Metabolism

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CHAPTER 5 Metabolism

Endocrinology

Diabetes

Prevalence is increasing throughout the world, partly related to increasing obesity. Better glycaemic control has been shown to improve morbidity and mortality. The World Health Organization defines diabetes as a random plasma glucose >11.1 mmol.L⁻¹ or fasting glucose >7.0 mmol.L⁻¹.

• Type 1: β-pancreatic cell destruction

• Type 2: defective insulin secretion and insulin resistance.

Pathophysiology

CVS. Results in micro- and macrovascular disease, accelerated atherosclerosis and cardiomyopathy. Autonomic neuropathy causes increased HR and BP during induction of anaesthesia. Increased need for inotropic support following CABG. Increased platelet aggregation.

Respiratory. Reduced FEV1 and FVC. Reduced sensitivity to hypoxia and hypercapnia. Increased risk of chest infections, decreased pulmonary diffusing capacity, central and peripheral obstructive sleep apnoea, aspiration pneumonia.

CNS. Neuropathy impairs neuromuscular transmission. Decreased response to tetanic stimulation.

Renal. Chronic failure is common, heralded by the onset of microalbuminuria. Progress of chronic renal failure can be limited with good diabetic control.

GI. Delayed gastric emptying and gastroparesis are secondary to autonomic neuropathy.

Other. Poor wound healing, increased risk of infection. Juvenile-onset diabetics may have reduced atlanto-occipital movement, making intubation difficult. Autonomic neuropathy impairs thermoregulation.

Drugs

Sulfonylureas, e.g. glibenclamide and tolbutamide, stimulate release of insulin by increasing β-cell sensitivity to glucose.

Biguanides, e.g. metformin, reduce basal glucose production.

Thiazolidinediones, e.g. pioglitazone, rosiglitazone, reduce peripheral insulin resistance, leading to a reduction of blood-glucose concentration and inhibit hepatic gluconeogenesis. Contraindicated in patients with ischaemic heart disease. NICE (May 2008) has recommended that, when glycaemic control is inadequate with existing treatment, a thiazolidinedione can be added to a sulphonylurea, and/or metformin.

Modifiers of glucose absorption, e.g. acarbose suppresses breakdown of complex carbohydrates in the gut.

Perioperative management

If possible, avoid drugs that may interfere with glycaemic control. Ketamine causes hyperglycaemia, β-blockers result in a slower recovery from hyperglycaemia and ganglion-blocking drugs reduce sympathetic-mediated gluconeogenesis. Sympathomimetics and diuretics antagonize insulin. β-blockers, clonidine, monoamine oxidase inhibitors (MAOIs) and salicylates potentiate insulin. Epidurals/spinals have minimal effect on glucose.

Check anion gap (= [Na⁺ + K⁺] − [HCO₃⁻ + CL−]) in ketoacidotic patients. Above 16 mEq/L is due to ketone bodies in ketoacidosis, lactic acid in lactic acidosis, increased organic acids from renal failure or a combination of these.

Avoid lactate-containing solutions, e.g. Hartmann’s.

Assess degree of stability by:

• frequency of hypoglycaemic attacks

• variations in insulin dosage

• glycosylated Hb <10%.

Control regimens

There are several different regimens. Omission of insulin avoids hypoglycaemia but risks severe hyperglycaemia and catabolism. Insulin infusion produces more stable blood glucose levels than bolus administration and is more physiological. Tight control of perioperative blood glucose may improve wound healing and reduce the risk of infection.

Alberti regimen (Alberti and Thomas 1979). Safe because glucose and insulin are provided together.

• 500 mL 10% glucose

• 10 mmol KCl

• 10 U soluble insulin (e.g. Actrapid)

• Give over 4 h with 2-hourly BM stix.

• <5 mmol, use 5 U/bag

• 5–10 mmol, as above

• >10 mmol, use 15 U/bag

• >20 mmol, use 20 U/bag.

Infusion regimen. Provides the tightest control of all regimens and is now becoming the method of choice for insulin-dependent diabetic patients. Separate infusions of glucose and insulin risk hypo/hyperglycaemia if one stopped without the other.

Guidelines for the Management of Diabetic Patients Undergoing Surgery

British National Formulary 59

Perioperative control of blood-glucose concentrations in patients with type 1 diabetes is achieved via an adjustable, continuous, intravenous infusion of insulin. Detailed local protocols should be available to all healthcare professionals involved in the treatment of these patients; in general, the following steps should be followed:

• Give an injection of the patient’s usual insulin on the night before the operation;

• Early on the day of the operation, start an intravenous infusion of glucose containing potassium chloride (provided that the patient is not hyperkalaemic) and infuse at a constant rate appropriate to the patient’s fluid requirements (usually 125 mL per hour); make up a solution of soluble insulin in sodium chloride 0.9% and infuse intravenously using a syringe pump piggy-backed to the intravenous infusion. Glucose and potassium infusions, and insulin infusions should be made up according to locally agreed protocols;

• The rate of the insulin infusion should be adjusted according to blood-glucose concentration (frequent monitoring necessary) in line with locally agreed protocols. Other factors affecting the rate of infusion include the patient’s volume depletion, cardiac function, and age.

Protocols should include specific instructions on how to manage resistant cases (such as patients who are in shock or severely ill or those receiving corticosteroids or sympathomimetics) and those with hypoglycaemia.

If a syringe pump is not available, soluble insulin should be added to the intravenous infusion of glucose and potassium chloride (provided the patient is not hyperkalaemic), and the infusion run at the rate appropriate to the patient’s fluid requirements (usually 125 mL per hour) with the insulin dose adjusted according to blood-glucose concentration in line with locally agreed protocols.

Insulinoma

Small β-islet cell tumours of the pancreas producing marked hypoglycaemia from insulin release. May be precipitated by food or starvation.

Diagnose by Whipple’s triad:

1. Plasma glucose <2.5 mmol.L⁻¹

2. Symptoms and signs of hypoglycaemia with fasting or exercise

3. Symptoms relieved by glucose.

Diazoxide may suppress insulin release. Discontinue preoperatively and initiate glucose infusion with BM stix every 15 min and every 5 min during tumour manipulation. Hyperglycaemic rebound may occur after tumour removal.

Suppressed islet cells take several days to recover, so monitor glucose for this period.

Cushing’s syndrome

Caused by excess cortisol from steroid therapy, adrenal hyperplasia, adrenal carcinoma or ectopic ACTH. Cushing’s disease is due to an ACTH-secreting pituitary tumour.

Symptoms and signs. Moon face, ‘buffalo hump’, thin skin, hirsutism, easy bruising, hypertension (85%), myocardial hypertrophy causing impaired LV function, diabetes (60%), osteoporosis (50%), pancreatitis (2%), muscle weakness, poor wound healing.

Perioperative problems. Careful positioning due to osteoporosis and fragile skin. Congestive cardiac failure, hyperglycaemia, hypertension.

Postoperative problems. Sleep apnoea (20%), steroids risk wound breakdown and infection.

Addison’s disease

Adrenocortical insufficiency due to autoimmune disease, TB, adrenal infiltration with amyloid, tumour, leukaemia, pituitary failure or surgical adrenalectomy.

Symptoms and signs. Tiredness, lethargy, weight loss, nausea, hyperpigmentation, muscle weakness, hypotension, hyponatraemia, hyperkalaemia and hypoglycaemia.

Perioperative problems. Hypotension, low intravascular volume and small heart causing heart failure with minor fluid overload. Hyperkalaemia (care with suxamethonium) and hypoglycaemia. Remember steroid replacement.

Acromegaly

This is characterized by excess growth hormone secretion resulting in soft tissue overgrowth.

Anatomical. Visual field defects, epiglottis and tongue overgrowth, recurrent laryngeal nerve palsy, headaches, rhinorrhoea, myocardial hypertrophy causing impaired LV function.

Endocrine. Causes diabetes and hypertension, osteoarthritis and osteoporosis, muscle weakness, peripheral neuropathy.

Surgery. Via transfrontal craniotomy or transethmoidal approach.

Perioperative: 25% have enlarged thyroid which may compress the trachea.

Postoperative. Addison’s disease, hypothalamic damage, CSF leak, diabetes insipidus, sleep apnoea.

Thyroid disease

Hyperthyroidism

Symptoms. Excitability, tremor, sweating, weight loss, palpitations, exophthalmos.

Signs. Tachycardia, atrial fibrillation (AF), heart failure, sweating, neuropathy, proximal myopathy and autoimmune diseases.

Diagnosis. Thyroid-stimulating hormone (TSH), free T₃/T₄, resin uptake, thoracic inlet X-ray/CT.

Hypothyroidism

Symptoms. Tiredness, lethargy, cold sensitivity, obesity, dry skin, constipation.

Signs. Anaemia, hypoglycaemia, bradycardia, pericardial effusion, hypothermia, polyneuropathy, hyponatraemia, impaired hepatic drug metabolism.

Diagnosis. TSH, free T₃/T₄, autoantibodies.

Anaesthetic management of thyroid disease

Aim for euthyroid patient, but risk of thyroid storm still remains in treated hyperthyroid patients. Antithyroid drugs (carbimazole, propylthiouracil) block T₃/T₄ synthesis but take 6 weeks to be effective. β-blockers are effective to control T₃/T₄-induced sympathetic stimulation, particularly thyroid storm. Check cord movement preoperatively. Assess tracheal compression and deviation by X-ray of thoracic inlet and CT scan. Thyroid hypertrophy may cause superior vena cava (SVC) obstruction and, if malignant, may invade surrounding structures. Exclude other autoimmune diseases.

Check that the patient can be manually ventilated before administration of a neuromuscular blocker. Enlarged tongue may make intubation difficult. Consider awake fibreoptic intubation. Use armoured tube. Avoid atropine if hyperthyroid. Isoflurane/sevoflurane cause least increase in T₄ of any volatile agent. CVS and respiratory depressant effects of drugs are magnified in hypothyroidism. Remifentanil provides good analgesia intraoperatively, contributes to the hypotensive anaesthetic required to provide a bloodless surgical field, and obtunds laryngeal reflexes to reduce the need for further doses of muscle relaxant.

Thyroid replacement therapy may precipitate myocardial ischaemia. Take care with fluid overload. There is a tendency to hypothermia with hypothyroidism. Provide eye care.

Extubate light, following direct inspection of the vocal cords. Damage to both nerves results in cords fixed in adduction. Postoperative airway obstruction may occur due to peritracheal haematoma or tracheal oedema. Thyroid resection risks postoperative hypoparathyroidism (causing hypocalcaemia) and hypothyroidism.

Hypoparathyroidism

Usually occurs following thyroidectomy. Symptoms include paraesthesia, muscle cramps, tetany, laryngeal stridor, CNS irritability and convulsions. Similar symptoms arise with metabolic/respiratory alkalosis.

Severe hypocalcaemia indicated by:

Trousseau’s sign. Tourniquet inflated above arterial pressure causes carpopedal spasm.

Chvostek’s sign. Percussion of the facial nerve produces facial muscle contraction.

Treat with 10–20 mL 10% calcium chloride.

Hyperparathyroidism

Symptoms and signs are due to hypercalcaemia: renal stones (50%), polyuria, bone pain (10%), osteoporosis and fractures; abdominal pain (5%), vomiting, pancreatitis and ulcers; psychoses. Hypercalcaemia worsens digitalis toxicity.

Intraoperative Nerve Monitoring During Thyroid Surgery

National Institute for Health and Clinical Excellence, March 2008

Guidance

The evidence on intraoperative nerve monitoring during thyroid surgery raises no major safety concerns. In terms of efficacy, some surgeons find intraoperative nerve monitoring helpful in performing more complex operations such as reoperative surgery and operations on large thyroid glands. Therefore, it may be used with normal arrangements for consent, audit and clinical governance.

Phaeochromocytoma

Pathology

Arises from chromaffin cells which secrete noradrenaline >> adrenaline. May be part of multiple endocrine neoplasia (MEN) syndrome. 10% are extra-adrenal.

Symptoms

Continuous or paroxysmal hypertension, headache, sweating, palpitations. Dilated and hypertrophic cardiomyopathies.

Noradrenaline causes systolic and diastolic hypertension with reflex bradycardia; adrenaline causes systolic hypertension, diastolic hypotension and tachycardia. Intraoperative cardiovascular instability is related to preoperative catecholamine levels.

Diagnosis

Liquid chromatography allowing direct measurement of urine adrenaline, noradrenaline and dopamine levels has generally replaced older methods, e.g. urine vanillyl mandelic acid (VMA).

Preoperative

• lower BP and prevent paroxysmal hypertensive crises

• increase intravascular volume

• decrease myocardial dysfunction.

Block catecholamine synthesis with α-methyltyrosine. Preoperative α- and then β-blockade, e.g. phenoxybenzamine (α₁ > α₂ blockade) followed by β-blocker if tachycardia persists. Consider ACE inhibitors and calcium-channel blockers.

Monitoring

Arterial line, CVP ± PCWP, glucose and temperature.

Induction and maintenance

Combined regional and GA advocated. Minimize sympathetic response to intubation. Suxamethonium causes abdominal muscle contraction, compressing tumour and releasing catecholamines. Induction with fentanyl, propofol and neuromuscular blockade. Maintenance with isoflurane in O₂/air/N₂O and fentanyl/alfentanil. Remifentanil also used successfully.

Avoid atropine, and histamine-releasing drugs. Droperidol causes hypertension. Draw up antihypertensive drugs for immediate administration, e.g. nitroprusside, phentolamine, labetalol.

Manipulation of the tumour causes catecholamine release with hypertension, tachycardia and pulmonary oedema. Ligation of the tumour reduces catecholamine release to cause severe hypotension, corrected with fluid loading ± noradrenaline infusion. Decrease in catecholamines also causes hypoglycaemia, so check plasma glucose frequently.

Postoperative

Of the patients, 50% remain hypertensive for several days postoperatively, as catecholamine levels do not return to normal for 7–10 days.

Carcinoid tumour

Pathology

Vasoactive amines are released from enterochromaffin cells of neural crest. Asymptomatic if the tumour lies proximal to liver portal flow where amines are deactivated. Secondaries in liver secrete amines (5HT, bradykinin, prostaglandins, histamine, substance P, neurotensin, neuropeptide K, pancreatic polypeptide), which escape into venous blood to cause hypertension (5HT), hypotension (bradykinin), flushing, wheezing, pulmonary stenosis, tricuspid regurgitation and diarrhoea.

Diagnosis

Measure urinary 5-hydroxyindoleacetic acid (5-HIAA). Chromogranin A is an important general tumour marker for all types of carcinoid tumors. Somatostatin receptor scintigraphy and positron emission tomography are used for staging and localization of the tumour.

Preoperative

Block amine production preoperatively with α-methyldopa. Preoperative octreotide also reduces amine secretion. Correct fluid and electrolyte balance. Give antibiotic prophylaxis for endocarditis if there is heart valve involvement.

Monitoring

Potential for wide swings in BP. Therefore, carry out invasive BP and CVP monitoring. Consider pulmonary artery pressure measurement if there are cardiac complications.

General anaesthesia

Avoid histamine-releasing drugs, which may cause cardiovascular instability and worsen wheeze. Benzodiazepine premedication and benzodiazepine + fentanyl induction provide good cardiovascular stability. Etomidate and propofol are also suitable.

Suxamethonium causes 5HT and histamine release. Vecuronium or if liver failure, atracurium, are the most suitable neuromuscular blocking drugs. Isoflurane produces good cardiovascular control and is rapidly eliminated postoperatively.

If regional techniques are used, avoid hypotension, which causes histamine release.

Use amine antagonists to control BP perioperatively:

• ketanserin or methysergide antagonize 5HT

• aprotinin antagonizes bradykinin production (but not now available – more effective to use preoperative octreotide and steroids)

• chlorphenamine antagonizes histamine

• give boluses of octreotide if patient is hypotensive during surgery.

Perioperative hyperglycaemia may occur. Use of catecholamines to treat perioperative cardiovascular collapse may precipitate peptide release and impair resuscitation efforts.

Postoperative

Hypotension may occur up to 3 days postoperatively and usually responds to octreotide. Good analgesia with continuous epidural infusion or fentanyl patient-controlled analgesia (PCA).

Perioperative Steroid Supplementation

Normal steroid response to surgery is dependent upon the magnitude and duration of the operation. Plasma cortisol increases rapidly, reaching a peak at 4–6 h and declining over a 48–72 h period. Major surgery is associated with as much as 100 mg endogenous cortisol release.

Therapy with glucocorticoids results in suppression of the hypothalamic–pituitary–adrenal (HPA) axis. Failure of cortisol secretion is due primarily to inhibition of synthesis of corticotrophin (ACTH). The HPA axis can be assessed preoperatively by the following:

1. Random cortisol

2. Short synacthen test – plasma cortisol is measured 0, 30 and 60 min after an injection of synthetic ACTH. Normal function results in cortisol levels >500 nmol/L

3. Insulin tolerance test – 0.1 U/kg insulin injected into fasting patient. Resulting hypoglycaemia (<2.2 mmol/L) causes release of ACTH from the pituitary. Normal function results in cortisol levels >500 nmol/L.

Anaesthetic implications

There is no evidence that aiming for cortisol levels higher than normal baseline values is of any benefit in patients with suppressed HPA function (i.e. those on steroid therapy). The current recommendations are summarized in Table 5.1.

Table 5.1 Recommendations for perioperative steroid supplementation

Preoperative		Additional steroid cover
Patients currently taking steroids
<10 mg/day	Assume normal HPA function	Additional steroid cover not required
>10 mg/day	Minor surgery	25 mg hydrocortisone on induction
	Moderate surgery	Usual preoperative steroids + 25 mg hydrocortisone on induction + 100 mg/day for 24 h
	Major surgery	Usual preoperative steroids + 25 mg hydrocortisone on induction + 100 mg/day for 48–72 h
Patients stopped taking steroids
<3 months		Treat as if on steroids
>3 months		No perioperative steroids necessary

Equivalent steroid doses

• Hydrocortisone 20 mg

• Prednisolone 5 mg

• Methylprednisolone 4 mg

• Betamethasone 0.75 mg

• Dexamethasone 0.75 mg.

Alberti K.G., Thomas D.J. The management of diabetes during surgery. Br J Anaesth. 1979;51:693-703.

Annane D., Bellissant E., Bollaert P.E., et al. Corticosteroids in the treatment of severe sepsis and septic shock in adults: a systematic review. JAMA. 2009;301:2362-2375.

Bacuzzi A., Dionigi G., Del Bosco A., et al. Anaesthesia for thyroid surgery: perioperative management. Int J Surg. 2008;6:S8.

British National Formulary 59. http://bnf.org.bnf/extra/current/450062.htm

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