were not shown to change with the manipulation of the gland.These findings raise the possibility that biochemical euthyroidism may not be an absolute prerequisite for thyroidectomy.
Use of beta-blockers is also associated with reduced thyroid gland vascularity, allowing for safe mobilization and resection of the gland by the surgeon.This minimizes the risk of excessive blood loss and damage to nerves or parathyroid glands 18,[40][41][42][43] .On the contrary, studies by Lennquist in 1985 42 and Adlerberth in 1987 43 reported no difference in the consistency and vascularity of thyroids prepared with beta-blockers compared with those prepared with ATD.Importantly, they also documented no significant difference in post-operative complications of haemorrhage, hypocalcaemia or recurrent laryngeal nerve injury between the two groups.
Failure, adverse side effects or non-compliance of medical therapy Avoidance of exposure to radioactivity to 131 I (children or pregnant/breast-feeding women) Large goitre (>80 g) Children <5 year of age Moderate to severe or sight threatening Graves' ophthalmopathy Presence of symptoms or signs of compression within the neck Substernal or retrosternal extension of thyroid Potential for coexisting thyroid cancer Coexisting hyperparathyroidism Thyroid-stimulating hormone producing pituitary tumours Patient preference