428 C KIRWAN & B PHILIPS Diabetic ketoacidosis Diabetic ketoacidosis (DKA) is a medical emergency that is characterized by hyperglycaemia, ketosis and acidosis This disorder primarily occurs in people with type 1 diabe- tes but a lso occurs in patients with type 2 diabetes. Urine \200 \200 CXR ECG Dipstick for ketones Microscopy and culture \200 Pathogenesis Ketoacidosis is a state of uncontrolled catabolism associ- ated with insulin d e \201 ciency. The absence of insulin causes an increase in hepatic glucose production, le ading to hyper- glycaemia. It also accelerates hepatic fatty acid breakdown producing exces s ketone bodies, which leads to ketoacido- sis. Concurrent osmotic diuresis and vomiting en hance \202 uid and electrolyte depletion. Subsequent renal hypoper- fusion results in imp aired excretion of ketones and hydro- gen ions, and the cycle self-perpetuates. Immediate management Dehydration is more life threatening than the hyperglycae- mia, so its correction takes precedence. Fluid The average \202 uid loss is 3 \200\2236l in DKA. The optimal rate at which \202 uid should be replaced is dependent upon the clinical state of the patient. \200 \200 0.9% Saline should be used initially. Fluids should be infused quickly when patients are in shock. An average regime may be: \200 \200 \200 \200 \200 \200 Causes \200 \200 Previously undiagnosed diabetes Stress of a concurrent illness \200 Interruption of insul in therapy \200 1l in 30min 1l in 1h 1l in 2h 1l in 4h 1l in 6h KCl should be added to each bag of \202 u id whilst mon- itoring the serum potassium level (see the electrolyte section) Most commonly UTI or pneumonia 25% of hospital admissions due to DKA are because the patient omitted their insulin Drugs \200 \200 Alcohol or substance abuse Corticosteroids Thiazide diuretics Patients who do not have an extreme volume de \201 cit may be effectively re-hydrated at a rate of 500ml/h for the \201 rst 4h followed by 250ml/h for the next 4h. More rapid resu scitation may not be necessary and can delay correction of the acidosis. Switch to dextrose saline when the blood glucose falls below 12mmol/l. Clinical presentation The symptoms and signs of DKA are related to hyperos- molality, volum e depletion and metabolic acidosis. History \200 Typically a 2 \200\2233 day history of gradual deterioration, per- haps precipitated by inf ection NB: the \202 uid regimes set out above are a guideline for patients with DKA. Excessive \202 uid can precipitate cerebral oedema, and inadequate \202 uid can lead to renal fail ure. Fluid management needs to be tailored to each individual patient and monitored careful ly throughout treatment Symptoms \200 \200 \200 \200 Polyuria and polydipsia Weight loss Vomitting Abdominal pain \200 Those of a concurrent i nfection/precipitating cause. Electrolytes Potassium Renal and GI losses contribute to a marked potassium depletion. Desp ite this, the plasma potassium concentration is usually normal or, elevated at presentation (1/3 cases). This is due to initial hyperosmolality and insulin de \201 ciency, which res ults in potassium movement out of the cells. \200 Can mimic peritonitis Signs \200 Volume depletion and shock \200 Hypotension, tachycardia, cool peripheries, low JVP, dry mucous membranes, increased skin t urgor There is a danger of hypokalaemia as glucose enters cells with insulin treatment Aim for a plasma K+ of 4 \200\2235mmol/l If K+ 3 \200\2234 mmol/l, aim to replace 40mmol KCl/h If K+ 4 \200\2235.5 mmol/l, aim to replace 20mmol KCl/h Measure plasma K+ every 2h Withhold K+ if oliguric (rare) or if initial K+ is >5.5mmol/l (the K+ will fall quickly as glucose re-ent ers cells) Acidosis \200 \200 \200 \200 \200 Kussmaul respiration, \200\230fruity odor \200\231 (specific to ketoacidosis) Neurological \200 Lethargy, visual disturbance, altered level of con- sciousness, seizures, coma Investigations \200 Sodium Reversing hyperglycaemia with insulin will lower the plasma osmolality, cause water to move from the extra- cellular \202 uid into cells, and raise the plasma sodium con- ce ntration. Thus, a patient with a normal initial plasma sodium concentration may become hype rnatraemic during therapy with insulin and 0.9% saline. Blood \200 \200 \200 \200 FBC U&E, glucose, LFT, CRP, amylase, osmolality Culture ABG (including lactate) 429 CHAPTER 24.8 Diabetic ketoacidosis 0.45% Saline is not, however, routinely used in the man- agement of DKA Add broad-spectrum antibiotics if infection is suspected Insert a bladder catheter if no ur ine has passed after 2h Place a central venous line if the patient is in shock or elderly t o assist the \202 uid management. \200 Phosphate The plasma phosphate concentration may initially be nor- mal or elevated, but pho sphate depletion is rapidly unmasked following insulin therapy, frequently leading to hypop hosphataemia. \200 Ongoing management \200 For the \201 rst 8h (at least): \200 \200 Adjust K+ replace ment according to results Alter insulin infusion and \202 uid type when targets are reach ed (see immediate management section) Seek the underlying cause Most patients remain asymptomatic and phosphate administration is not indicated. Monitor glucose hourly Monitior electrolytes 2 hourly Insulin Insulin lowers the plasma glucose concentration (primarily by reducing hepatic gluc ose production rather than enhancing peripheral utilization), decreases ketone pro- duction (by reducing both lipolysis and glucagon secretion) and may augment ketone utilization. \200 Complications and pitfalls in DKA \200 Patients may present with combined DKA and HONK (hyperosmolar non-ketotic ) Initial potassi um concentrations may be high but decrease rapidly after the initiation of treatment DKA ma y complicate type 2 diabetes mellitus as well as type 1 diabetes. Ketoacidosis is seen in a number of inborn errors of metabolism (often presenting in infancy) and in alcoholic and f asting ketoacidosis. It is unusual for the blood glu- cose to be raised in these conditions . IV bolus \200 6 \200\22310U stat Continuous IV infusion \200 50U of soluble insulin made up to 50ml with 0.9% saline to run through an infusion pump. St art infusion at 6U (6ml) per hour (10U (10ml) per hour if infection is present). Aim to low er the plasma glucose by 3.5 \200\2237mmol/l/h. When the blood glucose is <12 mmol/l, swit ch to either an insulin sliding scale protocol or the patients standard insulin regime. A m inimum infusion of 2U per hour should be continued until the ketoacidosis is corrected. Thi s may require co- administration of 5% dextrose. \200 Prognosis The mortality rate in patients with DKA is <5% in experi- enced centers. NICE guidelines Both IM and SC insulin therapy are as effective as IV therapy, if the patient is not in sho ck. However, their use is not recommended by most Diabetologists. There is con- cern that t he combination of volume depletion and secondary sympathetic activation decreases subcutane ous blood \202 ow, resulting in reduced insulin absorption. As normal blood flow returns, absorption improves and initial persistent hyperglycaemia can turn into delayed hypoglycae mia. http://guidance.nice.org.uk/topic/endocrine Further reading Adrogue HJ, Barrero J, Eknoyan G. Salutary effects of modest \202 uid rep lacement in the treatment of adults with diabetic ketoacido- sis. Use in patients without e xtreme volume de \201 cit. JAMA 1989; 262: 2108 \200\22313. Fisher JN, Kitabchi AE. A randomized study of phosphate therapy in the treatment of diabeti c ketoacidosis. J Clin Endocrinol Metab 1983; 57: 177 \200\22380. Acid \200\223base balance Trials do not demonstrate any clinical bene \201 t from the rout ine administration of sodium bicarbonate. \200 \200 Fisher JN, Shahshahani MN, Kitabchi AE. Diabetic ketoacidosis: low- dose insulin therapy by various routes. N Engl J Med 1977; 297: 238 \200\22341. Bicarbonate is not indicated when treating DKA Bicarbonate can raise pCO2 (by decreasing ac idaemic respiratory drive), thus reducing cerebral pH Bicarbonate slows the rate of recover y of ketosis Bicarbonate can lead to a post-treatment metabolic alkalosis. Kumar P, Clark M. Clinical medicine. Bailliere Tindall, 1994 Page, MM, Alberti, KG, Greenwo od, R, et al. Treatment of diabetic coma with continuous low-dose insulin infusion. BMJ 197 4; 2: 687. \200 Viallon A, Zeni F, Lafond P, et al. Does bicarbonate therapy improve the management of seve re diabetic ketoacidosis? Crit Care Med 1999; 27: 2690 \200\2233. Additional measures \200 Pass an NG tube \200\224to prevent gastric dilation and aspira- tion (essential in patients with reduced level of con- sciousness) 430 C KIRWAN & B PHILIPS Hyperosmolar diabetic emergencies Cultures ABG (including lactate) \200 Urine \200 Hyperosmolar non-ketotic state (HNS) is a medical emer- gency, usually but not exclusively, in older patients with type 2 diabetes. They present with marked dehydration, a raised blo od glucose (>50mmol/l) and often coma Remember patients with type 2 diabetes can also prese nt with DKA, and DKA and HNS can co-exist. Dipstick (check for ketones which may be there in small quantities if patient has been fast ing) Microscopy and culture CXR Electrocardiogram \200 Pathogenesis Non-ketotic coma occurs in patients with relative insulin de \201 ciency and is usually precipitated by an acute illness (e.g. infection), MI or stroke. Increased secre tion of coun- ter-regulatory hormones (glucagon, catecholamines and cortisol) exacerbates i nsulin resistance and glucose pro- duction is unrestrained. The resulting rise in serum osm o- larity (often >350mOsm/kg (normal 285 \200\223295mOsmol/kg)) causes an osmotic diuresis, volume depletion and haemo- concentration, further increasing blood glucose concentra- tio ns. Importantly endogenous insulin levels are suf \201 cient to inhibit hepatic lipolysis and ketogenesis, hence the absence of ketoacidosis. This gradual nature of the devel- opmen t, over 7 \200\22310 days, causes profound dehydration throughout all volume compartments. Immediate management NB: although the management of HNS appears similar to that of DKA, the re are important differences. Patients must be managed in a HDU or ICU as they often presen t in a precarious state with a high potential to dete- riorate. Dehydration is more life th reatening than the hyperglycae- mia, but it needs to be corrected more slowly than in DKA. Fluid The average \202 uid loss is up to 8 \200\22310l in HNS. This is largely due to hyp erglycaemic-induced osmotic diuresis. Due to the nature of patients with HNS, consideration must be made of co-morbidities such as cardiac failure when pre- scribing the \202 uid r eplacement regime. \200 0.9% Saline should be used initially. \200 As a guide, a maximu m starting rate of 15 \200\22320ml/kg/h ( 1 \200\2231.5l in the average adult) may be appro priate, but is likely to need to be reduced after the \201 rst few hours. Potassium shoul d be added to the \202 uid, but there may be exceptions (see electrolyte section). Subseq uent choice for \202 uid replacement depends on the state of hydration, serum electrolyte levels and urinary output. Switch to 5% dextrose when the blood glucose falls below 12mmol /l. You should aim to clear the \202 uid de \201 cit over the \201 rst 48h. NB: the \202 uid regimes set out above are a guideline for patients with HNS. Excessive \202 uid can precipitate cerebral oedema, and inadequate \202 uid can result in renal failure. In patients with renal or cardiac compromise, monitoring of serum osmolality and frequent asse ssment of cardiac, renal and mental status must be performed during \202 uid resusci- tat ion to avoid iatrogenic \202 uid overload. Causes \200 \200 Previously undiagnosed diabetes Stress of a concurrent illness \200 Most commonly UTI or pneumonia, MI, CVA Consumption of glucose-rich \202 uids (e.g. Lucozade) Drugs \200 \200 \200 Corticosteroids Thiazide diuretics Clinical presentation The symptoms and signs of HNS are related to the degree of hyperosmol ality and volume depletion. As the plasma osmolality rises to >330mOsmol/kg, neurological s ymp- toms become more prominant History \200 7 \200\22310 day history of gradual deterioration. Symptoms \200 \200 \200 \200 \200 Polyuria and polydipsia Lethargy Confusion Vomiting Those of a concurrent infection/precipi tating cause. Electrolytes Potassium Renal and GI losses contribute to a marked potassium depletion. Desp ite this, the plasma potassium concentra- tion is usually normal or elevated at presentatio n (1/3 cases). This is due to initial hyperosmolality and insulin de \201 ciency, which re sults in potassium movement out of the cells. \200 Signs \200 Neurological \200 Volume depletion and shock \200 Lethargy, altered level of consciousness, CVA, coma Hypotension, tachycardia, cool peripheries, low JVP, dry mucous membranes, increased skin t urgor Vascular \200\224MI, limb ischaemia (as a consequence of hyperosmolar state) There is a danger of hypokalaemia as glucose enters cells with insulin treatment Aim for a plasma K+ of 4 \200\2235mmol/l If K+ 3 \200\2234 mmol/l aim to replace 40mmol KCl per hour If K+ 4 \200\2235.5mmol/l aim to replace 20mmol KCl per hour Measure plasma K+ every 2h Wit hhold K+ if oliguric or if initial K+ is >5.5mmol/l (the K+ will fall quickly as glucose re enters cells) \200 \200 \200 \200 Investigations \200 Blood \200 \200 FBC U&E, glucose, LFTs, CRP, amylase, osmolality 431 CHAPTER 24.9 Hyperosmolar diabetic emergencies Ongoing management \200 For the \201 rst 8h at least: \200 \200 Adjust K+ replaceme nt according to results Alter insulin infusion and \202 uid type when targets are reached (see Immediate management section) Seek the underlying cause Sodium Reversing hyperglycaemia with insulin will lower the plasma osmolality, cause water to move from the extracellular \202 uid into cells, and raise the plasma sodium concentra tion. Thus, a patient with low or normal initial plasma sodium concentration may become hyp ernatraemic during therapy with insulin and 0.9% saline. \200 Monitor glucose hourly Monitior electrolytes 2 hourly \200 0.45% Saline is contraindicated. A rapid decrease in sodium concentration may precipitate s evere cerebral oedema. Pitfalls of HNS \200 Insulin It is often reported that patients with HNS may be particu- larly sensitive to insu lin and require lower doses than patients with DKA, though studies have not proven this. Th e rapid decrease in blood glucose that may be seen in HNS is more likely to be related to c orrection of the severe hypovolaemia with \202 uid repletion. However, in order to preven t rapid changes in plasma osmolality, a more cautious approach to insulin administration in the \201 rst 2h is recommended, and stat dose at treatment induc- tion should not be giv en. Cerebral oedema is a complication of therapy that typi- cally occurs within 24h after treat ment has been initi- ated. Headache is the \201 rst clinical sign, but marked neurologica l dysfunction can develop. The condition is precipitated by rapid changes in serum osmolali ty and carries a high mortality and morbidity, Patients often have a concurrent lactic acid osis, Prognosis The mortality of patients with HNS is 30 \200\22335% and increases with age, medi cal co-morbidity, severity of metabolic derangement and degree of impairment of consciousne ss . Unlike DKA, HNS is not an absolute indication for subse- quent insulin therapy, and su rvivors may do well on oral agents with good diet control. Further reading Adrogue HJ, Barr ero J, Eknoyan G. Salutary effects of modest \202 uid replacement in the treatment of adu lts with diabetic ketoacido- sis. Use in patients without extreme volume de \201 cit. JAMA 1989; 20; 262: 2108 \200\22313. Continuous IV infusion \200 50U of soluble insulin made up to 50ml with 0.9% saline to run through an infusion pump. St art infusion at 3U (3ml) per hour. Do not give initial bolus dose If, after 2h, the blood g lucose is not falling fast enough, increase the infusion to 6U (6 ml) per hour. Aim to lowe r the plasma glucose by 3.5 \200\2237mmol/l/h. When the blood glucose is <12mmol/l, switch to either an insulin sliding scale protocol or the patients standard hypoglycaemic regimen. \200 \200 \200 Kitabchi AE, Umpierrez GE, Murphy MB. Hyperglycemic crises in patients with diabetes mellit us. Diabetes Care 2003; 26 Suppl 1: S109. Kumar P, Clark M. Clinical medicine. Bailliere Tindall 1994 Malone ML, Gennis V, Goodwin JS . Characteristics of diabetic ketoacidosis in older versus younger adults. J Am Geriatr Soc 1992; 40: 1100 \200\2234. Additional measures \200 NG tube \200\224to prevent gastric dilation and aspiration (essential in patients with redu ced level of conscious- ness) Broad-spectrum antibiotics if infection is suspected Insert a bladder catheter Place a central venous line if the patient is in shock or elderly to assi st the \202 uid management. Newton CA, Raskin P. Diabetic ketoacidosis in type 1 and type 2 diabetes mellitus: clinical and biochemical differences. Arch Intern Med 2004;164: 1925 \200\22331. \200 \200 Page MM, Alberti KG, Greenwood R, et al. Treatment of diabetic coma with continuous low-dos e insulin infusion. BMJ 1974; 2: 687. Rosenthal NR, Barrett EJ. An assessment of insulin action in hyper- osmolar hyperglycemic n onketotic diabetic patients. Clin Endocrinol Metab 1985; 60: 607 \200\22310. Anticoagulation HNS results in a hypercoagulable state, increasing the risk of thromboembol ism \200 UFH or LMWH should be used formally to anticoagu- late patients with HNS. 432 B PHILIPS & S GORDON Thyroid emergencies: thyroid crisis/thyrotoxic storm A rare life-threatening disorder associated with hyperthy- roidism. Mortality may be as hig h as 30% with treatment. Characteristic features include: hyperpyrexia, severe tachy- cardi a, extreme restlessness and dehydration. LFTs \200 elevated transaminases, alkaline phosphatase and bilirubin Thyroid function tests \200 \200 suppressed thyroid-stimulating hormone (TSH) elevated T4 and T3 (concentrations do not corr elate well with severity of condition) Pathogenesis Most commonly occurs in patients with undiagnosed or poorly controlled hyperth yroidism (usually Graves \200\231 dis- ease) in association with a recognized precipitant. The exact pathogenesis is unknown but serum free thyroxine (T4) or triiodothyronine (T3) co ncentrations are increased. \200 Blood cultures ABG \200 Urine for microscopy and culture CXR \200 ECG \200 respiratory and metabolic acidosis \200 Causes \200 \200 \200 \200 \200 pulmonary oedema, cardiomegaly Graves \200\231 disease Toxic multi-nodular goiter Thyroid adenoma Trauma Excessive exogeno us thyroid hormones arrhythmias, LV hypertrophy Immediate management This is a medical emergency. Patients require immediate and aggressive supportive management in a critical care setting and early alleviation of the thyrotoxicos is. A thyrotoxic storm is usually precipitated by a trigger such as a severe infection, surgery , DKA, pulmonary throm- boembolism or parturition. Less common precipitants include, radioi odine therapy (Jod Basedow phenomenon), radiocontrast dyes, salicylates, haloperidol and am iodarone administration. Clinical presentation Four major features \200 Fever >38.5 C \200 Sinus or supraventricular tachycardia \200 Agitation, restlessness, emotional labil ity, confusion, psy- chosis, seizures and coma Diarrhea, vomiting, abdominal pain, jaundice . Supportive therapy \200 Oxygen: high \202 ow humidi \201 ed oxygen via mask and res- ervoir bag. Oxygen requirem ents will be markedly increased and the majority of patients will require intu- bation and ventilatory support to manage the severe respiratory and metabolic acidosis. Fluids: crysta lloid resuscitation to replace losses associ- ated with fever and underlying precipitants P otassium and magnesium frequently require replace- ment. Glucocorticosteroids. Thyrotoxicos is is associated with an increased requirement for and relative de \201 ciency of corticos teroids. In addition, corticosteroids decrease the peripheral conversion of T4 to T3. Doses : hydrocortisone, IV 100mg every 6h or dexamethasone 2mg every 6h Active cooling. Temperatu res can exceed 41 C, Cooling blankets and cold \202 uids are required. Occasionally patients present with profound exhaustion, tachycardia, hypore \202 exia, sev ere myopathy, marked weight loss and hypotension. This rare variant is termed apathetic hyp erthyroidism. Symptoms and signs The diagnosis of thyroid crisis is clinical. Treatment must start before biochemical con \201 rmation of the condition is obtained, and mortality is high (10 \200 \22330%) \200 \200 \200 Antithyroid drugs Management of the thyrotoxicosis should be initiated with the resuscitati on. A number of drug options are available. None is ideal in isolation. \200 Goiter (thyroid gland \201 ndings can vary) Fever >38.5 C. Skin maybe moist and warm Car diovascular: sinus tachycardia, AF, ventricular arrhyth- mias, systolic hypertension with a widened pulse pres- sure. Cardiomegaly and LV hypertrophy may be present Neurological: sym ptoms range from tremor and increas- ing restlessness to delirium, seizures, coma and death . Profound muscle weakness and rhabdomyolysis may occur GI: nausea and vomiting are common. Severe abdominal pain may indicate underlying GI precipitant. Jaundice is occasionally pre sent. B-Adrenoceptor antagonist are critical in the manage- ment of thyroid storm. Non-selective agents antagonize the peripheral effect of thyroid hormones, decrease con- version of T4 to T3, albeit slowly, and reduce catecho- lamine hypersensitivity, B1-selective agents are le ss effective peripherally. Higher doses than normal may be required because of increased cl earance. \200 Propranolol: IV dose 0.5mg increments up to 10mg, PO dose 60 \200\22380mg 4 hourly. Metopro lol: 2 \200\2235mg increments, up to 20mg IV or 100 \200\223200mg PO every 6h Esmolol: bolu s of 250 \200\223500mcg/kg followed by 50 \200\223 200mcg/kg/min infusion Investigations \200 FBC \200 Electrolytes \200 Glucose \200 Carbimazole: blocks the synthesis of thyroid hormone, 60 \200\223120mg orally, via NG tube or per rectum. Takes 1h to start working. Can cause neutropenia at 1 month. Propylthiourac il: blocks the synthesis of thyroxine and the conversion of T4 to T3. 200mg every 4h orally , via NG tube or per rectum. leucocytosis hypokalaemia, hypomagnesaemia, hypercalcaemia hyperglycaemia 433 CHAPTER 24.10 Thyroid emergencies: thyroid crisis/thyrotoxic storm Pitfalls of thyrotoxic crisis \200 Potassium iodide: blocks the synthesis and release of the thyroid hormones. Lugol \200\231s solution contains 130mg/ ml. Dose 0.3ml diluted to 50ml every 8h via NG or per rectum. \200 Mortality is increased with failure to recognize the syn- drome early. Differential diagnos is includes malignant hyperpyrexia syndromes (including illicit drug reactions) and severe sepsis. Supportive measures are common to all diagnoses. Avoid administering iodine-contain ing medications prior to initial doses of a thionamide. Avoid administration of medications with the potential to exacerbate the thyrotoxicosis (listed above). Patients may not have displayed all the signs of thyro- toxicosis prior to the thyroid storm being triggered. Iodine-containing compounds should only be given at least 1h after the administration of a thionamide. Prior administration of iodine-containing compounds may exacerbate thyrotoxicos is. Thionamides; pro- pylthiouracil, methimazole inhibit iodine uptake and utilization. Lithium carbonate is a similar alternative for patients allergic to iodine. Lithium blood c oncentrations should be monitored. Prognosis Thyrotoxic crisis is rare, and delay in its recognition exac- erbates the mortali ty. Once the crisis is under control, the patient \200\231s outcome depends on co-morbiditi es associated with the storm and de \201 nitive treatment of the underlying thyroid diseas e. Further reading Duggal J, Singh S, Kuchinic P, et al. Utility of esmolol in thyroid cris is. Additional measures \200 \200 \200 NG tube for the administration of oral medications Broad-spectrum antibiotics if infection is suspected. Invasive monitoring, central venous line, arterial blood pressure and cardiac output monitoring to guide \202 uid and management with inotropes and vasopressors. Digo xin. May be useful for rate control of atrial \201 brilla- tion in addition to B-blockade . Amiodarone. May be useful for the control of atrial \201 brilla- tion but should not be used prior to starting a thionamide because of potential aggravation of the thyroid crisis . Vitamin B complex. Vitamin B1 (thiamine) requirements are increased in thyrotoxicosis, an d de \201 ciency may be associated with peripheral neuropathies and Werncke \200\231s ence phalopathy. Vitamin B12 (cobalamin) de \201 ency may be associated with thyrotoxicosis. Da ntrolene. Has been used to control the hyperpyrexia syndrome. Reserpine and guanethidine ma y be useful in thyroid crises resistant to propranolol. Plasmapheresis has been used succes sfully to remove excess thyroid hormones in resistant thyrotoxicosis. Can J Clin Pharmacol 2006; 13: 292 \200\2235. Geffner DL, Hershman JM. Beta-adrenergic blockade for the treat- ment of hyperthyroidism Am J Med 1992; 93: 61 \200\2238. Nayak B, Burman K. Thyrotoxicosis and thyroid storm. Endocrinol Metab Clin North Am 2006; 35: 663 \200\22386. Parmar MS, Thyrotoxic atrial \201 brillation. Med Gen Med 2005; 7: 74. Tajiri J, Katsuya H, Kiyokawa T, et al. Successful treatment of thyrotoxic crisis with plasma exchange. Crit Care Med 1984; 12: 536 \200\2237. Tietgens ST, Leinung MC. Thyroid storm. Med Clin North Am 1995; 79: 169 \200\22384. Tsatsoulis A, Johnson EO, Kalogera CH, et al. The effect of thyro- toxicosis on adrenocarti cal reserve. Eur J Endocrinol 2000; 142: 231 \200\2235. Avoid Drugs known to increase free T3 and T4 concentrations, notably: NSAIDs, heparin, furo semide, phenytoin, carbe- mazepine, benzodiazepines. 434 B PHILIPS Thyroid emergencies: myxoedema coma Myxoedema coma is the extreme decompensated form of hypothyroidism associated with one or m ore organ system dysfunction. This may include but does not demand dete- rioration in menta l status. Many patients have neither non- pitting oedema nor coma. It is rare, but can have a very high mortality rate of 50 \200\22360% if recognized late. It presents at any age an d in either sex, but is most common in winter in elderly women. Signs \200 Neurological: Llethargy, altered level of consciousness, focal neurology, seizures, coma Ca rdiovascular: bradycardia, hypotension, cool periph- eries, shock Respiratory: decreased re spiratory rate, macroglossia, nasopharyngeal and laryngeal oedema GI: distended abdomen, ab sent bowel sounds, paralytic ileus, megacolon, dysphagia, aspiration Renal: urinary retenti on (bladder atony), oliguria Infection: signs of infection may be absent or masked because of hypothyroidism, but infection should always be suspected Pathogenesis Although a number of patients will have a history of thy- roid disease, radioi odine therapy or surgical thyroidectomy causing primary thyroid failure, many will have idi opathic primary hypothyroidism. Serum T3 and T4 are suppressed and TSH increased. The magni tude of changes does not correlate well with clinical presentation and can be very dif \201 cult to interpret in critical illness. More rarely (5%) patients will have hypothalami c or pituitary disease causing secondary thyroid failure \200 Investigations \200 Thyroid tunction tests. All patients with myxoedema coma have low free T4 and T3 blood conc entrations Primary hypothyroidism: low T4 and T3, high TSH \200 Secondary (pituitary dysf unction): low T4 and T3, low/ \200 low-normal TSH Sick euthyroid: low or normal TSH, very low free T3, low or normal free T4, increased inactive rT3 Precipitating factors \200 \200 \200 \200 \200 \200 \200 \200 Previously undiagnosed hypothyroidism Extreme cold weather Sepsis (pneumonia, UTIs) Trauma Cardiac or cerebrovascular events Drugs with antithyroid actions (e.g. amiodarone) CNS depr essant drugs (including anesthesia). Iatrogenic (i.e. failure to reinstate thyroid hormone replacement during hospitalization) \200 \200 Hypoglycaemia FBC: normocytic anemia and leucopenia Clinical chemistry: hyponatraemia, hypo phosphataemia, increased LDH and CK, hypercholesterolaemia Blood cultures ABG: hypoxaemia, hypercapnia and lactic acidosis. Urine microscopy and culture Urine sodium and osmolality: Na+ is normal or increased, urine osmolality is increased relative to plasma osmolality \200 \200 \200 The diagnosis of hypothyroidism in critically ill patients is fraught with dif \201 culty. Severe sepsis and a number of drugs (e.g. phenytoin, dopamine, corticosteroids and furosem - ide) interfere with thyroid hormone concentrations and assays CXE: cardiomegaly and pleural effusions ECG: slow rate, low voltage, prolonged QT and T wav e inversion/ \202 attening, conduction blockade. Clinical presentation The clinical presentation of myxoedema coma is often non-speci \201 c, making the diagnosis dif \201 cult, and a high index of suspicion is required. Three ma jor features: \200 Immediate management NB: this is a medical emergency requiring admission to intensive care for complex multi-organ support. Ventilatory support \200 \200 Oxygen Intubation and ventilation. Indications include: hypoven- tilation, hypoxia, respira tory and metabolic acidosis, air- way obstruction (macroglossia and laryngeal oedema), redu ced consciousness and precipitating respiratory infections. Altered mental state: may range from apathy, neglect, decreased intellectual function to co nfusion, delirium or coma Hypothermia Clinical features of hypothyroidism. \200 History There may be a history of prior thyroid disease, long-term thyroxine replacement th erapy, previous thyroid surgery or radioiodine therapy. NB: some patients may require ventilatory support for a prolonged period (several weeks) Cardiovascular resuscitation Hypotension and low cardiac output states are common. \200 Symptoms \200 \200 \200 \200 \200 \200 \200 \200 Intravascular volume is decreased by 10 \200\22320% despite an overall increase in total bo dy \202 uid and sodium. Fluid resuscitation should be guided by central venous and cardia c output monitoring. The \202 oatation of a pul- monary artery catheter may be warranted in cases com- plicated by cardiac disease Fluids should be warmed. Vasopressors and inotrop es are required to maintain perfusion pressures and cardiac output. Resistance to B-adrener gic agents is common. Hypothermia <35.5 C (may be profound, <30 C) Lethargy Cognitive dysfunction Confusion/dep ression/psychosis Those of a concurrent infection/precipitating cause. Anorexia/nausea Abdo minal pain Urinary retention \200 435 CHAPTER 24.11 Thyroid emergencies: myxoedema coma T4: initial oral dose 250mcg, followed by 100mcg 24h later and 50mcg daily thereafter Adjus t dosages according to clinical and laboratory \201 nd- ings. Adrenal function is impaired. Give hydrocortisone 100mg IV early, at the initiation of ther apy, followed by 50 \200\223100mg every 8h or 10mg/h hour continuous IV infusion. NB: cardiovascular resuscitation can be complex because of the severity of both the metabol ic derangement and concomitant cardiac disease. Give corticosteroids. NB: higher doses of hormones cannot be justi \201 ed by the current literature. Although m ore rapid correction may be tolerated by young patients, the risk of adverse cardiovas- cul ar events is signi \201 cant in the elderly, and mortality is increased. Warming Hypothermia is common and may be profound. A low tem- perature thermometer is requi red for accurate recordings. Patients require warm \202 uids, warm inspired gasses and ex ternal warming, e.g. warming blanket to achieve a tem- perature >34 C. Normothermia may no t be achieved until thyroid hormones are restored. NB: active warming will cause peripheral vascular dilata- tion and hypotension requiring increased \202 uid and vaso- pressor adm inistration. Additional measures \200 NG tube \200\224to prevent gastric dilation and aspiration (essential in patients with redu ced level of conscious- ness) Broad-spectrum antibiotics if infection is suspected Insert a bladder catheter \200 Pitfalls of myxoedema \200 \200 \200 \200 Electrolytes Sodium (Na+) Hyponatraemia is common, caused by a failure to excrete excess wa ter and may be severe (<120mmol/l). Correction should not exceed 12mmol/L/24h. \200 Adrenal insuf \201 ciency is a frequent association Hypoglycaemia must not be missed Warmi ng may precipitate hypotension High dose thyroid hormone replacement may be com- plicated b y serious cardiac events Patients do not absorb oral medications 0.9% Saline is adequate replacement; hypertonic saline is not indicated. Once \202 uid re suscitation is complete, water restriction is usually suf \201 cient to correct Na+ Prognosis Myxoedema coma is the rare extreme of a common condi- tion. Diagnosis is often di f \201 cult, and a high index of suspi- cion is required. However, with best care, mortali ty can be decreased from 60% \200\22325%. Glucose Hypoglycaemia can be severe, and requires early recogni- tion and treatment. \200 25g IV glucose followed by an infusion (20 \200\22350% glucose) via central venous access, titrated to maintain normogly- caemia. Further reading De Groot LJ, Dangerous dogmas in medicine: the nonthyroidal ill- ness syndrome. J Clin Endocrinol Metab 1999; 84: 151 \200\22364. Thyroid hormones Patients undoubtedly require thyroid hormone replace- ment to recover, but the optimum regimen remains con- troversial. Replacement is best achieved gradually; rapid replacement has been associated with sudden death from cardiac complications. In uncomplic ated hypothyroidism, the agent of choice is oral T4. In critically ill patients, oral T4 ma y be inadequately absorbed and the peripheral conver- sion of T4 to T3 is markedly decrease d. IV T4 is not available in the UK. T3 provides a more rapid correction of thyroid hormone function. Gradual replacement is recommended, and the following is a suggested regimen. \200 Jordan RM, Myxedema coma. Pathophysiology, therapy, and factors affecting prognosis. Med Clin North Am 1995; 79: 185 \200\22394. Kwaku MP, Burman KD, Myxedema coma, J Intensive Care Med 2007; 22: 224 \200\22332. Peeters RP, Wouters PJ, Kaptein E, et al. Reduced activation and increased inactivation of thyroid hormone in tissues of critically ill patients. J Clin Endocrinol Metab 2003; 88: 32 02 \200\22311. Rodr guez I, Fluiters E, P rez-M ndez LF, et al. Factors associated with mortality of pa tients with myxoedema coma: propective study in 11 cases treated in a single institution. J Endocrinol 2004; 180: 347-350. Wartofsy L. Myxedema coma. Endocrinol Metab Clin North Am 2006; 35; 687 \200\22398. T3: initial IV dose 10 \200\22320mcg followed by 10mcg every 8 \200\22312h or a continuous IV infusion 20mcg/day, until the patient is established on an oral T4 regimen. 436 J LIGHTFOOT & H REECE-SMITH Hypoadrenal crisis Hypoadrenal crisis is a life-threatening condition that is dif- \201 cult to diagnose, bu t easy to treat. The critically ill popula- tion are at higher risk, and therefore a high i ndex of suspicion is appropriate. Others Irradiation of the adrenals. Iron deposits of haemochroma- tosis. Secondary/tertiary Acute failure of the pituitary or hypothalamus is rare. Causes include: neoplasms, hemorrhage, infarction, radia- tion damage and granulomatous in \201 ltration. Prolonged administration of glucocorticoids leads to HPA axis suppression. These patients a re therefore at risk of developing a crisis if there is inadequate replacement and/ or othe r causes of hypoadrenalism. Typically suppression occurs in regimes of >7.5mg prednisolone (or equivalent) daily for >2 weeks. Causes A crisis can be precipitated de novo by acute failure of the hypothalamus, pituitary or adrenal glands, or as a result of smaller change in function of any part of the hypotha lamo- pituitary \200\223adrenal (HPA) axis on a background of chronic insuf \201 ciency. T he causes are divided up on the basis of the organ they affect into: primary (adrenal), sec ondary (pitui- tary) and tertiary (hypothalamus). Primary (Addison \200\231s disease) Autoimmune adrenalitis 70 \200\22390% of cases are caus ed by autoimmune conditions. Polyglandular autoimmune syndrome I and II each include autoim mune adrenalitis (predominantly female). Autoimmune adrenalitis as an isolated autoimmune a dre- nal insuf \201 ciency is more common in males. Clinical approach Hypoadrenal crisis usually presents with shock. The shock is usually high output and dependent on vasopressors. It is often initially misdiagnosed as septic shock. The clinical approach should be tailored to identify likely causes and to gather clues of p receding adrenal insuf \201 - ciency as these will guide treatment after the initial crisi s has been dealed with. Infectious causes As described by Thomas Addison, most cases were caused by TB with bilater al adrenal in \201 ltration and destruction. Now this accounts for 7 \200\22320%. Active T B seeds to the adrenals via haematogenous spread. Disseminated fungal disease from histopla smosis or paracoccidioidomycosis is a signi \201 cant cause of adrenal failure in high ris k areas. Patients who have developed AIDS are at risk of developing necro- tizing adrenalit its secondary to CMV infection and in \201 ltra- tion by Mycobacterium avium-intracellular e, cryptococci or Kaposi \200\231s sarcoma. History \200\224key points Potential causes \200 \200 Severe stress: sepsis, burns, trauma, surgery Other autoimmune conditions, such as hypothyr oidism or gonadal failure Foreign travel/potential contact with infectious diseases Steroid use: length of treatment/cessation/reduction Anticoagulation Drugs which interfere with st eroid metabolism or syn- thesis (ketoconazole, etomidate, metayapone, phenytoin and suramin ) Inherited clotting disorders Previous history of cancer Pregnancy Sudden onset \202 ank or epigastric pain (suggestive of adrenal haemmorhage) \200 \200 \200 Metastatic cancer Metastatic in \202 itration of the adrenal glands is common, and 40 \200 \22360% of patients with disseminated lung or breast can- cer have adrenal deposits. Clinic al manifestations are rare as most of the adrenal cortex must be destroyed before symptoms occur. \200 \200 \200 Adrenal hemorrhage/infarction Risk factors: \200 Stress states, especially sepsis. Hemorrhage is classically associated with meningococcal s epticaemia (Waterhouse \200\223Friderichsen syndrome). Similar \201 ndings from Streptoco ccus pneumoniae, Neisseria gonorrhoeae, Escherichia coli, Haemophilus influenzae and Staphy lococcus aureus have also been reported. Anticoagulation use, especially heparin. Thromobo- cytopaenic patients in their middle/old age are at high risk Hypercoaguable states, especi ally antiphospholipid syn- drome.