Ebook Oh''s intensive care manual (7/E): Part 2

(BQ) Part 2 book Oh''s intensive care manual has contents: Endocrine disorders, endocrine disorders, infections and immune disorders, severe and multiple trauma, environmental injuries, pharmacologic considerations, metabolic homeostasis,.... and other contents.

61 Adrenocortical Insufficiency in Critical Illness 660

62 Acute Calcium Disorders 666

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Diabetic emergencies

Richard Keays

Diabetes mellitus is due to an absolute or relative

defi-ciency of insulin The sustained effect of poor glycaemic

control results in a wide array of end-organ damage as

a consequence of small- and large-vessel pathology

Mortality and morbidity are related to the progress of

this damage but often there are acute metabolic

deterio-rations that can be life-threatening Diabetic

ketoacido-sis (DKA) and hyperosmolar hyperglycaemic state

(HHS) are two of the most common acute complications

of diabetes, both accompanied by hyperglycaemia The

pathophysiological changes that occur in both disease

states represent an extreme example of the super-fasted

state Coma may also result from severe hypoglycaemia

due to overtreatment – usually with insulin

DIABETES MELLITUS

Type I insulin-dependent diabetes mellitus (IDDM) has

a peak incidence in the young rising from 9 months to

14 years and declining thereafter In 25% of patients the

presentation is with ketoacidosis, especially in those

under 5 years of age Usually the fasting plasma glucose

is >7.8 mmol/L and glucose and ketones may be present

in the urine In the asymptomatic patient with an

equiv-ocal fasting plasma glucose, an impaired glucose

toler-ance test may be demonstrated

Type II non-insulin-dependent diabetes mellitus

(NIDDM) is prevalent in the elderly but can occur at

any age Truncal obesity is a risk factor and there is

ethnic variation in susceptibility Diagnosis is often

delayed and may be incidental from blood or urine

sugar screening.1 Increasingly it is recognised that

individuals can be in a prediabetic state of impaired

glucose regulation for many years, which makes them

5 to 15 times more likely to progress to diabetes It may

present with classical symptoms, as a diabetic

emer-gency, with complications of organ damage or

vascu-lar disease

EPIDEMIOLOGY

The worldwide prevalence of diabetes is estimated to

be 366 million people in 2011 Diabetes mellitus affects

about 6% of the world’s population and is set to rise to

552 million sufferers by 2030.2 Most of these (97%) will

have type II diabetes but the resources required to treat

the complications of type I diabetes are such that health care costs are equivalent between the two groups The annual incidence of DKA is around 14 episodes per thousand patients with diabetes and it has been esti-mated in the USA that about $1 billion are spent each year in treating DKA Hospital admissions for DKA have gone up by 30% in the last decade and this is most likely due to the increase in ketosis-prone type II diabetics HHS represents approximately 1% of primary admissions to hospital with diabetes as compared with DKA The mortality rate in HHS remains high at 5–20%, whereas the mortality in DKA has been falling dramati-cally in recent years and is less than 1% but still remains high in the elderly.3 An interplay of both genetic and environmental factors contribute to disease develop-ment In type I diabetes there is some evidence for genetic susceptibility but environmental factors play a greater part It varies across race and regions, being highest in northern Europe and the USA and lowest in Asia and Australasia Genetic factors in type 2 diabetes are evidently crucial, with a concordance between monozygotic twins approaching 100%

PATHOGENESISNormal carbohydrate metabolism depends upon the presence of insulin (Fig 58.1) However, different tissues handle glucose in different ways; for example, red blood cells lack mitochondria and therefore pyru-vate dehydrogenase and the enzymes involved in β-oxidation, whereas liver parenchymal cells are able to perform the full range of glucose disposal (Fig 58.2) Both DKA and HHS result from a reduction in the effect

of insulin with a concomitant rise in the tory hormones such as glucagon, catecholamines, cor-tisol and growth hormone Hyperglycaemia occurs as

counterregula-a consequence of three processes: increcounterregula-ased genesis, increased glycogenolysis and reduced periph-eral glucose utilisation The increase in glucose production occurs in both the liver and the kidneys as there is a high availability of gluconeogenic precursors such as amino acids (protein turnover shifts from bal-anced synthesis and degradation to reduced synthesis and increased degradation) Lactate and glycerol also become available owing to an increase in skeletal muscle glycogenolysis and an increase in adipose tissue

gluconeo-630 Diabetic emergencies

ketone levels and once again the exact contribution

of insulin deficiency or stress hormone increase to ketogenesis is undetermined As ketone bodies are comparatively strong acids, a large hydrogen ion load

is produced owing to their dissociation at physiological

pH The need to buffer hydrogen ions depletes the body’s alkali reserves and ketone anions accumulate, accounting for the elevated plasma anion gap

By contrast, HHS does not share the ketogenic tures of DKA Reduced levels of FFAs, glucagon, corti-sol and growth hormone have been demonstrated in HHS relative to DKA although this is by no means a consistent observation However, the presence of higher levels of C-peptide in HHS (with lower levels of growth hormone) relative to DKA suggests there is just enough insulin present in HHS to prevent lipolysis but not enough to promote peripheral glucose utilisation.6Hyperosmolarity, which is a prominent feature of HHS, is caused by the prolonged effect of an osmotic

fea-lipolysis respectively Lastly, there is an increase in

glu-coneogenic enzyme activity enhanced further by stress

hormones Although hepatic gluconeogenesis is the

main mechanism for producing hyperglycaemia a

sig-nificant proportion can be produced by the kidneys.4

What is unclear is the temporal relationship of these

changes, although an increase in both catecholamines

and the glucagon/insulin ratio are early features.5

Decreased insulin and increased epinephrine levels

activate adipose tissue lipase causing a breakdown of

triglycerides into glycerol and free fatty acids (FFAs)

Once again glucagon is implicated as hepatic oxidation

of FFAs to ketone bodies is stimulated predominantly

by its inhibitory effect on acetyl-CoA carboxylase The

resultant reduced synthesis of malonyl-CoA causes a

disinhibition of acyl-carnitine synthesis and subsequent

promotion of fatty acid transport into mitochondria

where ketone body formation occurs Both cortisol and

growth hormone are capable of increasing FFA and

Figure 58.1  Sources and fate of acetyl CoA. *Pyruvate conversion  

SterolsAmino acids

(13) glucuronidation. 

GlucosePentose

phosphates

GlycogenGlucose 6-P

4

10

1112

13

56

78

9

Clinical presentation 631

seen in children and occasionally in adults and may mimic an acute abdomen Dehydration presents with loss of skin turgor, dry mucous membranes, tachycar-dia and hypotension Mental obtundation occurs more frequently in HHS than DKA as more patients, by defi-nition, are hyperosmolar and the presence of stupor or coma in patients who are not hyperosmolar requires consideration of other potential causes for altered mental status.9 However, loss of consciousness is not a common presentation with DKA or HHS (<20%) Most hospitalisations are caused by infection (29%) or non-compliance with medication (17%) in previously diag-nosed diabetics; however, in some patients it is the first presentation with undiagnosed diabetes (17%).10 Given that there is a high likelihood of concurrent infection, most patients have a normal or low temperature and most patients also have a leucocytosis, whether there is infection present or not

DIABETIC KETOACIDOSISThis tends to occur more often in patients with type I diabetes, although a third of hospitalisations for DKA occurs in patients with type 2 diabetes The predomi-nant feature is ketoacidosis Rapid, deep breathing due

to the acidosis (Kussmaul breathing) may be present, as may the breath odour that is characteristic of ketones, which is somewhat like nail polish remover Insulin therapy omission or inadequate dosing is the common-est precipitant of DKA (40%) with underlying infection the next most likely cause (30%).6 Other causes should

be actively sought such as silent myocardial infarction, pancreatitis and drugs that interfere with carbohydrate metabolism Diagnostic criteria include pH < 7.3, HCO3

< 15 mmol/L and blood glucose >14 mmol/L ing acidaemia, ketonaemia and deteriorating conscious level indicate an increasing severity Blood glucose per

Increas-se is not a good determinant of Increas-severity and mic ketoacidosis is possible, depending on the hepatic

euglycae-glycogen stores prior to the onset of DKA – a patient

who has not been eating well in the recent past may well have a minimally elevated blood glucose A high amylase is frequently seen and may be extrapancreatic

in origin It should be interpreted cautiously as a sign

of pancreatitis

HYPEROSMOLAR HYPERGLYCAEMIC SYNDROMEHHS is more often seen in patients with type II diabetes and the dominant feature is hyperosmolarity (>320 mOsm/kg) HHS is typically observed in elderly patients with non-insulin-dependent diabetes mellitus, although it may rarely be a complication in younger patients with insulin-dependent diabetes, or those without diabetes following severe burns,11 parenteral hyperalimentation, peritoneal dialysis, or haemodialy-sis Patients receiving certain drugs including diuretics, corticosteroids, β-blockers, phenytoin and diazoxide

diuresis with impaired ability to take adequate fluids

It has been shown that, even when well, patients who

have suffered from HHS have impaired thirst reflexes

However, the hyperosmolarity seen in about one-third

of patients with DKA results from a shorter osmotic

diuresis and to variable fluid intake due to nausea and

vomiting – which is often ascribed to the brainstem

effects of ketones

Interestingly, hyperglycaemia with or without

ketoacidosis leads to a significant increase in

pro-inflammatory cytokine production, which resolves

when insulin therapy is commenced.7 This has led

others to postulate a wider beneficial anti-inflammatory

effect attributable to insulin therapy This

pro-inflammatory, pro-thrombotic state may explain the

relatively high incidence of thrombotic events

associ-ated with diabetic emergencies

CLINICAL PRESENTATION

DKA and HHS represent the two extremes of

presenta-tion due to the absolute or relative deficiency of insulin

However, up to one-third of cases can present with

mixed features.8 DKA develops over a shorter time

period whereas HHS appears more insidiously – see

Table 58.1 Polyuria, polydipsia and weight loss are

experienced for a variable period prior to admission

and, in patients with DKA, nausea and vomiting are

also common symptoms Abdominal pain is commonly

632 Diabetic emergencies

individual variation as to how much fluid will be required and simple vital signs such as heart rate, blood pressure and peripheral perfusion should guide the resuscitation Fluid challenges with assessment of response may be less likely to avoid the problems of fluid overload The usual urinary sodium concentra-tion is 60–70 mmol/L, which is roughly similar to half-normal saline and this is the logical fluid to use for rehydration.15 This avoids too great a sodium load and

is less likely to produce a hyperchloraemic acidosis, which, if rhabdomyolysis occurs, will further acidify the urine and promote precipitation of myoglobin in the renal tubule As insulin therapy is commenced extracellular water is driven into the intracellular com-partment, exacerbating hypovolaemia, which is why it

is most important to commence fluid resuscitation early This can also lead to a rapid rise in serum sodium concentrations as the true sodium in hyperglycaemia is higher than the measured sodium Such rapid changes

in sodium levels can lead to prolonged neurological dysfunction such as pontine myelinolysis.16

Inappropriate fluid replacement can lead to lems Studies of DKA and cerebral oedema are limited but there is some evidence that overaggressive replace-ment of water losses can precipitate cerebral and other forms of oedema Water losses do not need to be cor-rected rapidly and hyperosmolality should not be cor-rected more rapidly than 3 mOsm/kg H2O/h

prob-General guidelines are given in Figure 58.3 but it must

be remembered that each case needs individual tailoring

of treatment It is mostly agreed that the first litre should

be isotonic saline, even in patients with marked tonicity This should be given over the first hour If there

hyper-is any evidence of cardiovascular compromhyper-ise due to hypovolaemia, plasma expansion with colloids should also be given as a matter of urgency That saline has

a pH of 5.5 and a high chloride content is a source

of some concern as a resolving ketoacidosis would be compounded by a hyperchloraemic acidosis A recent study using a balanced electrolyte solution has shown reduced resuscitation-associated hyperchloraemia and

an improved serum bicarbonate level.17 For the next

2 hours 0.45% saline can be given if the serum sodium

is normal or high If the corrected sodium is low then 0.9% saline should be continued When the blood glucose falls below 15 mmol/L in DKA or HHS then a combination of 5 or 10% dextrose solution with some further saline-containing solution should be commenced (100–250 mL/h) and continued until the ketonaemia has resolved Assuming cardiovascular stability, the aim should be to correct the remaining fluid deficit gradually over the next 24–48 hours whilst also taking account of ongoing urinary losses

INSULIN THERAPYLow-dose, physiological insulin replacement resolves the biochemical abnormalities as quickly as higher

are at increased risk of developing this syndrome HHS

may be caused by lithium-induced diabetes insipidus.12

Not only may mental obtundation occur, but also

occa-sionally focal neurological features or seizures are

present

MANAGEMENT

ICU admission is indicated in the management of

DKA, HHS and mixed cases in the presence of

cardio-vascular instability, inability to protect the airway,

altered sensoria and the presence of acute abdominal

signs or symptoms suggestive of acute gastric

dilata-tion It is now possible to direct therapy to the

underly-ing metabolic problems of ketogenesis and acidosis

rather than the surrogate marker of the blood glucose

level This is increasingly important in euglycaemic

DKA Assessment of response to therapy guided by

measurement of ketone concentration is becoming part

of best practice.13

INITIAL ASSESSMENT

These conditions are medical emergencies and a prompt

and thorough history and physical examination should

be obtained with special attention paid to airway

patency, conscious level, cardiovascular and renal

status, possible sources of infection and state of

hydra-tion Some assessment of the severity of DKA is also

aided by the degree of acidosis The majority of patients

have a leucocytosis irrespective of whether or not they

have a source of sepsis Attention must also focus on

any underlying precipitant The two major factors

involved are inadequate insulin treatment and infection

causing a change in insulin responsiveness The latter

must be actively sought in the management of these

patients

FLUID REQUIREMENTS

Dehydration and sodium depletion develop as a result

of the osmotic diuresis that accompanies

hyperglycae-mia in both DKA and HHS In DKA there is an

addi-tional ketoanion excretion, which is approximately half

that of glucose This obligates cation (sodium,

potas-sium and ammonium) excretion and contributes to the

electrolyte losses Despite the dual osmotic load of

glucose and ketones in DKA, dehydration is often

worse in HHS owing to the more prolonged onset

Insulin itself also promotes salt, water and phosphate

reabsorption in the kidney and its lack can contribute

further to these losses The total osmolar load on the

kidney in DKA can be as much as 2000 mOsm/day.14

Fluid resuscitation is initially directed to repleting

the intravascular volume, and colloids achieve this

more rapidly than crystalloids Fluids alone will

reduce glucose and counterregulatory hormone levels

and diminish peripheral insulin resistance There is

Management 633

losses are augmented by secondary hyperaldosteronism and ketoanion excretion as potassium salts Typical total body deficits are shown in Table 58.1 Serum potassium levels may initially be high and potassium replacement should not commence until this has fallen

to <5.5 mmol/L Potassium can be replaced as a bination of the chloride and phosphate salt as this can avoid hyperchloraemia and hypophosphataemia Occa-sionally the presenting potassium level will be low (<3.3 mmol/L), which represents profound potassium depletion (600–800 mmol) and replacement should commence immediately and before insulin therapy is initiated If the patient is in between these two levels then 20–40 mmol of potassium may be given in the first hour – this should not generally be exceeded Further decisions regarding potassium replacement need to be adjusted with respect to serum levels and the urine output but usually 20–30 mmol/h are required ECG monitoring has been recommended where potassium replacement is needed for patients who present with hypokalaemia or cardiac rhythms other than sinus tachycardia.6

com-PHOSPHATE

A total body phosphate deficit of greater than 1 mmol/

kg is typical Once again the shift is from the cellular compartment with subsequent urinary loss; however, serum levels are typically normal or increased Insulin causes an intracellular shift of phos-phate and, although hypophosphataemia rarely results

intra-in adverse complications, muscle weakness, lytic anaemia and impaired cardiac systolic perform-ance can occur Routine phosphate replacement has not been shown to be beneficial in DKA,20 but correc-tion of severely low levels (<0.4 mmol/L) may be necessary Excessive phosphate replacement leads

haemo-to hypocalcaemia and serum calcium should be monitored

doses without running the risk of hypoglycaemia and

hypokalaemia, and gradual correction of

hyperglycae-mia is associated with a lower mortality.18 A recent

study has even questioned the need for an initial insulin

bolus dose, contending that commencing the infusion

at 0.14 U/kg/h may well be sufficient A bolus dose

(0.14 U/kg) may be required after 1 hour if the blood

glucose level has not fallen by at least 10%.19

Alterna-tively, a regimen consisting of an initial bolus dose of

0.1 U/kg followed by low dose (0.1 U/kg/h) insulin

infusion is similarly acceptable and safe Weight-based

fixed infusion rates are preferable to sliding-scale

regi-mens Intravenous rather than subcutaneous or

intra-muscular delivery is preferable as glucose decrement is

the same whatever route is chosen, but intravenous

insulin reduces ketone body production faster It is

mandatory to use the intravenous route where

hypo-volaemic shock is present The aim of treatment is

to achieve metabolic targets, specifically: increasing

bicarbonate concentration by 3 mmol/L/h, reducing

the blood glucose concentration by 3 mmol/L/h and

reducing the blood ketone concentration by 0.5 mmol/

L/h whilst maintaining normal potassium levels If

the glucose levels fail to reduce appropriately it may

indicate insufficient fluid resuscitation Severe insulin

resistance occurs in 10% of cases and will

neces-sitate the use of higher doses The insulin infusion

rate should be reduced to 0.02–0.05 U/kg/h when the

glucose level falls to below 12 mmol/L (DKA) or below

15 mmol/L (HHS), and maintained at a level tailored

to the patient’s need

ELECTROLYTE THERAPY

POTASSIUM

Hyperosmolarity causes a shift of potassium from

within cells to the extracellular space and this

potas-sium is lost as a result of the osmotic diuresis Renal

When glucose < 15 mmol/L5% dextrose 100–250 mL/hAND

‘saline’

Keep Na+ 140–150 mmol/L

Correct deficit gradually

Adjust for urine output

Normal saline15–20 mL/kg/h

0.45% saline4–14 mL/kg/h

0.45% saline4–14 mL/kg/h

634 Diabetic emergencies

if a high-chloride-containing fluid such as normal saline

is used.25MONITORINGThe following monitoring parameters are also under-taken as investigations on presentation:

1 Blood glucose concentration: initially every hour, then

less frequently

2 Blood urea and creatinine concentrations: on admission

and then at least daily Creatinine assays that rely

on a colorimetric method may be interfered with by the presence of acetoacetate, giving a falsely ele-vated value

3 Serum electrolytes:

a Serum sodium: on admission and at least daily It

represents the relative water and electrolyte losses and cannot be used to infer a state of hydration It may be normal (50% of cases), raised or lowered Each 1.0 mmol/L rise in blood glucose will decrease serum sodium by 0.3 mmol/L, so hypernatraemia represents a profound loss of water

b Serum potassium: initially every hour, then less

frequently (every 2–4 hours) DKA patients have

a K+ deficit of 3–5 mmol/kg However, serum concentrations are usually normal or raised because of a shift from the intracellular to the extracellular compartment due to acidaemia, insulin deficiency and hypertonicity Hypokalae-mia on admission represents severe potassium depletion (>600–800 mmol) and requires potas-sium administration before starting insulin therapy

c Serum chloride: as indicated

d Serum phosphate: on admission and every 1–2

days Routine replacement is not of any benefit Despite evidence that hypophosphataemia leads

to a decrease in 2,3-diphosphoglycerate levels, subsequent correction has no impact on the oxy-haemoglobin dissociation curve and dangerous hypocalcaemia may result20

e Serum magnesium: on admission and every 1–2

days Chronic hypomagnesaemia may be present and may contribute to insulin resistance, carbo-hydrate intolerance and hypertension Severe uncontrolled diabetes also results in magnesium depletion However, the benefits of replacement therapy have not been demonstrated but may be necessary if arrythmias are present

4 Serum ketones (if available): on admission This test

relies on the nitroprusside reaction and, because

it measures acetoacetate and acetone but not β-hydroxybutyrate, which is the main ketoacid

in DKA, it consequently underestimates the degree of ketoacidosis Near patient testing for β-hydroxybutyrate is now more readily available

MAGNESIUM

A chronic magnesium deficiency may be present in

type I or II diabetes and may be exacerbated by renal

impairment The benefits of magnesium replacement

have not been demonstrated in diabetic emergencies,

but the principles of magnesium supplementation are

similar to other critical care situations

CORRECTION OF ACIDOSIS

This occurs more slowly than the correction of blood

glucose but the use of bicarbonate in DKA remains

controversial Experimentally, metabolic acidaemia

impairs myocardial contractility, affects

oxyhaemo-globin dissociation and tissue oxygen delivery, alters

cellular metabolism, inhibits intracellular enzymes,

such as the pH-dependent enzyme

phosphofructoki-nase, and results in organ dysfunction Not only that,

but insulin resistance increases sharply below pH 7.2

Bicarbonate treatment to rapidly correct the acidosis

should offer some benefit but, in most studies, the use

of sodium bicarbonate fails to provide any benefit

There are no haemodynamic benefits that could not be

attributed purely to osmotic load of sodium

adminis-tered.21 There is no doubt that blood pH can be

improved but at the expense of worsening the

intracel-lular acidosis.22 Sodium bicarbonate treatment may

cause paradoxical cerebrospinal fluid (CSF) acidosis.23

It is also associated with other side-effects that may

overshadow any potential benefits such as: increased

CO2 production, hypokalaemia, rebound alkalosis,

volume overload and altered tissue oxygenation In the

context of DKA, sodium bicarbonate also delays the

clearance of ketones and may enhance further hepatic

production even when insulin and glucose are being

delivered.24 At pH > 7.0 insulin will block lipolysis and

ketoacid production; however, when the pH is between

6.9 and 7.1 it remains uncertain whether bicarbonate is

beneficial or otherwise Although a recent systematic

review of trials in both adult and paediatric

popula-tions concluded that there was no obvious benefit with

bicarbonate treatment, there were reassuringly few

clinically significant complications resulting from its

use either.23 These studies did not include patients with

pH < 6.85 and recommendations in such patients are

difficult Below pH 6.9 most authorities would

recom-mend the use of bicarbonate to correct the pH partially

to the threshold The threshold for correction is

debat-able (between pH 6.9 and 7.15) but life-threatening

hyperkalaemia is an undisputed indication for

bicarbo-nate therapy

Sometimes there is a persistent acidosis without

ketosis Regeneration of bicarbonate in DKA once

insulin activity has been restored occurs via two

mecha-nisms: renal and hepatic The latter requires a

metabo-lisable substrate, typically ketones, which are lost to the

body especially if the diuresis is substantial The former

is slow and hyperchloraemia may persist, particularly

Prognosis 635

progressive signs of brainstem herniation are present the mortality is high with only 7–14% likely to make a complete recovery The risks of brain herniation are related to the degree of acidosis and the volume of initial fluid resuscitation Oedema formation most likely occurs due to a vasogenic mechanism28 and cer-ebral hyperaemia with loss of autoregulation is evident, which can take up to 36 hours to resolve.29,30 It has been recommended that plasma osmolality is reduced slowly and that glucose must be added to the hydrating fluids when the plasma glucose has fallen below 15 mmol/L

in DKA and HHS Fatal cases of cerebral oedema have been reported in HHS as well and treatment is aimed

at maintaining plasma osmolality with intravenous mannitol

Some degree of brain dysfunction is apparent even in those patients who are not comatose but who have severe DKA as measured by sensory evoked potentials This reverts to normal with correction of the ketoacidosis.31

Hypoxia, non-cardiogenic pulmonary oedema and myocardial infarction can also occur – particularly in the elderly

INTERMEDIATE

A reversible critical illness motor syndrome has been described in HHS and led to slowness to wake up and reversible tetraplegia.32 Deep venous thrombosis and pulmonary embolism occur more frequently in DKA and are a significant cause of mortality in HHS.33,34Prophylaxis with subcutaneous heparin is advisable Full anticoagulation may be indicated in HHS.3LATE

Various movement disorders can rarely persist after recovery from HHS.35 The effects of neuroglycopenia can result in an array of late complications from amnesia

to optic atrophy

PROGNOSIS

In a series of 610 patients with DKA or HHS the overall mortality was 6.2% HHS is a more serious disease and has an associated mortality 2–3 times higher than DKA; nevertheless DKA is approximately six times com-moner A retrospective analysis of causes of death in this group of patients revealed that pneumonia was the commonest cause of death (37%), followed by myocar-dial infarction (21%), with mesenteric or iliac thrombo-sis accounting for 16% of deaths.36 Rhabdomyolysis has been reported in both DKA and HHS and, when present, increases the mortality.37 The likelihood of a poorer outcome in HHS was associated with: older age, low blood pressure, low sodium, pH and bicarbonate plasma levels, and high urea plasma levels, of which urea has the strongest association.38 Mortality is also

5 Urinary glucose and ketones: 4-hourly; ketonuria may

persist up to 2 days after the correction of acidosis

due to the presence of acetone, which is not an acid

anion and is highly lipid soluble The ratio of

ace-toacetate : β-hydroxybutyrate (approximately 1 : 3)

increases as acidosis improves with treatment; this

can lead to the paradoxical impression that ketosis

is worsening but is merely an anomaly of the

nitro-prusside test

6 Arterial blood gases: frequently, as indicated

7 Serum osmolality and anion gap: initially and as

indi-cated Serum osmolality can be measured with an

osmometer or estimated

8 Serum lactate: if acidosis is severe and anion gap is

large

9 Full blood count and coagulation studies: daily and as

indicated Leucocytosis with left shift may occur in

the absence of sepsis

10 Chest X-ray

11 Blood cultures, urine and sputum microscopy and

culture and culture of relevant specimens: as

indicated

12 Pulse oximetry: continuously

13 Electrocardiogram: 12-lead recording and continuous

monitoring

14 Invasive haemodynamic monitoring: as indicated

15 Neurological status and observations: including

Glasgow Coma Scale and computed tomography

(CT) scans as indicated for persistent coma or

wors-ening neurological state

16 Other investigations: as indicated (e.g liver function

tests, serum amylase, cardiac enzymes and

creati-nine clearance)

COMPLICATIONS

EARLY

The commonest early complications are hypoglycaemia

due to overtreatment with insulin, hypokalaemia due

to inadequate replacement and hyperglycaemia due to

interruption of insulin A hyperchloraemic acidosis can

develop in about 10% of patients with DKA It can be

exaggerated by excessive saline use and is not usually

clinically significant except in cases of acute renal

failure or extreme oliguria

Clinically apparent cerebral oedema is a rare (0.5–

1%) but extremely serious complication of DKA

occur-ring predominantly in children and the mortality is

high (25%), with a quarter of survivors being left with

some permanent neurological sequelae Recent studies

have suggested a subclinical incidence approaching

50%.26 Risk factors for developing cerebral oedema

include: degree of hypocapnia and dehydration, the

failure of serum sodium to rise with treatment and

the use of sodium bicarbonate.27 It also occurs in

young adults and may be associated with rapid

deterio-ration in conscious level with or without seizures If

636 Diabetic emergencies

increased risk associated with long-acting sulfonyl urea agents Alcoholic ketoacidosis is a syndrome of hypogly-caemia, ketoacidosis and dehydration associated with starvation, vomiting, upper abdominal pain and neuro-logical changes including seizures and coma Hypogly-caemia may complicate other disease states (e.g liver and renal failure, or adrenocortical insufficiency).Severe hypoglycaemia (blood glucose <1 mmol/L) is

a medical emergency Brain metabolism uses half the glucose produced by the liver and neuronal stores of glycogen are depleted within 2 minutes, after which the brain is susceptible to damage Urgent glucose infusion (50 mL of 50% glucose) is required and leads

to rapid resolution of coma Intramuscular glucagon

is an alternative especially suited to out-of-hospital circumstances, but achieves a slower result when com-pared with intravenous glucose.40 Hypoglycaemia due

to long-acting insulins or oral hypoglycaemic agents will require ongoing glucose infusion

age-related in DKA Pregnant women with type I

diabetes are more likely to have a worse outcome from

DKA than non-pregnant diabetic women who develop

DKA The presence of hypothermia is also a poor

prog-nostic sign

Survival depends upon establishing a high index of

suspicion and a rapid diagnosis.39

HYPOGLYCAEMIC COMA

This results from overtreatment with insulin and is the

commonest cause of diabetic coma Clinically, there is

confusion, agitation progressing to coma and fitting

Tremor, tachycardia and sweating may be blunted by

diabetic autonomic neuropathy It may be precipitated

in known type I diabetic patients (up to 10% of patients

per year) by missed meals, exercise and overdose of

insulin or oral hypoglycaemic agents Changing therapy

or insulin periods are susceptible periods and there is an

http://www.expertconsult.com

Access the complete references list online at 

3 Nyenwe E, Kitabchi A Evidence-based management

of hyperglycemic emergencies in diabetes mellitus

Diabetes Res Clin Pract 2011;94:340–51

8 Magee MF, Bhatt BA Management of

decompen-sated diabetes Diabetic ketoacidosis and

hypergly-cemic hyperosmolar syndrome Crit Care Clin 2001;

17(1):75–106

13 Joint British Diabetes Societies Inpatient Care

Group The management of diabetic ketoacidosis

in adults March 2010 Online Available: http://

www.diabetes.org.uk/Documents/

18 Wagner A, Risse A, Brill HL, et al Therapy of severe

diabetic ketoacidosis Zero-mortality under

very-low-dose insulin application Diabetes Care 1999;

22(5):674–7

19 Kitabchi A, Murphy M, Spencer J, et al Is a priming dose of insulin necessary in a low-dose insulin pro-tocol for the treatment of diabetic ketoacidosis? Dia-betes Care 2008;31:2081–5

23 Chua H, Schneider A, Bellomo R Bicarbonate in betic ketoacidosis – a systematic review Ann Inten-sive Care 2011;1:23

dia-27 Glaser N, Barnett P, McCaslin I, et al Risk factors for cerebral edema in children with diabetic ketoaci-dosis The Pediatric Emergency Medicine Collab-orative Research Committee of the American Academy of Pediatrics N Engl J Med 2001;344: 264–9

References 636.e1

REFERENCES

1 Harris MI Undiagnosed NIDDM: clinical and public

health issues Diabetes Care 1993;16:642–52

2 International Diabetes Federation IDF Diabetes

Atlas 5th ed Brussels, Belgium: International

Diabe-tes Federation; 2011 Online Available: http://

www.idf.org/diabetesatlas

3 Nyenwe E, Kitabchi A Evidence-based management

of hyperglycemic emergencies in diabetes mellitus

Diabetes Res Clin Pract 2011;94:340–51

4 Meyer C, Woerle HJ, Dostou JM, et al Abnormal

renal and hepatic glucose metabolism in type 2

dia-betes mellitus J Clin Invest 1998;102(3):619–24

5 Schade DS, Eaton RP The temporal relationship

between endogenously secreted stress hormones and

metabolic decompensation in diabetic man J Clin

Endocrinol Metab 1980;50(1):131–6

6 Kitabchi AE, Umpierrez GE, Murphy MB, et al

Man-agement of hyperglycemic crises in patients with

diabetes Diabetes Care 2001;24(1):131–53

7 Stentz FB, Umpierrez GE, Cuervo R, et al

Proin-flammatory cytokines, markers of cardiovascular

risks, oxidative stress, and lipid peroxidation in

patients with hyperglycemic crises Diabetes 2004;53:

2079–86

8 Magee MF, Bhatt BA Management of

decompen-sated diabetes Diabetic ketoacidosis and

hypergly-cemic hyperosmolar syndrome Crit Care Clin

2001;17(1):75–106

9 Umpierrez GE, Khajavi M, Kitabchi AE Review:

dia-betic ketoacidosis and hyperglycemic hyperosmolar

nonketotic syndrome Am J Med Sci 1996;311(5):

225–3

10 Wachtel TJ, Tetu-Mouradjian LM, Goldman DL, et al

Hyperosmolarity and acidosis in diabetes mellitus: a

three-year experience in Rhode Island J Gen Intern

Med 1991;6(6):495–502

11 Inglis A, Hinnie J, Kinsella J A metabolic

complica-tion of severe burns Burns 1995;21(3):212–14

12 [No authors listed] Hyperosmolar coma due to

lithium-induced diabetes insipidus Lancet 1995;

346(8972):413–17

13 Joint British Diabetes Societies Inpatient Care

Group The management of diabetic ketoacidosis

in adults March 2010 Online Available: http://

www.diabetes.org.uk/Documents/

14 DeFronzo RA, Goldberg M, Agus ZS The effects of

glucose and insulin on renal electrolyte transport

J Clin Invest 1976;58(1):83–90

15 Hillman K Fluid resuscitation in diabetic

emergen-cies – a reappraisal Intensive Care Med 1987;

13(1):4–8

16 McComb RD, Pfeiffer RF, Casey JH, et al Lateral

pontine and extrapontine myelinolysis associated

with hypernatremia and hyperglycemia Clin

Neu-ropathol 1989;8(6):284–8

17 Mahler S, Conrad S, Wang H, et al Resuscitation

with balanced electrolyte solution prevents

hyper-chloremic metabolic acidosis in patients with

dia-betic ketoacidosis Am J Emerg Med 2011;29(6):

670–4

18 Wagner A, Risse A, Brill HL, et al Therapy of severe diabetic ketoacidosis Zero-mortality under very-low-dose insulin application Diabetes Care 1999; 22(5):674–7

19 Kitabchi A, Murphy M, Spencer J, et al Is a priming dose of insulin necessary in a low-dose insulin pro-tocol for the treatment of diabetic ketoacidosis? Dia-betes Care 2008;31:2081–5

20 Fisher JN, Kitabchi AE A randomized study of phate therapy in the treatment of diabetic ketoacido-sis J Clin Endocrinol Metab 1983;57(1):177–80

phos-21 Cooper DJ Hemodynamic effects of sodium nate Intensive Care Med 1994;20:306–7

bicarbo-22 Forsythe SM, Schmidt GA Sodium bicarbonate for the treatment of lactic acidosis Chest 2000;117: 260–7

23 Chua H, Schneider A, Bellomo R Bicarbonate in betic ketoacidosis – a systematic review Ann Inten-sive Care 2011;1:23

dia-24 Okuda Y, Adrogue HJ, Field JB, et al productive effects of sodium bicarbonate in diabetic ketoacidosis J Clin Endocrinol Metab 1996;81: 314–20

Counter-25 Matz R Severe diabetic ketoacidosis Diabet Med 2000;17(4):329

26 Glaser N, Wootton-Gorges SL, Buonocore MH, et al Frequency of sub-clinical cerebral edema in children with diabetic ketoacidosis Pediatr Diabetes 2006;7: 75–80

27 Glaser N, Barnett P, McCaslin I, et al Risk factors for cerebral edema in children with diabetic ketoacido-sis The Pediatric Emergency Medicine Collaborative Research Committee of the American Academy of Pediatrics N Engl J Med 2001;344:264–9

28 Figueroa RE, Hoffman WH, Momin Z, et al Study

of subclinical cerebral edema in diabetic ketoacidosis

by magnetic resonance imaging T2 relaxometry and apparent diffusion coefficient maps Endocr Res 2005;31:345–55

29 Roberts JS, Vavilala MS, Schenkman KA, et al ebral hyperemia and impaired cerebral autoregula-tion associated with diabetic ketoacidosis in critically ill children Crit Care Med 2006;34:2217–23

Cer-30 American Diabetes Association Hyperglycemic crises in patients with diabetes mellitus Diabetes Care 2001;24(1):154–61

31 Eisenhuber E, Madl C, Kramer L, et al Detection of subclinical brain dysfunction by sensory evoked potentials in patients with severe diabetic ketoacido-sis Intensive Care Med 1997;23(5):587–9

32 Kennedy DD, Fletcher SN, Ghosh IR, et al Reversible tetraplegia due to polyneuropathy in a diabetic patient with hyperosmolar non-ketotic coma Inten-sive Care Med 1999;25(12):1437–9

33 Ceriello A Coagulation activation in diabetes tus: the role of hyperglycaemia and therapeutic pros-pects Diabetologia 1993;36(11):1119–25

melli-34 Whelton MJ, Walde D, Havard CW Hyperosmolar non-ketotic diabetic coma: with particular reference

to vascular complications Br Med J 1971;1(740): 85–6

636.e2 Diabetic emergencies

35 Lin JJ, Chang MK Hemiballism–hemichorea and

non-ketotic hyperglycaemia J Neurol Neurosurg

Psychiatry 1994;57(6):748–50

36 Hamblin PS, Topliss DJ, Chosich N, et al Deaths

associated with diabetic ketoacidosis and

hyperos-molar coma 1973–1988 Med J Aust 1989;151(8):439,

441–2, 444

37 Wang LM, Tsai ST, Ho LT, et al Rhabdomyolysis in

diabetic emergencies Diabetes Res Clin Pract 1994;

26(3):209–14

38 Piniés JA, Cairo G, Gaztambide S, et al Course and

prognosis of 132 patients with diabetic non ketotic

hyperosmolar state Diabete Metab 1994;20(1):43–8

39 Small M, Alzaid A, MacCuish AC Diabetic molar non-ketotic decompensation Q J Med 1988; 66(251):251–7

hyperos-40 Patrick AW, Collier A, Hepburn DA, et al son of intramuscular glucagon and intravenous dex-trose in the treatment of hypoglycaemic coma in an accident and emergency department Arch Emerg Med 1990;7(2):73–7

Diabetes insipidus and other 

polyuric syndromes

Alastair C Carr

Diabetes insipidus (literal translation ‘tasteless siphon’)

refers to a syndrome characterised by pathological

polyuria, excessive thirst and polydipsia Polyuria is

arbitrarily defined as a urine loss of >3 litres per day in

an adult of normal mass or >2 L/m2 in children The

urine produced in DI is inappropriately dilute having

both low specific gravity and low osmolality in the face

of a high or normal plasma osmolality

Three subtypes of DI are recognised: (i) nephrogenic

DI – caused by insensitivity of the kidney to antidiuretic

hormone (ADH), (ii) central/hypothalamic/neurogenic DI

– caused by reduced or absent production of ADH, and

(iii) gestational DI – caused by an increase in the

placen-tal production of vasopressinase or as a variant of

central or nephrogenic DI developing during

preg-nancy A separate disorder is occasionally classified as

a fourth form of DI: primary polydipsia (also called

psy-chogenic or neurogenic polydipsia or polydipsic DI)

This is caused by excessive water ingestion usually due

to psychological disturbance but occasionally

associ-ated with a lesion of the hypothalamus In the context

of hospital in-patients, a similar iatrogenic condition is

created by overenthusiastic administration of

intrave-nous solutions of dextrose 5% or hypotonic saline

Although water overload will reduce plasma

osmolal-ity and reduce the abilosmolal-ity of the kidney to maximally

concentrate urine, the diuresis of hypo-osmolar urine

seen with water overload is not pathological but

physi-ological and appropriate In this instance, plasma

osmo-lality is low or in the low–normal range and the body

is attempting to restore plasma osmolality to normality

by reducing water reabsorption in the kidneys and

inducing a water diuresis

In critically ill patients, polyuria may be the sole part

of the DI syndrome apparent to the clinician Patients

are seldom in control of their own fluid intake and are

frequently unable to report thirst The recognition of DI

is important as failure to recognise and treat the

syn-drome appropriately will result in severe dehydration

and hyperosmolality with a significant risk of

morbid-ity and mortalmorbid-ity As there are many causes of polyuria

in the critically ill (Box 59.1), it is important to adopt a

systematic approach to the clinical assessment,

investi-gations, diagnosis and management of such patients

The classification as a solute or water diuresis is

not always absolute; the table provides a convenient

structure but a diuresis should be considered in terms

of the individual patient and both physical and chemical assessments A diuresis may frequently rep-resent the clearance of both an excess of water and solute such as is usually the case following the resolu-tion of septic shock with multi-organ failure

bio-BACKGROUND PHYSIOLOGY AND ANATOMYOSMOLALITY

Osmolality is the measure of osmoles (Osm) of solute per kilogram of solvent and includes both permeant (e.g urea) and impermeant solutes (e.g sodium) It may change owing to both water movement and the move-ment of permeant solute Osmolarity is the measure of osmoles per litre of solute and, unlike osmolality, is temperature dependent Normal plasma osmolality is

in the range of 275–295 mOsm/kg Plasma osmolality can be estimated from several equations.1 The formula

of Worthley2 below is both simple and correlates well with measured values.3

plasma osmolality mOsm kg

Na urea glucose

All units of solute are mmol/L

Where a patient is markedly uraemic, a value of

8 mmol/L is substituted for the actual urea Actual osmolality may differ markedly from estimated osmo-lality in the presence of unmeasured, osmotically active solutes such as mannitol, ethanol, bicarbonate, lactate and amino acids Whenever concern exists that a patient may be hyper- or hypo-osmolal, osmolality should be measured by assessing the freezing point depression of the plasma or urine Increasing the osmolality results in depression of the freezing point

The osmolal gap is the difference between the lated and measured osmolality in plasma or urine The normal osmolal gap is <10 mOsm/kg An increased osmolal gap indicates the presence of an unmeasured osmotically active solute

calcu-TONICITYTonicity describes the ability of a solution of imper-meant solute (such as sodium) to cause the movement

638 Diabetes insipidus and other polyuric syndromes

NORMAL URINARY OSMOLALITY

In health, urinary osmolality is usually maintained between 500 and 700 mOsm/kg As the obligatory solute load to be excreted is relatively constant in value, urine osmolality will fall in response to an increased intake in free water and rise in response to dehydration

or water restriction (Fig 59.1) The minimum ity of urine achievable in man is around 25 mOsm/kg Diuresis refers to the passage of a high volume of urine (>1.5 mL/kg/h) and may be transient or persist-ent, physiological or pathological The production of

osmolal->3 L/day is arbitrarily defined as polyuria Water resis occurs when the total solute in the urine excreted per day is within the normal range but the osmolality

diu-of the urine passed is low An osmotic or solute diuresis occurs when the total solute passed per day is higher than normal; the urine passed is usually iso-osmolar to plasma if the extracellular fluid volume is expanded or hyperosmolar if the patient is hypo- or euvolaemic.PLASMA OSMOLALITY AND PLASMA   

VOLUME REGULATIONChanges in plasma osmolality and changes in plasma volume can occur in tandem or independently of one another Whereas normal plasma osmolality lies

in a population range of 275–295 mOsm/kg (270–

280 mOsm/kg in pregnancy), individuals tend to vary less than ±1% around their set value In pregnancy this

of water between itself and another fluid compartment

It may be considered an index of the water

concentra-tion rather than the solute concentraconcentra-tion as the solute is

impermeant The tonicity of plasma is largely

deter-mined by its sodium content; the main solute in

extra-cellular fluid that is not freely permeable to cross into

the intracellular space This characteristic facilitates the

control of extracellular fluid volume through the

regu-lation of sodium balance

It is possible for a solution to be both hypotonic and

iso-osmolar Dextrose solution 5% is an example of this;

the solution contains no impermeant solute (assuming

no absence of insulin, glucose freely enters the cell) but

is iso-osmolar with the intracellular milieu

SOLUTE AND WATER INTAKE AND LOSSES

Assuming a normal diet, in a 75 kg man there is every

day an obligatory loss of around 800 mmol of solute:

approximately 300 mmol of urea and 500 mmol of

cations and anions The maximum concentrating ability

of the healthy kidney is around 1200 mOsm/kg;

conse-quently, a minimum of 666 mL of urine a day is required

to excrete osmotically active solutes Additionally,

insensible losses of water (respiratory water, faecal

water and sweat) approximate 10 mL/kg/day and this

rises markedly with fever and hot dry climates Thus,

obligatory water losses of around 1.5 litres per day arise

owing to insensible losses and obligatory solute

excretion

Figure 59.1  Urine output rises and urine osmolality falls in health as a function of increasing water intake. Assuming normal solute ingestion, normal solute excretion (around 800 mmol/day) is preserved between water intakes of 1.5 and 32 litres/day. 

12001000800600400200

2025

1510

05

Urine osmolality vs urine volumeFluid intake vs urine volume

Hyperglycaemia,  azotaemia  (uraemia),  Fanconi 

syn-drome,  renal  tubular  acidosis,  glomerulonephritis, 

hyperaldosteronism,  Addison  disease,  anorexia 

nervosa,  migraines,  paroxysmal  tachycardia  (via 

Background physiology and anatomy 639

Direct inputs from the sympathetic nervous system

to the PVN and SON can stimulate ADH release via α-adrenoreceptors Other central osmoreceptors lie outside the blood–brain barrier in the subfornical organ and come into contact with plasma It is believed that ANP and AII8 act via these receptors to inhibit or elicit ADH synthesis, ADH release and to modify the sensa-tion of thirst Additional osmoreceptors in the mouth, stomach, and liver are believed to play a role in the anticipation of an osmolal load following ingestion of food and pre-emptively can stimulate ADH synthesis

in the hypothalamus

As the baroreceptor and osmoreceptor inputs to the PVN and SON are distinct, it is possible to lose the normal ADH response to hyperosmolality but maintain

a normal ADH response to hypovolaemia.9 ally, in animal experiments, when hypotension increases the basal plasma ADH concentration, there is a simul-taneous resetting of the osmomolality–plasma ADH response curve in an attempt to preserve osmoregula-tory function from the new higher baseline.10 If this did not occur, the ADH response to hypotension would always result in the development of a hypo-osmolal state in addition to causing vasoconstriction

Addition-The normal response of osmoreceptors to changing plasma osmolality in terms of ADH is illustrated in

Figure 59.2 At plasma osmolalities of <275 mOsm/kg, the osmoreceptors remain hyperpolarised and virtually

no ADH release occurs via them At osmolalities

>295 mOsm/kg, the osmoreceptors are maximally depolarised and plasma concentrations of ADH of

>5 pg/mL are attained Other inputs and influences upon ADH release are summarised in Figure 59.3 and

Box 59.2

Figure 59.2  Plasma antidiuretic hormone (ADH) and plasma osmolality in health and partial cranial diabetes insipidus. 

20

1015

set value falls but the limited variability around it does

not The body regulates osmolality and volume by

sep-arate mechanisms Water balance and osmolality are

maintained via osmoreceptors, which mediate their

control via control of thirst and ADH production

Control of the plasma volume is maintained via

volume receptors and sodium receptors, which mediate

their actions through the sympathetic nervous system

and the renin–angiotensin–aldosterone system

Addi-tionally, the volume receptors have inputs to the

hypothalamus via which they too can mediate ADH

release and the sensation of thirst Atrial natriuretic

peptide (ANP) and brain natriuretic peptide (BNP),

predominantly released from atrial and ventricular

myocytes respectively, inhibit the release of renin,

aldosterone, vasopressin and endothelin leading to

both a natriuresis and a diuresis.4

THIRST

In health fluid intake is determined by the sensation of

thirst and the subsequent ingestion of fluid A plasma

osmolality of >290 mOsm/kg, elevated angiotensin

II (AII) concentrations, sympathetic nervous system

activation and circulating volume depletion of 5–10%

are all associated with the onset of thirst Fluid and

solute excretion are largely regulated through the

kidney, although some solutes such as ethanol and

glucose are largely cleared through metabolism rather

than excretion

In the ICU, the patient loses control over intake of

fluids and solute and frequently has impaired excretory

mechanisms Thus both volume and solute homeostasis

may become heavily dependent upon the skills of

attending clinicians

OSMORECEPTORS AND OTHER INPUTS TO THE 

SUPRAOPTIC AND PARAVENTRICULAR NUCLEI

Detection of osmolality occurs largely at osmo- (Na+)

receptors sited around the anterior aspect of the third

ventricle of the brain These are sensitive to plasma

osmolality and CSF sodium concentration Hypertonic

saline is a more potent stimulus than isotonic

equi-ososmolar solutions of other solutes.5 These

osmorecep-tors link to the cells of the paraventricular nuclei (PVN)

and supraoptic nuclei (SON), the sites of ADH

synthe-sis The axons of the cells in the PVN and SON form

part of the pituitary stalk linking the hypothalamus to

the pituitary gland, in which they terminate A smaller

proportion of the axons terminate in the median

emi-nence where they release ADH and oxytocin, which is

transported to the anterior lobe of the pituitary by

portal vessels The ADH and oxytocin so released cause

release of ACTH and prolactin respectively; the ADH

acts synergistically with corticotropin-releasing factor

(CRF) but is also believed to have ACTH secretagogue

properties in its own right.6,7

640 Diabetes insipidus and other polyuric syndromes

some cross-reactivity at receptors and in function.11 It is synthesised in the SON and PVN, bound to neuro-physin, transferred through axons to the posterior pitui-tary gland and stored in granules prior to release Synthesis to replace any released stores is a rapid process (1–2 hours from synthesis to storage) and patients with damage to the pituitary can achieve near-normal plasma concentrations of ADH, in terms of osmoregulatory function, via release of newly synthesised ADH via the axons terminating in the median eminence However, the higher plasma concentrations associated with hypovolaemia cannot be achieved Normal osmoregu-latory plasma ADH concentrations are in the range

of 1–8 pg/mL but rise as high as 40 pg/mL in aemic patients under the influence of the sympathetic nervous system, baroreceptor responses and AII.Once released from the pituitary, ADH has a plasma half-life of around 10–35 minutes.12 It is metabolised by hepatic, renal and placental vasopressinases and around 10% of the active hormone is excreted unchanged in the urine

ADH (8-arginine vasopressin) is a nine amino acid

peptide that differs from oxytocin at only two residues

but shares the disulphide bond between the 1st and 6th

ones This similar structure and conformation results in

Elevated ANP, BNPHypo-osmolalityHypervolaemiaHypertensionEthanolCranial DI

Baroreceptor inputs fromcarotid and aortic bodiesand osmoreceptor inputsfrom the hepatic portal circulation

Raised serumosmolality

Hypophyseal portal veins

from median eminence

within the pituitary stalk

hypophyseal axonaltracts withinpituitary stalk

Hypothalamo-Emetogenic stimuliand nociceptiveinputsPVN

SFOSON

ME

ADH

CRF

ADHAP

ACTH

PPAPo

Background physiology and anatomy 641

with α-adrenoceptor agonists may restore organ fusion pressure but also cause ischaemic damage The use of low-dose ADH infusions at 0.5–3 U/h titrated against urine output reduces the need for catecho-lamine support and also reduces perturbations in

per-plasma osmolality and fluid balance;

1-deamino-8-O-arginine vasopressin (DDAVP) has similar benefits but causes less vasoconstriction It is preferred for the treat-ment of cranial diabetes insipidus associated with brainstem death where hypotension is not a concomi-tant feature

Coagulation

ADH increases circulating levels of tissue plasminogen activator, factor VIII and von Willebrand factor.21 These effects may be mediated by V2 receptors but this remains controversial At high but physiological concentrations

it can act as a platelet -aggregating agent.22,23 Platelet aggregation is mediated through activation of platelet V1 receptors.24 ADH and its synthetic analogue DDAVP are used as first-line treatments in patients with von Willebrand’s disease, and may be used in bleeding associated with renal failure and platelet dysfunction

ACTH secretion

ADH transported via the portal venous system between the median eminence and the anterior pituitary acts upon V3 receptors in the anterior pituitary to stimulate release of ACTH, which in turn increases plasma corti-sol The ADH both increases the efficacy of CRF in releasing ACTH and also has independent efficacy in stimulating ACTH release itself In septic shock, it is possible that ADH insufficiency partially accounts for the relative adrenal insufficiency noted in certain patients The relative importance and potency of ADH compared with CRF in stimulating ACTH release in humans is unclear

VOLUME RECEPTORSVolume homeostasis takes precedence over sodium homeostasis and so rises and falls in sodium will occur

in order to preserve the circulating volume In mic patients, sodium homeostasis is maintained Sodium concentration is detected by both the osmore-ceptors of the SFO outside the blood–brain barrier and the juxtaglomerular apparatus, which secretes renin in response to reduced GFR and a lower sodium load in the tubule.25 The predominant determinants of sodium balance, however, are the high-pressure baroreceptors

euvolae-in the pulmonary veeuvolae-ins, left atrium, carotid seuvolae-inus and aortic arch.26 Reduced stretch of these receptors increases sympathetic nervous system activity and acti-vation of the renin–angiotensin–aldosterone system, resulting in reduced sodium excretion (via reduced GFR) and increased reabsorption of sodium in the proximal and distal convoluted tubules Additionally, release of ADH can be stimulated resulting in

barrier, nociception, splenic contraction and

thermoreg-ulation These actions are mediated through V1, V2 and

V3 receptors It also has actions on the uterus and

mammary tissue mediated through oxytocin receptors

Cardiac inotropic effects are reported to be mediated

through purinergic P2 receptors, but this remains

con-troversial.13 Animal studies give conflicting reports of

both positive and negative inotropic effects and their

receptor mediation.14

Antidiuresis

ADH binds to V2 receptors on the basal membranes of

the principal cells of the collecting duct and distal

tubule The activated receptor induces production of

cAMP by adenylate cyclase and this in turn activates

protein kinases, which effect the integration into the

luminal membrane of vesicles containing aquaporin-2

highly selective water channels The production of

prostaglandin E2 (PGE2) inhibits cAMP production

PGE2 synthesis is stimulated by the action of ADH on

V1 receptors on the luminal membrane of the collecting

duct.15 Thus, a form of autoregulatory limitation of the

antidiuretic effect of ADH may exist Hypokalaemia,

lithium and hypercalcaemia also antagonise the renal

actions of ADH

ADH also increases the urinary concentrating ability

of the kidney by increasing the expression of urea

trans-port proteins in the collecting duct and reducing renal

medullary blood flow (V1 mediated) facilitating an

increase in medullary interstitial hypertonicity This

hypertonicity additionally depends upon intact

func-tioning of the ascending loop of Henle where sodium

and chloride are reabsorbed without absorption of water

at the same time Interference with this process reduces

the osmolal gradient between the collecting duct and

the interstitium and reduces water absorption even in

the presence of ADH and functioning aquaporin-2

In low dose, administration of exogenous ADH may

paradoxically cause a diuresis in patients with septic

shock.16 This may be due to increased renal perfusion

pressure resulting in an increase in GFR

Vasoconstriction

At higher concentrations (>40 pg/cm), ADH activates

not only V2 receptors but also V1 receptors through

which it causes preferential vasoconstriction in muscle,

skin and fat with relative sparing of coronary, cerebral

and mesenteric circulations However, these relative

sparing effects are controversial, with some authors

reporting relative sparing and others reporting

signifi-cant vasoconstriction.17–20 Activation of V1 receptors

activates phospholipase C and increases inositol

tri-phosphate intracellularly Ultimately this increases

intracellular free calcium and leads to smooth muscle

constriction in the blood vessel wall

In brain-dead organ donors, a failure to produce

ADH may result in the development of both

hypotension and cranial diabetes insipidus with

distur-bances of osmolality and organ function Treatment

642 Diabetes insipidus and other polyuric syndromes

lesions, whereas transient DI is more likely to be ated with acute inflammatory or oedematous lesions with some recovery of ADH secretion occurring as the inflammation or oedema resolves An exception to this

associ-is the transient DI seen following excassoci-ision or tion of the posterior pituitary; ADH produced in the hypothalamus can still be released into the systemic circulation from capillaries in the median eminence

destruc-In the past the majority of acquired non-traumatic CDI was categorised as idiopathic but it has become apparent that the majority of these cases are associated with abnormality of the inferior hypophyseal arterial system31 or autoimmune reactivity against ADH-producing cells.32 However, association does not neces-sitate causality

When the normal release of ADH into the circulation

in response to rising plasma osmolality is reduced or absent, inappropriately high urine volumes are passed and the urine osmolality becomes inappropriately low for the state of water depletion being suffered by the patient Where ADH is entirely absent from the circula-tion, over 20 litres of very dilute urine (25–200 mOsm/kg) per day may be produced If the patient is unable

to drink freely (most ICU patients), or the thirst nisms are impaired, profound dehydration will result very rapidly unless appropriate interventions are made by the physician Where ADH deficiency is rela-tive rather than absolute, it is possible for the patient

mecha-to partially concentrate the urine and values of 500–800 mOsm/kg would not be atypical However, these osmolalities are inappropriately low relative to the plasma osmolality In partial ADH deficiency, volumes of urine as low as 3 litres per day may be evidenced These are still inappropriately high when assessed in terms of the solute excretion of the patient, but are more difficult to recognise as being due to DI as there are many other causes of diureses of this magni-tude Additionally, extrinsic stimulants of ADH release (see Box 59.2) may have an antidiuretic effect further complicating the diagnosis

The plasma osmolality measured in central DI is usually in the higher regions of the normal range or very slightly supranormal It is remarkably constant in those with free access to water and intact thirst mecha-nisms as they will drink huge quantities of water to regulate and maintain their water balance Hyper-osmolality or hypernatraemia suggests impaired sensa-tion of thirst or inability to access water (see water deprivation test later) and can also be seen if patients are administered large quantities of isotonic saline or Hartman’s solution to replace their hypotonic urine losses If unrecognised and untreated, hyperosmolality and hypernatraemia may result in death

Cranial diabetes insipidus is usually associated with reduced production of ADH or damage to the normal release mechanisms of ADH However, there can be dysfunction of the osmolality sensing mechanism at receptor or intracellular signalling levels whilst actual

concomitant water retention Conversely, stretch of the

baroreceptors will result in a fall in sodium retention

through reduced activity of the sympathetic nervous

and renin–angiotensin–aldosterone systems Stretch

additionally results in the release of ANP/BNP and a

natriuresis through reduced sodium reabsorption in the

distal convoluted tubule and collecting duct ADH

release is reduced by the fall in sympathetic nervous

tone from the baroreceptors ADH secretion may also

be inhibited by the action of ANP on cerebral

osmore-ceptors lying outside the blood–brain barrier.27

The role of low-pressure baroreceptors in the

sys-temic venous circulation and right atrium is less clearly

defined When venodilatation occurs, as is seen in

sepsis or when there is a reduction in cardiac output,

reduced baroreceptor signalling in the high-pressure

system will result in both sodium and water retention

as outlined previously This will expand the

extracel-lular fluid compartment and potentially cause tissue

oedema As sepsis resolves, venous tone is restored,

capillary leak reduces, an increase in the loading of the

high-pressure baroreceptors results and a natriuresis

takes place Patients may become transiently polyuric

as they clear the excess salt and water accumulated

whilst shocked During this physiological diuresis,

plasma osmolality remains tightly within the normal

range provided that renal concentrating mechanisms

have not been injured during the septic episode or by

drug administration

CRANIAL DIABETES INSIPIDUS (CDI)

CONGENTIAL CDI

Congenital CDI is rare and usually inherited as an

autosomal dominant characteristic that results from

mutations of the gene encoding an ADH precursor –

preprovasopressin neurophysin II.28 The onset of the

disease may occur anywhere between 1 year of age and

middle adult life and is associated with the final

destruc-tion of the ADH-producing cells due to an

accumula-tion of the abnormal ADH precursor.29 Until the

destruction of the SON and PVN cells occurs, ADH

secretion (facilitated by expression of the normal

gene) and regulation of plasma osmolality are often

unaffected

ACQUIRED CDI

Acquired CDI may be transient or permanent and can

arise from an absolute (complete) or relative

(incom-plete) lack of ADH Complete central DI is usually

asso-ciated with lesions above the level of the median

eminence, in the supraoptic or paraventricular nuclei

or of the neurohypophyseal stalk whereby the

pro-duction of ADH in the hypothalamus is terminated.30

Permanent central DI tends to be associated with

transecting, obliterating or chronic inflammatory

Cranial diabetes insipidus (CDI) 643

impairment of the release of ADH (0–5 days in tion), then (ii) a phase of normal or reduced urine output – the ADH previously stored in the pituitary gland is gradually released into the circulation as the cells storing it involute (3–6 days in duration), and finally (iii) persistent polyuria as the pituitary stores exhaust and no replacement hormone from the hypoth-alamus is produced During the second phase of this pattern, administration of fluids may result in volume overload and hyponatraemia as the ADH release is not under feedback control from osmoreceptors but occurs

dura-in an uncontrolled manner as a result of pituitary degeneration Effectively, there is a transient syndrome

of inappropriate ADH (SIADH) secretion The triphasic pattern is usually associated with sudden severe damage to the hypothalamus or pituitary from trauma, surgery or intracranial bleed, and careful, regular clini-cal and biochemical assessment is essential to ensure normal water balance and osmolality during this transi-tion from DI to SIADH and back to DI again

The exact nature of the urinary pattern seen in DI is relatively unimportant and gradual resolution may occur over several months in those with transient DI Imaging the hypothalamus and pituitary with T1 MRI may provide prognostic information as to whether recovery is likely or not; hypothalamic lesions have a poorer prognosis than pituitary ones.35 What is essential

is that meticulous assessments of the patient and their plasma and urinary biochemistry as well as fluid inputs and outputs are made to prevent the development of unnecessary fluid and solute imbalances that could lead

to worsening morbidity or mortality It is important to maintain a high level of suspicion for the development

of DI in anyone who is suffering from pituitary disease

or who has suffered a pituitary injury as the symptoms may have gradual onset Anterior pituitary failure can lessen the impact of central DI because of the deficiency

of ACTH and cortisol, which reduces GFR and free water loss Additionally, the loss of feedback inhibition may stimulate increased release of ADH from the median eminence Thus, in Sheehan’s syndrome and pituitary apoplexy, the presenting symptoms tend not

to be those of DI with polyuria However, once costeroid therapy is commenced then polyuria indicat-ing DI may become apparent or exacerbated Conversely, patients with persistent DI of idiopathic origin should have long-term endocrine follow-up as a number will

corti-go on to develop tumours of the pituitary several years after the diagnosis of DI.36,37

TREATMENT OF CDIFour separate problems have to be addressed when treating CDI:

1 Associated anterior pituitary dysfunction should be

considered and managed when present

2 Hypernatraemia must be recognised and treated

with painstaking care

ADH production and storage are normal It is possible

to have a normal release of ADH in response to

barore-ceptor detection of hypotension but subnormal release

in response to hyperosmolality This has been described

in association with chronic hypernatraemia.33

The main recognised causes of central DI are listed

in Box 59.3 A particularly common cause of DI seen in

the ICU is traumatic or post-surgical brain injury

Trans-sphenoidal surgery for treatment of suprasellar

tumours can result in DI in between 10 and 70% of

patients; the frequency parallels the magnitude of the

tumour being removed Additionally, transcranial

surgery may cause the development of DI in the absence

of a fall in plasma ADH This is postulated to be due to

the release of a hypothalamic ADH precursor that acts

as a competitive antagonist of both ADH and synthetic

analogues The presence of a competitive antagonist

effectively creates an endocrinological picture similar to

nephrogenic DI with normal or high plasma ADH

levels but an inappropriate diuresis of dilute urine

Following surgery or traumatic brain injury, several

different patterns of polyuria can be seen Immediate

polyuria is common and may be transient or

perma-nent Occasionally it is preceded by a period of oliguria

due to an initial surge of ADH release Additionally, a

classical triphasic pattern of urine output may be

observed with: (i) transient polyuria due to transient

644 Diabetes insipidus and other polyuric syndromes

with hypernatraemia, extreme caution is required in the resuscitation, which should take place with isotonic saline solution and frequent reassessments of plasma sodium and cardiovascular and neurological status Where the hypernatraemia is very marked (>155 mmol/L), consideration of a combination of iso-tonic (0.9%) and hypertonic saline should be given to reduce the rate of sodium reduction In the face of hypertonicity of the plasma, cells reduce their chloride and potassium conductance in addition to synthesising intracellular osmolytes If 0.9% saline (effective osmo-lality 290 mOsm/kg when diluted by plasma proteins)

is infused rapidly into hypertonic plasma with a sodium

of 160 mmol/L, an effective osmolality of 330 mOsm/

kg, a rapid drop in plasma osmolality may cause bral and other organ oedema, seizures and death By reducing the tonicity of the plasma gradually, the cells have time to down-regulate their synthesis of intracel-lular osmolytes and increase potassium and chloride conductance to reduce swelling as plasma tonicity falls

cere-CORRECTION OF POLYURIA AND ADH DEFICIENCY

At mild levels of polyuria (2–3 mL/kg/h) where there

is an expectation that the condition may resolve, it may

be appropriate to merely replace the previous hours’ urine output with an appropriate fluid (usually 5% dex-trose or 0.18% saline/4% dextrose) whilst undertaking regular measurements of plasma and urine osmolality and electrolytes Care must be taken not to give so much dextrose as to result in hyperglycaemia, hyperos-molality and osmotic diuresis

Where polyuria is expected to be persistent or is excessive, either ADH/AVP or DDAVP may be admin-istered DDAVP is a selective V2 receptor agonist and thus is less likely to cause hypertension It is also longer acting, resisting breakdown by vasopressinases, and

is usually administered once or twice daily The usual daily dose rate, when administered intrave-nously, intramuscularly or subcutaneously is 1–4 µg daily ADH may be administered subcutaneously or by intravenous infusion and DDAVP may be presented intranasally, subcutaneously, intravenously or orally

In the acute situation, an ADH infusion (0.1–3 U/h) can

be conveniently titrated against urine output The use

of the infusion ensures 100% bioavailability and tates re-establishment of the hypertonic renal medul-lary interstitium before changing the patient to the longer acting DDAVP The dose of ADH or DDAVP is often higher during the acute onset phase of CDI – this may be due to the loss of hypertonicity in the medullary interstitium or due to biologically inactive ADH precur-sors released from the damaged hypothalamic–pituitary tract, which act as competitive antagonists at the V2 renal receptors The dose of ADH or DDAVP used is the minimum dose required to control urine output to

facili-an acceptable rate Excessive administration cfacili-an result

in water retention and the development of osmolal syndromes

hypo-3 Any deficit of total body water must be recognised

and addressed (this may be urgent if the patient is

shocked)

4 The underlying deficiency of ADH causing the

poly-uria must be addressed

In all ICU patients with DI, hourly urine measurements,

hourly fluid losses and fluid inputs and at least

twice-daily urine and plasma osmolalities are recommended

In shocked patients and those with hypernatraemia,

hourly monitoring of plasma sodium is recommended

to prevent worsening of hyperosmolality or over-rapid

correction of hypernatraemia

ANTERIOR PITUITARY DYSFUNCTION

If this is present, it requires recognition and treatment

In the emergent situation with a shocked patient,

hydrocortisone 100 mg can be administered as an i.v

bolus, and steroid replacement continued if needed

Steroid administration may worsen the diuresis but

will improve cardiovascular stability in patients with

pituitary ablation

HYPERNATRAEMIA

If the patient with CDI and ongoing water diuresis

has had restricted access to fluids and developed

hyperosmolality/hypertonicity, or has developed

hypertonicity through replacement of dilute urine with

equal volumes of isotonic (to plasma) intravenous

fluids, then sudden reduction in plasma tonicity may

result in cerebral oedema, pontine myelonecrosis and

permanent neurological damage as a result of water

moving into brain cells down an osmotic gradient (see

below) In order to counteract cellular dehydration in

chronic (>24 hours) hypernatraemic states, the brain

accumulates intracellular organic osmolytes such as

amino acids, taurine and sorbitol.38–40

When a euvolaemic state is present, arginine

vaso-pressin or DDAVP may be administered to reduce

urine output (see below) At the same time, fluid

restric-tion should be imposed and replacement of the

previ-ous hour’s urine output undertaken with an appropriate

fluid to avoid a fall in concentration of sodium by more

than 0.5 mmol/h.41 Absolute safety data are not

avail-able to determine the ideal rate of reduction of plasma

sodium However, when a patient has been

hypernat-raemic for more than 48 hours, a fall of more than

8 mmol/L in any 24-hour period should be avoided.42

Several formulae exist to guide fluid replacement

regi-mens controlling the rate of fall of plasma sodium

con-centrations; reliance on these is not recommended and

extremely close monitoring with hourly review of

plasma sodium is less likely to result in sudden

unex-pected changes in tonicity.43

DEHYDRATION AND HYPOVOLAEMIA

If associated with shock, hypovolaemia requires

rapid resuscitation If hypovolaemia is also associated

Nephrogenic diabetes insipidus 645

severe polyuria and polydipsia due to expression of the abnormal gene Non-sex-linked genetic abnormalities can also cause NDI Approximately 10% of cases of

congenital NDI have mutations of the AQP 2 (aquaporin 2) gene, which codes for the AQP2 channel Over 40 mutations, both autosomal dominant and recessive, have been described to date

The remainder of cases of congenital NDI arises from

a variety of pathophysiologies that result in failure to generate a hypertonic renal medulla, with inability to reabsorb water even if the V2 receptor and acquaporin2 channels are normal A lack of the Kidd antigen (a blood group antigen) results in an inability to concen-trate urine to more than 800 mOsm/kg even with water deprivation and exogenous ADH administration.46 This

is because the antigen is also expressed in the collecting duct epithelium where it functions as a urea transporter (urea transport B protein) and facilitates movement of urea from urine into the medullary interstitium main-taining some of the gradients required to facilitate water reabsorption Similarly, patients with mutations

in chloride channel genes, potassium channel genes or the sodium–potassium–chloride co-transporter gene resulting in the Bartter syndrome are unable to generate

a hypertonic medullary interstitium However, in these patients the defect is more marked and urine can rarely

be concentrated above 350 mOsm/kg.47With congenital NDI, early diagnosis and manage-ment are essential as avoidance of hypernatraemia and dehydration facilitate the achievement of normal devel-opmental milestones and avoid the cerebral damage once commonly accepted as an inevitable association

of NDI

ACQUIRED NDILithium-associated nephrotoxicity remains the com-monest form of acquired NDI with more than 20% of patients on chronic lithium therapy developing polyu-ria Lithium is taken up into the principal cells of the collecting duct via sodium channels and inhibits intra-cellular adenylate cyclase, antagonising the effects of ADH Additionally, it reduces the medullary interstitial hypertonicity possibly through reducing expression of urea transport protein B If patients with early lithium-related NDI are prescribed amiloride, some reversal of both the polyuria and lithium mediated toxicity is pos-sible Amiloride’s natriuretic action is achieved through closure of the luminal sodium channels in the collecting duct, the sodium channels through which lithium enters the cells.48 Indomethacin increases intracellular cAMP and counteracts the diminution of this and AQP2 caused by lithium, resulting in a marked and immedi-ate drop in urine output However, care is required as NSAIDs may worsen renal failure, reducing GFR and lithium excretion thereby worsening toxicity

Hypercalcaemia, hypokalaemia, release of ureteric

or urethral obstruction and hypoproteinaemia are also

Other drugs may also be used to reduce the polyuria

of CDI Provided there is some residual ADH synthesis,

chlorpropamide, clofibrate and carbamazepine are all

reported to enhance ADH release and also increase the

renal responsiveness to ADH Thiazide diuretics may

also be effective Although these agents all reduce urine

output, there is little place for them in the modern

man-agement of CDI in the ICU where DDAVP and ADH

have excellent safety profiles and are more easily

titrated to effect These alternative drugs are discussed

later in the treatment of nephrogenic DI

NEPHROGENIC DIABETES INSIPIDUS

Nephrogenic diabetes insipidus (NDI) may be

congeni-tal or acquired (Box 59.4) As the majority of congenital

cases present in the first week of life, the majority of

cases seen in the adult ICU are acquired The

common-est of these are lithium toxicity due to long-term drug

treatment, hypercalcaemia and post-obstructive

uropa-thy following relief of ureteric or urethral obstruction

CONGENITAL NDI

Some 80–90% of patients with congenital NDI have an

X-linked recessive abnormality of the AVPR 2 gene

coding for the V2-receptor.28,44 Different mutations of

the gene are described but the majority result in

trap-ping of the V2-receptor intracellularly, and unable to

integrate into the membrane of the collecting duct cell

Drugs have been developed that can facilitate receptor

integration into the membrane, restoring some of the

urine-concentrating abilities of ADH.45 The sex linkage

results in the vast majority of affected patients being

male However, female children can also present less

mutationsBartter syndromeGitelman syndromeUrea transport protein B (Kidd Ag) deficiency/

absence

646 Diabetes insipidus and other polyuric syndromes

volume can fall by as much as 30% Combined with a solute-reduced diet, the fall in urine pro-duction can be as high as 50%

b Amiloride is a useful adjunct to thiazide diuretics

in NDI where it causes a further slight reduction

in urine output and combats the hypokalaemia associated with the thiazides It may have benefit

in its own right in lithium-associated ity where it blocks the sodium channels through which lithium enters the principal cells If admin-istered before lithium damage becomes irrevers-ible, it can both reduce the damage to the cells themselves and reverse the antagonism of lithium

nephrotoxic-on the effects of ADH

Loop diuretics are not effective in reducing the diuresis of NDI as, whilst they reduce intravascu-lar volume and stimulate the sympathetic nervous system in a similar manner to thiazides, they also reduce interstitial medullary sodium concentra-tions and hypertonicity thus reducing water rea-bsorption by the collecting duct rather than enhancing it

4 ADH: where NDI is not absolute (most cases of

acquired NDI), supplementing endogenous ADH

to create supraphysiological concentrations in the plasma can result in a fall of urine production by up

to 25% This may occur by antagonism of the effects

of any V2 receptor antagonists present or through greater receptor occupation Care is required with long-term use as hypertension and its associated complications may result

5 NSAIDs: PGE2 increases GFR and urine flow and decreases intracellular cAMP and thus aquaporin expression NSAIDs reduce the formation of renal PGE2 and when used alone may reduce urine output

by up to 50%.51 Combination with low-solute diet and a thiazide diuretic may provide additional anti-diuretic benefit.52 However, the use of NSAIDs has to be weighed against their long-term complica-tions This is particularly true in the ICU population who are at increased risk of both renal impairment and gastric erosions Indomethacin is cited to have greater treatment benefit than other NSAIDs in NDI.53 It is also more likely to produce unwanted adverse effects

6 Chlorpropamide: this oral hypoglycaemic agent

enhances both ADH release and the sensitivity of the kidney to it It is suggested to act via increasing the hypertonicity of the renal medulla Doses of 250 mg o.d or b.d are prescribed, but are likely to cause hypoglycaemia.54 Its use is therefore reserved for severe refractory cases of partial NDI

7 Clofibrate: this oral lipid-lowering agent is reported

to enhance ADH release and increase the renal sitivity to ADH.55 Its use in CDI has largely been superseded by the introduction of safer, more effica-cious DDAVP therapy Its use in treatment of DI has been associated with myopathy.56 If considered for

sen-recognised as causing NDI and are associated with

reduced expression of AQP2 channels, urea transport

proteins and a loss of interstitial hypertonicity These

defects normally cause milder polyuria than that

associ-ated with lithium toxicity Finally, the attritions of

ageing lead to loss of urinary concentrating ability It is

suggested that this is due to a combination of

patho-physiological changes characteristic of both NDI and

CDI with relative reductions of both AQP2 and AVP

production.49

TREATMENT OF NDI

The treatment of NDI aims to minimise the occurrence

of hypernatraemia and hypovolaemia and wherever

possible to remove the underlying cause

1 Correct reversible causes: stop any drugs suspected in

the aetiology; then correct hypokalaemia,

hypercal-caemia and hypoproteinaemia

2 Reduce solute load: as urine output is determined by

the solute load to be excreted, reducing the solute

intake will reduce the urine volume accordingly;

if maximum urine concentration is 250 mOsm/kg,

a solute intake of 750 mOsm day requires

produc-tion of at least 3 litres of urine to clear the solute,

whereas if intake is reduced to 500 mmol then 2

litres of urine will suffice In ICU, the reduction of

solute can be difficult as many drugs and diluents

have a high solute load Additionally, patients may

be catabolic and have a high protein requirement

It may be more appropriate not to aim to restrict

solute intake for certain patients but to monitor fluid

balance closely and ensure adequate appropriate

replacement:

a Restrict salt intake (aiming at <100 mmol/day)

b Reduce protein intake aiming to provide the

minimum daily requirement including essential

amino acids This should be done with specialist

dietetic advice and requires careful follow-up to

avoid protein malnutrition It is not appropriate

to protein-restrict children where it may adversely

affect normal growth and development)

3 Diuretics – thiazides and amiloride:

a Thiazides – whereas DI loses water in excess to

solute rendering the plasma hyperosmolal,

result-ing in intracellular dehydration to maintain the

intravascular volume, thiazide diuretics cause

solute loss in excess of water and lead to a drop

in intravascular volume This causes activation of

the sympathetic nervous system and the renin–

angiotensin–aldosterone system and a fall in

glomerular filtration and ANP Additionally,

thi-azides are associated with an increased

expres-sion of AQP2 channels in the collecting duct.50

These neuroendocrine changes lead to an increase

in proximal tubular reabsorption of sodium and

water and an increase in ADH release Less

ultra-filtrate reaches the collecting duct and urine

647 Gestational DI (GDI)

Solute elimination also increases; a small reduction in urine-concentrating ability may have a more marked effect The volume of urine passed per day increases as

a result of passage of an increased solute load ing urinary proteins, glucose and amino acids), increased drinking and a raised GFR A diagnosis of DI therefore requires careful differentiation from a physi-ological polyuria or potentially pathological polyuria

(includ-of separate aetiology (e.g gestational diabetes) in pregnancy

GDI occurs in around 1 : 300 000 pregnancies and can result from:

1 Increased destruction of ADH by excessive

pro-duction of placental vasopressinases67 (especially gemellar pregnancies) or reduced deactivation of vasopressinases (e.g in acute fatty liver of preg-nancy,68 pre-eclampsia or HELLP syndrome) – this may be unresponsive to exogenous ADH adminis-tration as it too is rapidly metabolised DDAVP can

be used instead as it is resistant to degradation by placental vasopressinase

2 Permanently deficient reserve of ADH secretion,

which in the non-pregnant state is asymptomatic but

in the pregnant state is unmasked by the higher vasopressinase activity that cannot be compensated for by increased secretion.69 This condition responds

to treatment with ADH/DDAVP and is indicative of latent, subclinical DI that predated pregnancy Investigation and follow-up following pregnancy

is warranted as a proportion of patients in this category will develop later hypothalamo–pituitary axis pathologies such as tumours or autoimmune hypophysitis

3 Central DI associated with Sheehan syndrome and

pituitary apoplexy – Sheehan syndrome is est, and is usually preceded by major bleeding or hypotension at the time of delivery Pituitary apo-plexy has been described antenatally too.70

common-4 Gestational nephrogenic DI of unknown aetiology

that is resistant to both ADH and DDAVP, with lution in the postnatal period.71

reso-The treatment of GDI varies depending on the ing cause In all cases, it is important not to allow the patient to become hypernatraemic and hyperosmolal as this is likely to have adverse effects on both mother and child Where hypernatraemia and hyperosmolality do occur, careful correction is required in a closely moni-tored, very gradual, stepwise fashion A lowering of sodium by as little as 10 mmol/L per day has been associated with pontine myelinolysis.72

underly-The associations between acute fatty liver of nancy, HELLP and pre-eclampsia and DI are well rec-ognised, if not fully understood It has been suggested that liver dysfunction results in reduced clearance of the vasopressinases released by the placenta and thus increased clearance of maternal ADH.73,74 It is important

preg-to bear these associations in mind as the polyuria of

treatment of partial NDI, biochemical markers of

myopathy should be measured regularly

8 Carbamazepine: carbamazepine can also be tried as

a treatment in partial NDI although it is more

effec-tive in treating partial CDI It increases the renal

responsiveness to ADH, but requires a dose rate

three times higher than that effective as an

antiepi-leptic This high dose rate limits its usefulness

in therapy

9 Molecular chaperones: novel drugs described as

‘molecular chaperones’ are being developed to treat

NDI where the V2 receptor is functional and intact

but confined to the intracellular space, unable to

integrate into the basolateral membrane of the

prin-cipal cell.57 The drugs are membrane-permeable V2

receptor antagonists and are believed to cause

refold-ing of the receptor in a form that allows normal

processing of the receptor into the membrane.58

These are showing some success in animal models

of congenital NDI and with human V2R mutations

associated with NDI in testing in vitro Early studies

in humans report some success.59 Unfortunately, a

recent study with Relcovaptan (SR49059), whilst

showing very promising clinical results, had to be

discontinued owing to possible interference in the

cytochrome P450 pathway Nevertheless, other

chaperone molecules are currently being explored

for human testing.60

GESTATIONAL DI (GDI) (BOX 59.5)

In pregnancy the normal range of plasma osmolalities

falls to 265–285 mOsm/kg and the plasma sodium is

<140 mmol/L The reduction in osmolality is attributed

to a resetting of the central osmostat61,62 with the onset

of development of thirst at an osmolality around

10 mOsm/kg lower than in the non-pregnant state

This has been attributed to increases in the plasma

con-centration of human chorionic gonadotropin (hCG).63

The retention of water and sodium is mediated by

reduced baroreceptor stimulation.64

During pregnancy, the placenta produces

vaso-pressinases (cysteine–aminopeptidases) that increase

ADH metabolism up to fourfold65 and relaxin, which

contributes to the 50% increase in GFR and

venodilata-tion.66 Aldosterone concentrations rise up to fivefold

Idiopathic gestational NDI (resolves post-partum)

648 Diabetes insipidus and other polyuric syndromes

solute in the urine Normally, between 600 and

900 mOsm/day of solute are excreted in the urine Values higher than this indicate a solute diuresis

A spot urine osmolality may be measured; osmolality higher than 300 mOsm/kg, is suggestive of a solute diuresis It would not be uncommon in the critically ill patient to encounter simultaneous impairment of both water reabsorption and impaired solute elimination In this instance, 24-hour solute excretion will be increased but the urine may be hypo-osmolal

THE DIAGNOSIS OF POLYURIC SYNDROMESMEASURE AND CALCULATE PLASMA 

is not obvious gross fluid and solute overload of the patient

Where the patient is polyuric with a high plasma osmolality and maximum urine osmolalities are being achieved, an osmotic diuresis is implied The diuresis may be inappropriate in as much as it is leading to dehydration, but appropriate in that the kidneys are retaining as much water as they can for the large solute

load being excreted If there is a normal osmolal gap (the

difference between measured and calculated plasma osmolality, normal <10 mOsm/kg), hyperglycaemia, hypernatraemia or hyperkalaemia are implied If the osmolal gap is greater than 10 mOsm/kg, investigation should be undertaken to look for an unmeasured solute such as ethanol, mannitol, ethylene glycol, sorbitol or methanol If plasma osmolality is less than 280 mOsm/

kg, urine osmolality would also be expected to be lower than this to clear free water This picture implies water overload, which may be iatrogenic or patient mediated Low plasma osmolality with high urine osmolality implies SIADH and would not normally be associated with polyuria

WATER DEPRIVATION AND ADH TESTS

In health, being deprived of water rapidly results in

an increase in plasma osmolality, which causes ADH release and an increase in urine osmolality to 1000–1200 mOsm/kg in order to preserve water and reduce plasma osmolality back towards its normal value When the cause of polyuria is unclear and the

DI may mask the hypertension and fluid overload of

pre-eclampsia and HELLP leading to later diagnosis,

delayed management and poorer outcome.75

POLYDIPSIA (PSYCHOGENIC/ 

NEUROGENIC/PRIMARY)

Polydipsia may result from: (i) a psychiatric disorder

or disturbance,76 (ii) drugs that give the sensation of

dry mouth77 or airways to the patient (e.g oxygen

therapy, phenothiazines, anticholinergics), or (iii)

hypothalamic lesions that directly disturb the thirst

centre78 (e.g sarcoidosis) In all three of the above

causes of polydipsia, excessive drinking is associated

with the production of large quantities of urine of

appropriate osmolality If the fluid ingested is largely

hypotonic, the urine will be hypo-osmolal and result

from a fall in ADH secretion If the fluid ingested is

hypertonic, the urine will have high osmolality but

remain of high volume because of the combination of

low ADH production and high ANP production causing

a solute diuresis

Polydipsia may also result from the appropriate

detection by osmoreceptors of a raised plasma

osmolal-ity due to raised glucose, alcohol or sodium The

glyco-suria itself will cause an osmotic diuresis and plasma

osmolality may be normal or raised depending on the

severity of the hyperglycaemia and any accompanying

ketoacidosis and dehydration

Excessive drinking of hypotonic fluids leads to

hyponatraemia and may progress to water intoxication

with cerebral oedema, confusion, impaired

conscious-ness, seizures and death It has also been postulated

that long-term polydipsia may lead to the development

of dysregulation of ADH secretion and cranial DI.79

These are important considerations in patients

present-ing with reduced consciousness and polyuria; water

intoxication, more usually associated with SIADH, and

DI may coexist

SOLUTE DIURESIS

Just as failure to reabsorb water can result in polyuria,

failure to reabsorb solute can result in an osmotic load

in the tubule that opposes water absorption in the

con-voluted tubules and collecting duct The commonest

cause of this in the general patient population is

glyco-suria In the ICU setting, a solute diuresis may also be

associated with the administration of diuretic drugs,

high-protein feeds (increased urea load), supranormal

quantities of sodium and other solutes through fluids,

feeds and drugs, recovery from acute renal failure with

tubular inability to reabsorb solute, and drug-induced

tubular damage

To differentiate a solute diuresis from a water

diure-sis it is advisable to measure the 24-hour excretion of

The diagnosis of polyuric syndromes 649

Step 5: plasma and urine osmolalities are plotted

against plasma ADH concentrations (Fig 59.5).INTERPRETATION OF THE TESTS   

(SEE FIGS 59.4 AND 59.5)

In complete DI, plasma osmolality will rise but urine osmolality will not rise above 300 mOsm/kg Upon administration of ADH, patients with complete CDI will raise their urine osmolality to 500 mOsm/kg or higher, whereas there will be no rise in urine osmolality

in complete NDI In complete CDI the original plasma ADH measurement will be zero, whereas in complete NDI the initial ADH measurement will be normal or high depending upon the corresponding plasma osmo-lality at the time of measurement In partial DI, plasma osmolality will rise and urine osmolality will also increase but usually plateaus between 400 and

800 mOsm/kg In partial CDI the ADH will initially be normal or low and will rise with increasing plasma osmolality but is unlikely to rise above 4–5 pg/mL In partial NDI, the ADH will initially be normal or high and will increase with plasma osmolality to >8 pg/mL but without achieving a correspondingly appropriate rise in urine concentration

Following administration of ADH or DDAVP, urine osmolality is expected to at least double in complete

patient is not already clinically dehydrated, a water

deprivation test may be useful to determine the

cause of the diuresis In patients with severe polyuria,

the test is potentially dangerous as dehydration

and hyperosmolality may develop very rapidly

resulting in permanent cerebral damage and

cardiovas-cular collapse It is therefore necessary to undertake

the test under very close supervision during daylight

hours

The limitations of the test should also be

appreciated:

1 In acute CDI, release of ADH precursors from injured

brain tissue may render interpretation of ADH tests

unreliable through cross-reactions with ADH

meas-urement assays

2 At high concentrations of ADH, the urine

concentra-tions achieved in partial NDI and primary

polydip-sia may be similar

3 Patients with partial CDI may occasionally become

hypersensitive to relatively small rises in ADH,

which may be induced by the rise in osmolality

associated with water deprivation and thus

maxi-mally concentrate urine once osmolality is raised

leading to an erroneous diagnosis of primary

polydipsia.80

4 In patients with chronic hypernatraemia and CDI

secondary to osmoreceptor dysfunction,

hypovolae-mia with water deprivation may cause sufficient

baroreceptor stimulus to release ADH and suggest

normal urine concentrating abilities.81

Step 1: plasma and urine osmolalities, plasma ADH

and patient body weight are measured at time zero and

access to i.v./oral fluids is denied

Step 2: plasma and urine osmolalities and patient

body weight are measured hourly until either three

consecutive urine osmolalities are within 30 mOsm/kg

of one another or plasma osmolality is >295 mOsm/kg,

or the patient loses more than 5% of the body weight

from baseline At this time, plasma ADH is measured

again

Step 3: if plasma osmolality is >295 mOsm/kg and

urine osmolality is <800 mOsm/kg, ADH (5 units AVP

s.c or 4 µg DDAVP s.c.) is administered to the patient

and plasma and urine osmolalities are measured hourly

for 3 hours (this time is necessary to allow time for

at least partial recovery of the medullary interstitial

hypertonic gradient in patients with primary

polydip-sia) DDAVP is preferred to AVP as it avoids

misinter-pretation of results in the presence of vasopressinases,

which would rapidly metabolise AVP and suggest a

diagnosis of NDI rather than CDI Although neither

is the correct diagnosis if vasopressinases are present,

the treatment is as for CDI (i.e the administration of

DDAVP)

Step 4: urine osmolality is then plotted against

plasma osmolality (Fig 59.4)

Figure 59.4  Urine versus plasma osmolality during water 

deprivation testing. DDAVP = 1-deamino-8-O-arginine 

vasopressin; CDI = cranial diabetes insipidus; 

NDI = nephrogenic diabetes insipidus. (Adapted from Sands JM, Bichet DG Nephrogenic diabetes insipidus

Normal

Partial CDI

Complete CDIComplete NDI

Partial NDI or

‘polydipsic DI’

DDAVPadministered

Plasma osmolality (mosmol/kg)

650 Diabetes insipidus and other polyuric syndromes

hypo-osmolal or iso-osmolal to plasma following ADH/DDAVP administration However, this generali-sation is indicative only and for greater certainty it is preferred to have measured sequential ADH concentra-tions to assess hypothalamic–pituitary function inde-pendently of the renal concentrating ability

Water deprivation tests should not be conducted in infants, patients with pre-existing hypovolaemia or hyperosmolality In the latter two categories, treatment

of the fluid deficit and/or solute excess should precede further investigations In infants and in adults with equivocal water deprivation test results, an infusion of hypertonic saline should be considered

HYPERTONIC SALINE INFUSION TEST

In patients with equivocal results from a water tion test and in those at high risk of dehydration and hypovolaemia from water deprivation, a hypertonic saline infusion test may be undertaken to establish the cause of a water diuresis Interpretation of the test is as for the water deprivation test, but there is a clearer demarcation between partial CDI and primary polydip-sia (the latter having a normal rise in ADH in response

depriva-to increasing plasma osmolality, whereas the former will have no rise or an obtunded one) and the risk of missing a diagnosis of CDI secondary to osmoreceptor dysfunction is reduced.82

Hypertonic saline is available in multiple different concentrations Care is required in calculating the appropriate infusion rate to use for the test as this varies with the concentration of the hypertonic preparation stocked 0.0425 mmol/kg/min of hypertonic sodium chloride solution is infused for up to 3 hours or until a plasma osmolality of 300 mOsm/kg is achieved.Blood samples are taken 30 minutes before and at 30-minute intervals throughout the duration of the test and plasma sodium, osmolality and ADH are meas-ured Urine samples are collected before and where possible at 60-minute intervals throughout the test period and measurements of osmolality and sodium performed Thirst and blood pressure are recorded at 30-minute intervals

MRI-T-1-WEIGHTED IMAGING OF THE NEUROHYPOPHYSEAL TRACT

Imaging may be helpful in differentiating partial CDI from psychogenic polydipsia where results of a water deprivation test and the history make the differentia-tion uncertain In CDI, the normal bright spot (stored ADH34) seen in the posterior pituitary is usually reduced

or absent, whereas in psychogenic polydipsia it is usually well preserved or even enhanced (Fig 59.6).Although rapid and less labour intensive than a hypertonic saline infusion test, the results of MRI are not yet held to be entirely specific or sensitive It is reported that the signal is often reduced in nephrogenic

CDI and rise by 10–50% in partial CDI or NDI In

com-plete NDI, there will be no rise in urine osmolality

Partial CDI may be inferentially differentiated from

partial NDI on the basis of urine osmolality alone; in

the former, urine osmolality rises above plasma

osmo-lality whereas in partial NDI it tends to remain

Normal subjectsand CDI afteradministration

of ADH

Partial cranial DIComplete cranial DI

Complete

NDI PartialNDI

300Plasma osmolality (mmol/kg)

Urine osmolality (mmol/kg)

320280

The diagnosis of polyuric syndromes 651

diabetes (possibly due to ADH store depletion ary to over-secretion)28 and in up to 30% of elderly subjects without any clinical symptoms of DI.83 Addi-tionally, the signal intensity may change bi-directionally over time, even in young subjects.84 Given these find-ings, MRI-derived diagnostic information should prob-ably be considered indicative rather than conclusive.OTHER TESTS

second-Other tests have been explored to investigate polyuric syndromes in patients believed to have DI Non-osmotic stimuli of ADH release such as nicotine, nausea and hypotension are not considered sufficiently reliable or consistent to be of practical use More promisingly, it appears that the biochemically stable C-terminal glyco-protein cleaved from the ADH pro-hormone at the time

of pro-hormone activation is relatively easy to measure and correlates well with plasma ADH concentrations This ‘plasma copeptin’ may offer a future alternative to ADH for measurement during standard water depriva-tion and hypertonic saline tests.85

gland (arrowhead). (Reproduced with permission from

Journal of Clinical Endocrinology and Metabolism

2012;97:3426–37, Wiebke Fenske and Bruno Allolio

Clinical Review: Current State and Future Perspectives in

the Diagnosis of Diabetes Insipidus.)

http://www.expertconsult.com

Access the complete references list online at 

5 McKinely MJ, Denton DA, Weisinger RS Sensors for

antidiuresis and thirst – osmoreceptors or CSF

sodium detectors? Brain Res 1978;141:89–103

11 Antunes-Rodrigues J, de Castro M, Elias LLK, et al

Neuroendocrine control of body fluid metabolism

Physiol Rev 2004;84:169–208

26 Schrier RW Water and sodium retention in

edema-tous disorders: role of vasopressin and aldosterone

Am J Med 2006;119(7A):S47–53

31 Maghnie M, Altobelli M, di Iorgi N, et al Idiopathic

central diabetes insipidus is associated with

abnor-mal blood supply to the posterior pituitary gland

caused by vascular impairment of the inferior

hypo-physeal artery system J Endocrinol Metab 2004;89:

1891–6

35 Makaryus AN, McFarlane SI Diabetes insipidus: diagnosis and treatment of a complex disease Clev Clin J Med 2006;73(1):65–71

49 Sands JM, Bichet DG Nephrogenic diabetes idus Ann Intern Med 2006;144:186–94

insip-59 Bernier V, Morello JP, Zarruk A, et al Pharmacologic chaperones as a potential treatment for x-linked nephrogenic diabetes insipidus J Am Soc Nephrol 2006;17:232–43

75 Aleksandrov N, Audibert F, Bedard MJ, et al tional diabetes insipidus: a review of an underdiag-nosed condition J Obstet Gynaecol Can 2010;32(3): 225–31

Gesta-References 651.e1

REFERENCES

1 Dorwart WV, Chalmers L Comparison of methods

for calculating serum osmolality from chemical

con-centrations and the prognostic value of such

calcula-tions Clin Chem 1975;21/2:190–4

2 Worthley LI, Guerin M, Pain RW For calculating

osmolality, the simplest formula is the best Anaesth

Intensive Care 1987;15(2):199–202

3 Rasouli M, Kalantair KR Comparison of methods for

calculating serum osmolality: multivariate linear

regression analysis Clin Chem Lab Med 2005;43(6):

635–40

4 Lee CY, Burnett JC Jr Natriuretic peptides and

thera-peutic applications Heart Fail Rev 2007;12(2):

131–42

5 McKinely MJ, Denton DA, Weisinger RS Sensors for

antidiuresis and thirst – osmoreceptors or CSF

sodium detectors? Brain Res 1978;141:89–103

6 Keller-Wood M ACTH responses to CRF and AVP

in pregnant and non-pregnant ewes Am J Physiol –

Regulatory Integrative Comp Physiol 1998;274:

1762–8

7 Kalogeras KT, Nieman LK, Friedman TC, et al

Infe-rior petrosal sinus sampling in healthy human

sub-jects reveals a unilateral corticotropin-releasing

hormone-induced arginine vasopressin release

asso-ciated with ipsilateral adrenocorticotropin secretion

J Clin Invest 1996;97(9):2045–50

8 Stricker EM, Sved AF Thirst Nutrition 2000;16:

821–6

9 Halter JB, Goldberg AP, Robertson GL, et al Selective

osmoreceptor dysfunction in the syndrome of chronic

hypernatraemia J Clin Endocrinol Metab 1977;44:

609–16

10 Holmes CL, Patel BM, Russell JA, et al Physiology

of vasopressin relevant to management of septic

shock Chest 2001;120:989–1002

11 Antunes-Rodrigues J, de Castro M, Elias LLK, et al

Neuroendocrine control of body fluid metabolism

Physiol Rev 2004;84:169–208

12 Czaczkes JW Physiologic studies of antidiuretic

hormone by its direct measurement in human

plasma J Clin Invest 1964;43:1625–40

13 Holmes CL, Landry DW, Granton JT Science review:

vasopressin and the cardiovascular system parts 1

and 2 Crit Care 2003;7:427–34; 2004;8:15–23

14 Hantash, BM, Thomas AP, Reeves JP Regulation

of the cardiac L-type calcium channel in L6 cells

by arginine–vasopressin Biochem J 2006;400(Pt 3):

411–19

15 Bankir L Antidiuretic action of vasopressin:

quanti-tative aspects and interaction between V1a and V2

receptor mediated effects Cardiovasc Res 2001;51:

372–90

16 Landry DW, Levin HR, Gallant EM, et al

Vaso-pressin pressor hypersensitivity in vasodilatory

septic shock Crit Care Med 1997;95:1122–5

17 Maturi MF, Martin SE, Markle D, et al Coronary

vasoconstriction induced by vasopressin Production

of myocardial ischaemia in dogs by constriction of

non-diseased small vessels Circulation 1991;83: 2111–21

18 Vanhoutte PM, Katusic ZS, Shepherd JT Vasopressin induces endothelium-dependent relaxations of cere-bral and coronary but not of systemic arteries

J Hypertens Suppl 1984;2:S421–2

19 Okamurat T, Ayajiki K, Fujiokah H, et al nisms underlying arginine vasopressin induced relaxation in isolated monkey coronary arteries

Mecha-J Hypertens 1999;17(5):673–8

20 Sellke FW, Quillen JE Altered effects of vasopressin

on the coronary circulation after ischaemia J Thorac Cardiovasc Surg 1992;104:357–63

21 Nussey SS, Bevaqn DH, Ang VT, et al Effects of arginine vasopressin (AVP) infusions on circulating concentrations of platelet AVP, factor VIII:C and von Willebrand factor Thromb Haemost 1986;55(1): 34–6

22 Haslam RJ, Rosson GM Aggregation of human blood platelets by vasopressin Am J Physiol 1972; 223:958–67

23 Wun T, Paglieroni T, Lanchant NA Physiological concentrations of arginine vasopressin activate human platelets in vitro Br J Haematol 1996;92: 968–72

24 Filep J, Rosenkranz B Mechanisms of vasopressin induced platelet aggregation Thromb Res 1987;45: 7–15

25 Vander AJ Renal Physiology 5th ed New York: McGraw Hill; 1995 p 116–44

26 Schrier RW Water and sodium retention in tous disorders: role of vasopressin and aldosterone

edema-Am J Med 2006;119(7A):S47–53

27 Richard D, Bourque CW Atrial natriuretic peptide modulates synaptic transmission from osmoreceptor afferents to the supraoptic nucleus J Neurosc 1996; 16(23):7526–32

28 Babey M, Kopp P, Robertson GL Familial forms of diabetes insipidus: clinical and molecular character-istics Nat Rev Endocrinol 2011;7:701–14

29 Hedrich CM, Zachurzok-Buczynska A, Gawlik A, et

al Autosomal dominant neurohypophyseal diabetes insipidus in two families Molecular analysis of the vasopressin–neurophysin II gene and functional studies of three missense mutations Horm Res 2009;71(2):111–19

30 Shucart WA, Jackson I Management of diabetes insipidus in neurosurgical patients J Neurosurg 1976;44:65–71

31 Maghnie M, Altobelli M, di Iorgi N, et al Idiopathic central diabetes insipidus is associated with abnor-mal blood supply to the posterior pituitary gland caused by vascular impairment of the inferior hypo-physeal artery system J Endocrinol Metab 2004;89: 1891–6

32 Pivonello R, De Bellis A, Faggiano A, et al Central diabetes insipidus and autoimmunity: Relationship between the occurrence of antibodies to arginine vasopressin-secreting cells and clinical, immunologi-cal and radiological features in a large cohort of

651.e2 Diabetes insipidus and other polyuric syndromes

patients with central diabetes insipidus of unknown

etiology J Clin Endocrinol Metab 2003;88:1629–36

33 Halter JB, Goldberg AP, Robertson GL, et al Selective

osmoreceptor dysfunction in the syndrome of chronic

hypernatraemia J Clin Endocrinol Metab 1977;44:

609–16

34 Repaske DR, Medlej R, Gulteken EK, et al

Heteroge-neity in clinical manifestation of autosomal dominant

neurohypophyseal diabetes insipidus caused by a

mutation encoding Ala-1-Val in the signal peptide of

the arginine vasopressin/neurophysin II/copeptin

precursor J Clin Endocrinol Metab 1997;82:51–6

35 Makaryus AN, McFarlane SI Diabetes insipidus:

diagnosis and treatment of a complex disease Clev

Clin J Med 2006;73(1):65–71

36 Charmandari E, Brook CG 20 years of experience in

idiopathic central diabetes insipidus Lancet 1999;

353:2212–13

37 Sudha LM, Anthony JB, Grumbach MM, et al

Idio-pathic hypothalamic diabetes insipidus, pituitary

stalk thickening and the occult intracranial

germi-noma in children and adolescents J Clin Endocrinol

Metab 1997;82:1362–7

38 Arieff AI, Kleeman CR Studies on mechanisms of

cerebral edema in diabetic comas Effects of

hyperg-lycemia and rapid lowering of plasma glucose in

normal rabbits J Clin Invest 1973;52(3):571–83

39 Kreis R, Ross BD Cerebral metabolic disturbances in

patients with subacute and chronic diabetes mellitus:

detection with proton MR spectroscopy Radiology

1992;184(1):123–30

40 Lee JH, Arcinue E, Ross BD Organic osmolytes in the

brain of an infant with hypernatremia N Engl J Med

1994;331:439–42

41 Blum D, Brasser D, Kahn A, et al Safe oral

rehydra-tion of hypertonic dehydrarehydra-tion J Pediatric

Gastroen-terol Nutr 1986;5:232–5

42 Lindner G, Funk G Hypernatraemia in critically ill

patients J Crit Care 2013;28(2):216

43 Lindner G, Schwarz C, Kneidinger N, et al Can we

really predict the changes in serum sodium levels?

An analysis of currently proposed formulae in

hyper-natraemic patients Nephr Dial Tranplan 2008;23:

3501–8

44 Spanakis E, Milord E, Gragnoli C AVPR2 Variants

and mutations in nephrogenic diabetes insipidus:

review and missense mutation significance J Cell

Physiol 2008;217:605–17

45 Robben JH, Sze M, Knoers NV, et al Functional

rescue of vasopressin V2 receptor mutants in MDCK

cells by pharmacochaperones: relevance to therapy

of nephrogenic diabetes insipidus Am J Physiol

Renal Physiol 2007;292:F253–260

46 Sands JM, Gargus JJ, Fröhlich O, et al Urinary

con-centrating ability in patients with Jk(a-b-) blood type

who lack carrier-mediated urea transport J Am Soc

Ameliora-49 Sands JM, Bichet DG Nephrogenic diabetes idus Ann Intern Med 2006;144:186–94

insip-50 Kim GH, Lee JW, Oh YK, et al Nephrogenic diabetes insipidus is associated with up-regulation

of aquaporin-2, Na-Cl cotransporter and epithelial sodium channel J Am Soc Nephrol 2004;15: 2836–43

51 Lam SS, Kjellstrand C Emergency treatment of lithium-induced diabetes insipidus with non-steroidal anti-inflammatory drugs Ren Fail 1997;19: 183–8

52 Hochberg Z, Even L, Danon A Amelioration of polyuria in nephrogenic diabetes insipidus due to aquaporin-2 deficiency Clin Endocrinol 1998;49: 39–44

53 Libber S, Harrison H, Spector D Treatment of rogenic diabetes insipidus with prostaglandin syn-thesis inhibitors J Pediatr 1986;108:305–11

neph-54 Thompson P Jr, Erll JM, Schaaf M Comparison of clofibrate and chlorpropamide in vasopressin respon-sive diabetes insipidus Metabolism 1977;26:749–62

55 Moses AM, Howanitz J, vanGemert M, et al Clofibrate-induced antidiuresis J Clin Invest 1973;52: 535–42

56 Matsukura S, Matsumoto J, Chihara K, et al Clofibrate-induced myopathy in patients with diabe-tes insipidus Endocrinol Jpn 1980;27:401–3

57 Robben JH, Kortenoeven ML, Sze M, et al lular activation of vasopressin V2 receptor mutants

Intracel-in nephrogenic diabetes Intracel-insipidus by nonpeptide agonists Proc Natl Acad Sci USA 2009;106(29): 12195–200

58 Wuller S, Wiesner B, Loffler A, et al erones post-translationally enhance cell surface expression by increasing conformational stability of wild type and mutant vasopressin V2 receptors J Biol Chem 2004;279(45): 47254–63

Pharmacochap-59 Bernier V, Morello JP, Zarruk A, et al Pharmacologic chaperones as a potential treatment for x-linked nephrogenic diabetes insipidus J Am Soc Nephrol 2006;17:232–43

60 Los EL, Deen PM, Robben JH Potential of tide (ant)agonists to rescue vasopressin V2 receptor mutants for the treatment of X-linked nephrogenic diabetes insipidus J Neuroendocrinol 2010;22(5): 393–9

nonpep-61 Durr JA, Stamoutsos B, Lindheimer MD lation during pregnancy in the rat Evidence for resetting of the threshold for vasopressin secretion during gestation J Clin Invest 1998;68:337–46

Osmoregu-62 Lindheimer MD, Davison JM Osmoregulation, the secretion of arginine vasopressin and its metabolism during pregnancy Eur J Endocrinol 1995;132: 133–43

63 Davison JM, Shiells EA, Philips PR, et al Serial ation of vasopressin release and thirst in human pregnancy Role of human chorionic gonadotrophin

evalu-References 651.e3

in the osmoregulatory changes of gestation J Clin

Invest 1988;81(3):798–806

64 Schrier RW, Durr J Pregnancy: an overfill or

under-fill state Am J Kidney Dis 1987;9:284–9

65 Davison JM, Sheills EA, Barron WM, et al Changes

in the metabolic clearance of vasopressin and in

plasma vasopressinase throughout human

preg-nancy J Clin Invest 1989;83(4):1313–18

66 Dschietzig T, Stangl K Relaxin: a pregnancy hormone

as central player of body fluid and circulation

home-ostasis Cell Mol Life Sci 2003;60(4):688–700

67 Durr JA, Haggard JG, Hunt JM, et al Diabetes

insip-idus in pregnancy associated with abnormally high

circulating vasopressin activity N Engl J Med 1987;

316:1070–4

68 Cammu H, Velkeniers B, Charels K, et al Idiopathic

acute fatty liver of pregnancy associated with

tran-sient diabetes insipidus Br J Obstet Gynaecol 1987;

94:173–8

69 Iwasaki Y, Osio Y, Kondo K, et al Aggravation of

subclinical diabetes insipidus during pregnancy

N Engl J Med 1991;324:522–6

70 de Heide LJM, van Tol KM, Doorenbos B Pituitary

apoplexy presenting during pregnancy Netherl J

Med 2004;62(10):393–6

71 Jin-no Y, Kamiya Y, Okado M, et al Pregnant woman

with transient diabetes insipidus resistant to

1-desamino-8-D-arginine vasopressin Endocrin J

1998;45:693–6

72 Hoashi S, Margey R, Haroum A, et al Gestational

diabetes insipidus, severe hypernatraemia and

hyperemesis gravidarum in a primigravid

preg-nancy Endoc Abstr 2004;7:297

73 Krege J, Katz VL, Bowes WA Transient diabetes

insipidus of pregnancy Obstet Gynecol Surv 1989;

44:789–95

74 Barbey F, Bonny O, Rothuizen L, et al A pregnant

woman with de novo polyuria-polydipsia and

ele-vated liver enzymes Nephrol Dial Transplant 2003;

18(10):2193–6

75 Aleksandrov N, Audibert F, Bedard MJ, et al tional diabetes insipidus: a review of an underdiag-nosed condition J Obstet Gynaecol Can 2010; 32(3):225–31

Gesta-76 de Leon J Polydipsia: a study in a long-term atric unit Eur Arch Psychiatry Clin Neurosci 2003;253:37–9

psychi-77 Rao KJ, Miller M, Moses A Water intoxication and thioridazine Ann Intern Med 1975;82:61–5

78 Martin JB, Riskind PN Neurologic manifestations

of hypothalamic disease Prog Brain Res 1992;93: 31–40

79 Dundas B, Harris M, Narasimhan M Psychogenic polydipsia review: etiology, differential, and treat-ment Curr Psychiatry Rep 2007;9(3):236–41

80 Zerbe RL, Robertson GL A comparison of plasma vasopressin measurements with a standard indirect test in the differential diagnosis of polyuria N Engl

J Med 1981;305:1539–46

81 Bayliss PH, Robertson GL Osmoregulation of pressin secretion in health and disease Clin Endocri-nol 1988;29:549–76

vaso-82 Doczi T, Tarjanyi J, Kiss J Syndrome of inappropriate antidiuretic syndrome after head injury Neurosur-gery 1982;10:685–688

83 Terano T, Seya A, Tamura Y, et al The relation between the lack of the posterior pituitary bright signal on magnetic resonance images and posterior pituitary hormone in elderly subjects Pathophysiol-ogy 1996;3(3):163–7

84 Brooks BS, el Gammal T, Allison JD, et al Frequency and variation of the posterior pituitary bright signal

on MR images AJNR Am J Neuroradiol 1989;10(5):943–8

85 Fenske W, Allolio B Current state and future spectives in the diagnosis of diabetes insipidus: a clinical review Clin Endocrinol Metab 2012;97: 3426–37

Thyroid emergencies

Jonathan M Handy and Alexander M Man Ying Li

Thyroid emergencies are a rare cause for admission to

critical care However, mortality is high unless specific

treatment is provided in an expeditious manner

Abnor-mal thyroid function tests are commonly encountered

during critical illness; numerous factors must be

con-sidered before interpreting these findings as indicating

thyroid disease

BASIC PHYSIOLOGY

Thyroid hormones affect the function of virtually

every organ system and must be constantly available

for these functions to continue The two biologically

active hormones are tetraiodothyronine (thyroxine

or T4) and tri-iodothyronine (T3) These are synthesised

by incorporating iodine into tyrosine residues, a process

which occurs in thyroglobulin contained within the

lumena of the thyroid gland (Fig 60.1) Stimulation

of hormone release by thyroid-stimulating hormone

(TSH) results in endocytosis of thyroglobulin from

the lumen into the follicular cells, followed by

hydroly-sis to form T4 and T3, which are released into the

circulation.1

Both T4 and T3 contain two iodine atoms on their

inner (tyrosine) ring They differ in that T4 contains two

further iodine atoms on its outer (phenol) ring whereas

T3 contains only one, resulting in a comparatively

longer plasma half-life for T4 of 5–7 days compared

with that of 10 hours for T3 T4 is produced solely by the

thyroid gland whereas the majority of T3 is synthesised

peripherally by the removal of one iodine atom

(deio-dination) from the outer ring of T4 If deiodination of

an inner ring iodine atom occurs, the metabolically inert

reverse-T3 (rT3) is formed This is produced in

prefer-ence to T3 during starvation and many non-thyroidal

illnesses, and the ratio of inactive (rT3) to active T3

syn-thesis appears to play an important role in the control

of metabolism.2 Numerous factors can affect the

periph-eral deiodination process (Box 60.1) Both T4 and T3 are

highly protein bound in the serum, predominantly to

thyroid-binding globulin (TBG), but to a lesser extent

to albumin and pre-albumin Changes in concentration

of these serum-binding proteins have a large effect on

total T4 and T3 serum concentrations Such protein

changes do not, however, effect the concentration

of free hormone or their rates of metabolism The

serum-binding proteins act as both a store and a buffer

to allow an immediate supply of the metabolically active free-T4 (fT4) and free-T3 (fT3) In addition, protein binding reduces the glomerular filtration and renal excretion of the hormones

On reaching the target organs, fT4 and fT3 enter the cells predominantly by diffusion Here, microsomal enzymes deiodinate the fT4 to form fT3 This varies in differing tissues, the majority occurring in the liver, kidney and muscle The fT3 subsequently diffuses into the nucleus where it binds nuclear receptors and exerts its affect through stimulation of messenger RNA (mRNA) with subsequent synthesis of polypep-tides including hormones and enzymes The role of thyroid hormones in development and homeostasis

is widespread and profound; the most obvious effects are to stimulate basal metabolic rate and sensi-tivity of the cardiovascular and nervous systems to catecholamines

The regulation of thyroid function is nantly determined by three main mechanisms, the latter two providing physiological control First, avail-ability of iodine is crucial for the synthesis of the thyroid hormones Dietary iodide is absorbed and rapidly distributed in the extracellular fluid, which also con-tains iodide released from the thyroid gland and from peripheral deiodination processes This becomes trapped within thyroid follicular cells, from which it is actively transported into the lumen to be oxidised into iodine and subsequently combined with tyrosine.3Other ions such as perchlorate and pertechnetate share this follicular cell active transport mechanism and thus act as competitive inhibitors for the process

predomi-Secondly, thyroid hormone release is controlled by

a close feedback loop with the anterior pituitary ished levels of circulating hormones trigger secretion of TSH, which acts on the follicular cells of the thyroid gland causing them to release thyroglobulin-rich colloid from the lumena This thyroglobulin is hydrolysed to form T4 and T3 for systemic release Increased levels

Dimin-of T4 and T3 cause diminished TSH secretion, resulting

in the follicular cells becoming flat and allowing increased capacity for colloid storage As a result, less thyroglobulin is mobilised and hydrolysed with less T4 and T3 release The degree to which TSH is secreted in response to changes in circulating thyroid hormones is

Thyroid crisis (thyroid storm) 653

dependent on the hypothalamic hormone releasing hormone (TRH), which is itself modulated by feedback from the thyroid hormones (see Fig 60.1) TRH secretion is inhibited by dopamine, glucocorti-coids and somatostatin

thyrotropin-Lastly, further regulation occurs during the dependent peripheral conversion of fT4 to fT3 It is this latter stage that provides the rapid and fine control of local fT3 availability All of these mechanisms may be altered by drugs and in pathological states

enzyme-THYROID CRISIS (THYROID STORM)Thyrotoxic storm is arguably the most serious compli-cation of hyperthyroidism, with reported mortality ranging from 10 to 75% in hospitalised patients.4,5 Crisis most commonly occurs as a result of unrecognised or poorly controlled Grave’s disease; however, other underlying diseases may be the cause.6,7 Females out-number males Laboratory findings are inconsistent owing to acute disruption of the normal steady state of the circulating hormones and there is no definitive value that separates thyrotoxicosis from thyroid storm The latter is a clinical diagnosis, and a scoring system has been proposed to guide the likelihood of the diag-nosis (Table 60.1).8 Precipitating factors are not always present, though many have been identified (Box 60.2).CLINICAL PRESENTATION ( Box 60.3 )

The classic signs of thyroid crisis include fever, cardia, tremor, diarrhoea, nausea and vomiting.9However, presentation is extremely variable and may range from apathetic hyperthyroidism (apathy, depres-sion, hyporeflexia and myopathy)10 to multiple organ

tachy-Figure 60.1  Synthesis of tetraiodothyronine (T4) and 

Thyroid follicle

containing thyroglobulin

Thyroid cells

TSH or thyrotropin from pituitary

Thyroxine binding protein

Proteolytic enzymes

Oxydizing enzyme

Coupling

enzyme

Amino acids Blood-

Triiodo-tyrosine (T 3 )

Body cell

BMR and other functions

l – → l – → l 2 → DIT → T

3 → T 4 + T 3 MIT T 4 TSH or thyrotropin

2.  Add a further 10 points if atrial fibrillation is present.

3.  Add a further 10 points if an identifiable precipitating factor is present.

4.  Total score of 45 or greater is highly suggestive of thyroid storm. Total score of 25–44 supports impending crisis. Total score of less  than 25 makes thyroid storm unlikely.

CNS = central nervous system; GI = gastrointestinal.

*Adapted from Tietgens ST, Leinung MC. Thyroid storm. Medical Clinics of North America, 1995;79:169–184.

654 Thyroid emergencies

dysfunction.11,12 Differential diagnosis includes sepsis

and other causes of hyperpyrexia such as adrenergic

and anticholinergic syndromes

FEVER

This is the most characteristic feature Temperature

may rise above 41°C There have been suggestions that

pyrexia is present in all cases of thyroid storm,13 though

normothermia has also been reported.11 Pyrexia is rare

in uncomplicated thyrotoxicosis and should always

raise suspicion of thyroid storm It is not clear whether

this febrile response is due to alteration of central

ther-moregulation or elevation of basal metabolic

thermo-genesis beyond the body’s ability to lose heat

CARDIOVASCULAR FEATURES

Fluid requirements may be substantial in some

patients, whereas diuresis may be required in those

with severe heart failure Cardiac decompensation can

occur in young patients with no known antecedent

cardiac disease Systolic hypertension with widened

pulse pressure is common initially; however,

hypoten-sion supervenes later Shock with vascular collapse is a

pre-terminal sign.14

NEUROMUSCULAR FEATURES

Tremor is a common early sign, but as ‘storm’ progresses

central nervous dysfunction evolves with progression

from agitation and anxiety to encephalopathy or even

coma.15 Thyroid storm has been reported in association

with status epilepticus and cerebrovascular accident.16

Weakness may be a feature, particularly with apathetic

thyrotoxicosis.11 Thyrotoxic myopathy and

rhabdomy-olysis may be present,11,17 the latter being differentiated

from the former by its association with markedly

ele-vated creatine phosphokinase levels A number of other

syndromes of neuromuscular weakness have been

described including hypokalaemic periodic

paraly-sis18,19 and myasthenia gravis.20

GASTROINTESTINAL FEATURES

Diarrhoea, nausea and vomiting are common, though the patient may present with symptoms of an acute abdomen.21 Severe abdominal tenderness should raise the possibility of an abdominal emergency Liver func-tion tests may be abnormal due to congestion or necro-sis and tenderness over the hepatic area may be present Hepatosplenomegaly may be present The presence of jaundice is a poor prognostic sign.14

RESPIRATORY CONSIDERATIONS

Dyspnoea at rest or on exertion may be present for a number of reasons Oxygen consumption and carbon dioxide production are increased with subsequent increase in the respiratory burden This may be exa-cerbated by pulmonary oedema, respiratory muscle weakness and tracheal obstruction from enlarged goitre (rare)

LABORATORY FINDINGSNumerous abnormalities may be found:

• fT4 and fT3 are usually increased, though this does not correlate with clinical severity; TSH is undetectable

• hyperglycemia in non-diabetics

• leucocytosis with a left shift, even in the absence of infection (leucopenia may be present in patients with Graves’ disease)

• abnormal liver function tests and naemia

hyperbilirubi-• hypercalcemia due to haemoconcentration and the effect of thyroid hormones on bone resorption

• hypokalaemia and hypomagnesaemia (particularly

•  Neuromuscular:

–  Tremor–  Encephalopathy, coma–  Weakness

•  Gastrointestinal:

–  Diarrhoea, nausea and vomiting

•  Respiratory:

–  Dyspnoea–  Increased  oxygen  consumption  and  carbon  dioxide production

•  Goitre (possible airway compromise)

•  Laboratory abnormalities

Thyroid crisis (thyroid storm) 655

THIONAMIDES

These drugs block de novo synthesis of thyroid mones within 1–2 hours of administration, but have no effect on the release of preformed glandular stores of thyroid hormones Transient leucopenia is common (20%) and agranulocytosis can rarely occur with carbi-mazole use

hor-Propylthiouracil

This is usually considered the drug of choice in thyroid storm owing to its ability to partially block peripheral conversion of T4 to T3 Its main mechanism of action is

to block the iodination of tyrosine Only enteral rations are available and absorption may be unpredict-able during thyroid crisis Rectal administration has been reported The loading dose is 100 mg followed by

prepa-100 mg every 2 hours

Methimazole

Methimazole lacks peripheral effects, but has a long duration of action making administration easier and more reliable It may be used in combination with drugs that block peripheral T4-to-T3 conversion (such

as iopanoate or ipodate) Only enteral preparations are available, though rectal administration has been reported Loading dose is 100 mg followed by 20 mg every 8 hours

Carbimazole

This is metabolised to methimazole and is rarely ated with agranulocytosis Only enteral preparations are available

associ-IODINE

The release of preformed glandular thyroid hormones

is inhibited by administering either inorganic iodine or lithium Enterally administered iodides include Lugol’s solution and sodium or potassium iodide Intravenous infusion of sterile sodium iodide may be used at a dose

of 1 g 12-hourly; however, this is not always available commercially If not, it may be prepared by the hospital pharmacy Iodine therapy should not commence without prior thionamide administration Used alone,

it will enrich hormone stores within the thyroid gland and exacerbate thyrotoxicosis

Iodine-containing contrast media (e.g ipodate and iopanoate) may be used instead of the simple iodides, the former blocking T4-to-T3 conversion and inhibiting the cardiac effects of thyroxine Ipodate is administered orally as a loading dose of 3 g followed by 1 g daily As with the iodides, treatment should always be preceded

by thionamide administration

LITHIUM

Lithium carbonate has a similar, though weaker, action

to iodine and can be used in patients with iodine allergy An initial dose regimen of 300 mg 6-hourly has been used with subsequent dosage adjusted to maintain serum drug levels at about 1 mmol/L.29 Renal and neu-rological toxicity tend to limit its use

• serum cortisol should be elevated – if low values are

found, adrenal insufficiency should be considered

and treated; adrenal reserve in thyrotoxic patients is

often exceeded in the absence of absolute adrenal

insufficiency

MANAGEMENT

Treatment is aimed at:

• control and relief of adrenergic symptoms

• correction of thyroid hormone abnormalities

• the precipitating cause

• investigation and treatment of the underlying

thyroid disease

• supportive measures

BETA-ADRENERGIC BLOCKADE

This is the mainstay of controlling adrenergic

symp-toms.22 Intravenous propranolol titrated in 0.5–1mg

increments while monitoring cardiovascular response

diminishes the systemic hypersensitivity to

catechol-amines In addition it inhibits peripheral conversion

of T4 to T3.23 Concurrent administration of enteral

pro-pranolol is the norm, with doses as high as 60–120 mg

4–6-hourly often being necessary owing to enhanced

elimination during thyroid crisis.24 An alternative

regimen uses intravenous esmolol with a loading

dose of 250–500 µg/kg followed by infusion at 50–

100 µg/kg/min This allows rapid titration of beta

blockade while minimising adverse reactions.25 Patients

with contraindications to beta blockade or who exhibit

resistance to this treatment may be successfully treated

with reserpine or guanethidine, though their onset of

action is slow and side-effects may be significant

DIGOXIN

Control of heart rate and rhythm may result in

signifi-cant improvement in cardiac performance Electrolyte

imbalance, particularly hypokalaemia and

hypomagne-saemia, should be corrected prior to drug therapy

Rela-tive resistance to digoxin may occur due to increased

renal clearance26 and increased Na/K ATPase units in

cardiac muscle.27 Arterial thromboembolic phenomena

are common (10–40%) in thyrotoxicosis-related atrial

fibrillation This may be due to a procoagulant state or

an increased incidence of mitral valve prolapse

Anti-coagulation is controversial given the increased

sensi-tivity to warfarin and potential for bleeding; however,

it should be considered in the management of these

patients

AMIODARONE

Amiodarone has theoretical benefits in thyrotoxicosis

as it inhibits peripheral conversion of T4 to T3 and

reduces the concentration of T3-induced adrenoceptors

in cardiac myocytes.28 It does, however, cause profound

(and sometimes physiologically irrelevant) changes to

thyroid function tests and should not therefore be used

as the first-line agent

656 Thyroid emergencies

The condition should be considered in any patient presenting with a reduced level of consciousness and hypothermia The crisis occurs most commonly in elderly women with long-standing undiagnosed or undertreated hypothyroidism in whom an addi-tional significant stress is experienced Numerous pre-cipitating factors have been identified (Box 60.4).CLINICAL PRESENTATION ( Box 60.5 )

Myxoedema coma can be defined when decreased mental status, hypothermia and clinical features of hypothyroidism are present (Box 60.5) When these fea-tures are present, diagnosis is straightforward; however, asymptomatic or atypical presentation (e.g decreased mobility) may occur.32 The presence of hypotension and bradycardia at presentation, a need for mechanical ven-tilation, hypothermia unresponsive to treatment, sepsis, intake of sedative drugs, lower GCS, high APACHE II score, and high SOFA score have been associated with

an increased predicted mortality.33

NEUROMUSCULAR

Alteration of conscious or mental state is present in all patients This can range from personality changes to coma, with about 25% of patients experiencing seizures prior to the onset of coma Electroencephalogram usually reveals non-specific changes Weakness is common and skeletal muscle dysfunction may develop secondary to increased membrane permeability The latter can lead to a rise in creatine phosphokinase Hyponatraemia is present in up to 50% of patients and

STEROIDS

Glucocorticoids reduce T4-to-T3 conversion and may

modulate any autoimmune process underlying the

thyroid crisis (e.g Graves’ disease) In addition, relative

glucocorticoid deficiency may be a feature of the crisis

An ACTH stimulation test is desirable prior to

admin-istration of hydrocortisone (100 mg 6- to 8-hourly);

alternatively dexamethasone (4 mg 6-hourly) can be

administered until the test has been performed

Com-bination therapy with iodides can produce rapid results

Glucocorticoids are the most effective treatment for

type-2 amiodarone-induced thyrotoxicosis.30

OTHER THERAPIES

Plasmapheresis, charcoal haemoperfusion and

dantro-lene have all been used as novel therapies in thyroid

storm; however, their use is not established or proven

SUPPORTIVE THERAPY

Fluid management

Fluid management may be extremely difficult in

patients suffering from thyroid storm, particularly the

elderly Fluid losses may be profound due to diarrhoea,

vomiting, pyrexia and reduced intake However,

con-gestive cardiac failure may also develop as a result

of the high cardiac demand Echocardiography and

cardiac output monitoring may be invaluable in guiding

therapy for such patients

Nutrition

Thyrotoxic patients have high energy expenditure and

may present with a significant energy, vitamin and

nitrogen deficit Nutritional requirements should take

account of any deficit and the ongoing hypercatabolic

state Thiamine is usually supplemented

Drug therapy

Consideration should be given to the enhanced

metab-olism and elimination of drugs that occurs in

thyro-toxic patients Salicylates and furosemide should be

avoided as both displace thyroid hormones from their

binding proteins and can rapidly exacerbate systemic

symptoms

Precipitating factors

Both the precipitating factors and the disease process

underlying the thyroid crisis should be sought and

treated aggressively Infection is the leading precipitant

of crisis; thus early microbiological cultures and

antibi-otic therapy should be considered

MYXOEDEMA COMA

Myxoedema coma is the extreme manifestation of

hypothyroidism, which, although rare, carries a

mortal-ity ranging from 30 to 60% The term is a misnomer in

that the majority of patients present with neither the

non-pitting oedema known as myxeodema nor coma.31

Myxoedema coma 657

must nevertheless be excluded as a precipitant of the crisis ECG changes include bradycardia, decreased voltage, non-specific ST and T changes, varying types of block and prolonged QT interval All of the cardiovas-cular abnormalities are reversible with thyroid hormone treatment.35

RESPIRATORY FEATURESHypothyroidism causes numerous respiratory altera-tions (see Box 60.5) There is a propensity to respiratory alkalosis, particularly during artificial ventilation This

is due to low metabolic rate which may be compounded

by iatrogenic hyperventilation.36 Diaphragmatic ness may occur owing to abnormalities of the phrenic nerve; as a result, exercise tolerance may be signifi-cantly reduced These abnormalities improve with thyroid hormone replacement, though full recovery can take several months

weak-LABORATORY FINDINGSThyroid function tests will reveal low T4 and T3; TSH is raised in primary and low in secondary and tertiary hypothyroidism

Hyponatraemia is common and usually develops owing to free water retention resulting from excess vasopressin secretion or impaired renal function.37 It may be severe and can contribute to diminished mental function Although total body water is increased, intra-vascular volume is usually decreased

Hypoglycaemia may result from hypothyroidism alone, or as a result of concurrent adrenal insufficiency (Schmidt’s syndrome) The mechanism is probably reduced gluconeogenesis, but infection and starvation may contribute

Azotaemia and hypophosphataemia are common; renal function may be severely abnormal owing to low cardiac output and vasoconstriction Mild leucopenia and normocytic anaemia are frequently present, though macrocytic and pernicious anaemia due to autoimmune dysfunction may occur

Arterial blood gases often reveal respiratory sis, hypoxia and hypercapnia

acido-MANAGEMENTThe mainstay of therapy consists of thyroid hormone replacement, steroid replacement and supportive meas-ures Once clinical diagnosis has been made or is sus-pected, blood should be collected for thyroid function and plasma cortisol tests This should be followed by thyroid hormone treatment, which should not be delayed to await laboratory results Consideration should be given to identifying and treating precipitat-ing factors and complications of the crisis

THYROID HORMONE THERAPY

All patients with suspected myxedema coma should receive presumptive treatment with thyroid hormone

may contribute to alterations in conscious level (see

below) Lumbar puncture often reveals elevated protein

levels and a high opening pressure

HYPOTHERMIA

Hypothermia represents the decrease in thermogenesis

that accompanies reduced metabolism and is

exacer-bated by low ambient temperatures Mortality is

pro-portional to the degree of hypothermia A low-reading

thermometer should be used during assessment

CARDIOVASCULAR FEATURES

Diastolic hypertension is due to increased systemic

vascular resistance and blood volume reduction.34

However, myxoedema is associated with bradycardia

and impaired myocardial contractility, with reduced

cardiac output and hypotension a common feature

Although pericardial effusions may occur, tamponade

is uncommon Creatine phosphokinase may be elevated,

though this more commonly originates from skeletal

than from cardiac muscle Acute coronary syndrome

addi-Patients usually present with intravascular fluid depletion despite peripheral oedema Cardiac output monitoring may help guide fluid resuscitation and therapy Echocardiography is useful in identifying cardiac dysfunction, pericardial effusions and assisting

in assessment of intravascular volume status Cardiac monitoring should be used to alert to the presence of arrhythmias Inotropes and vasopressors should be avoided where possible owing to their potential to pre-cipitate cardiac arrhythmias Where inotropes are required, increased dosage may be necessary as reduc-tion in β-adrenoceptors is common; α-adrenoceptor function is usually preserved

Hyponatraemia is reversible with thyroid hormone treatment, but severe abnormalities contributing to neurological dysfunction may require more expedi-tious correction Free water intake should be restricted and hypertonic saline solutions may be required Hypotonic fluid therapy should be avoided If glucose therapy is required, hypertonic solutions (20–50%) should be infused via a central venous catheter.Precipitating factors must be considered As with all critically ill patients, microbial cultures should be col-lected and antibiotic therapy commenced unless cul-tures are negative Prophylaxis against venous thromboembolism and peptic ulceration should be con-sidered Enteral feeding should be attempted, but may

be unsuccessful if gastrointestinal dysfunction and stasis is present

NON-THYROIDAL ILLNESSNon-thyroidal illness describes the phenomenon of starved or systemically unwell patients with abnormal serum thyroid function tests but with no apparent thyroidal illness Low T3, T4 and TSH are commonly found, the degree of abnormality correlating with the severity of illness Variants of these hormone levels are well described Low serum T3 is a frequent finding and occurs due to down-regulation of the monodeiodinase enzyme that converts T4 to T3, while rT3 may increase owing to increased activity of the T4-to-T3 monodeiodinase.42

Serum T4 is also commonly low in the critically ill This is due to a decrease in the concentration of thyroid hormone-binding proteins and the presence of inhibi-tors that reduce T4 binding to these proteins There

is also suggestion that T4 entry into cells may be impaired.43 Free T4 levels should be normal in less severe illness; however, in severe illness the level may

The optimum speed, type, route and dose of thyroid

hormone replacement in myxoedema coma are

unknown owing to the rarity of the condition and

paucity of trials The severity of clinical presentation

does not correlate with the doses of replacement

hormone that are required Rapid replacement can

result in life-threatening myocardial ischaemia or

arrhythmias; delayed therapy exposes patients to

pro-longed risk of complications from the crisis Both

sce-narios are associated with increased mortality

Some experts favour administration of T3 as it is

biologically more active; has more rapid onset of action,

and bypasses the impaired deiodination of T4 to T3 that

occurs in hypothyroidism and non-thyroidal illness

High serum T3 concentration has, however, been

associ-ated with increased mortality38 and T3 is expensive and

may be difficult to obtain T3 may be administered

orally or intravenously and has been combined with T4

therapy.39,40 In one study of 23 successive patients

suf-fering from myxoedema coma, those who received oral

L-thyroxine had no difference in outcome from those

receiving i.v thyroxine.33

Most authorities recommend use of T4 alone38,40,41 as

the delayed conversion to T3 allows more gradual

replacement of the deficient hormone Bioavailability of

orally administered T4 is unpredictable given the high

incidence of gastrointestinal dysfunction; therefore

intravenous administration is more frequently used A

loading dose of intravenous levothyroxine 100–500 µg

is recommended40 as this saturates the binding proteins

This should be followed by 50–100 µg daily until

con-version to the bioequivalent oral formulation is

possi-ble The doses must be adjusted to allow for patient age,

weight and their cardiovascular risk factors; the lower

doses should be administered to patients who are

elderly, frail or have co-morbidities (particularly

car-diovascular disease)

CORTICOSTEROIDS

Corticosteroids are an important part of treatment as

relative or absolute hypoadrenalism may occur

concur-rently with hypothyroid disease A random serum

cor-tisol level should be collected prior to commencing

hydrocortisone therapy at 100 mg 8-hourly If ACTH

stimulation test is warranted, dexamethasone 4 mg

6-hourly should be commenced with conversion to

hydrocortisone or cessation of treatment once the

results are known If random serum cortisol levels

return at normal levels, steroid treatment can be

discontinued

SUPPORTIVE THERAPY

Hypothermia should be treated by passive rewarming

where possible, but active measures may be required

Appropriate cardiovascular, temperature gradient,

electrolyte and acid–base monitoring should be

pro-vided during the rewarming phase in order to prevent

haemodynamic and metabolic compromise

Non-thyroidal illness 659

Cushing’s syndrome Where assays are performed, TSH should not be interpreted in isolation as low values will not discriminate between true thyroid versus non-thyroidal disease If low T4 is also present, non-thyroidal illness is likely If T4 is elevated then hyperthyroidism

is the likely diagnosis, though elevated T4 has been documented in non-thyroidal illness

Given the alterations in these hormones and culties with their assay during critical illness, thyroid hormone replacement should not be undertaken on the strength of TFT results alone Additional laboratory and clinical indications must also be present (Table 60.2)

diffi-be low owing to inadequate correction during the fT4

assay.44

Low serum TSH levels were previously thought to

be associated with the euthyroid state; however, more

recent work suggests that acquired transient central

hypothyroidism is present in these patients.45 Cytokines

such as tumour necrosis factor-α are known to inhibit

TSH secretion Such phenomena are probably

evolu-tionary adaptations to conserve protein and energy

during severe illness Elevated TSH may also occur in

non-thyroidal illness, but few of these patients prove to

have hypothyroidism following recovery from their

acute illness

Changes in thyroid function test (TFT) are well

described during starvation, sepsis, bone marrow

trans-plantation, surgery, myocardial infarction, coronary

artery bypass surgery, and probably any critical illness

However, replacement of thyroid hormone in these

patients is of no benefit and may be harmful;46 hence

thyroid function should not be assessed in critically ill

patients unless there is a strong clinical indication to do

so A number of specific non-thyroidal illnesses are

associated with abnormal TFTs These include: some

psychiatric illnesses, hepatic disease, nephritic

syn-drome, acromegaly, acute intermittent porphyria and

 = tri-iodothyronine; TSH = thyroid-http://www.expertconsult.com

Access the complete references list online at 

1 Kopp P Thyroid hormone synthesis In: Braverman

LE, Utiger RD, editors The Thyroid: Fundamental

and Clinical Text 9th ed Philadelphia: Lippincott

Williams & Wilkins; 2005 p 52

2 Marshall W, Bangert S The thyroid gland In:

Mar-shall W, Bangert S, editors Clinical Chemistry 5th

ed Mosby: Elsevier; 2004 p 161–75

14 Wartofsky L Thyroid storm In: Wass JAH, Shalet

SM, Gale E, et al., editors Oxford Textbook of

Endo-crinology and Diabetes Oxford: Oxford University

Press; 2002 p 481–5

43 De Groot LJ Dangerous dogmas in medicine: the nonthyroidal illness syndrome J Clin Endocrinol Metab 1999;84(1):151–264

45 Chopra IJ Clinical review 86: Euthyroid sick drome: is it a misnomer? J Clin Endocrinol Metab 1997;82(2):329–34

syn-46 Utiger RD Altered thyroid function in nonthyroidal illness and surgery To treat or not to treat? N Engl J Med 1995;333(23):1562–3

References 659.e1

REFERENCES

1 Kopp P Thyroid hormone synthesis In: Braverman

LE, Utiger RD, editors The Thyroid: Fundamental

and Clinical Text 9th ed Philadelphia: Lippincott

Williams & Wilkins; 2005 p 52

2 Marshall W, Bangert S The thyroid gland In:

Mar-shall W, Bangert S, editors Clinical Chemistry 5th

ed Mosby: Elsevier; 2004 p 161–75

3 Spitzweg C, Heufelder AE, Morris JC Thyroid iodine

6 Naito Y, Sone T, Kataoka K, et al Thyroid storm due

to functioning metastatic thyroid carcinoma in a burn

patient Anesthesiology 1997;87(2):433–5

7 Tewari K, Balderston KD, Carpenter SE, et al

Papil-lary thyroid carcinoma manifesting as thyroid storm

of pregnancy: case report Am J Obstet Gynecol

1998;179(3 Pt 1):818–19

8 Burch HB, Wartofsky L Life-threatening

thyrotoxi-cosis Thyroid storm Endocrinol Metab Clin North

Am 1993;22(2):263–77

9 Waldstein SS, Slodki SJ, Kaganiec GI A clinical study

of thyroid storm Ann Intern Med 1960;52:626–42

10 Yi-Sun Y, Chong-Jen Y, Fen-Yu T Apathetic

hypothy-roidism associated with thyroid storm Geriatrics

Gerontol Int 2004;4(4):255–8

11 Jiang YZ, Hutchinson KA, Bartelloni P, et al Thyroid

storm presenting as multiple organ dysfunction

syn-drome Chest 2000;118(3):877–9

12 Rufener S, Arunachalam V, Ajluni R, et al Thyroid

storm precipitated by infection The Endocrinologist

2005;15(2):111–14

13 Mazzaferri EL, Skillman TG Thyroid storm A

review of 22 episodes with special emphasis on the

use of guanethidine Arch Intern Med 1969;124(6):

684–90

14 Wartofsky L Thyroid storm In: Wass JAH, Shalet

SM, Gale E, et al., editors Oxford Textbook of

Endo-crinology and Diabetes Oxford: Oxford University

Press; 2002 p 481–5

15 Aiello DP, DuPlessis AJ, Pattishall 3rd EG, et al

Thyroid storm Presenting with coma and seizures

In a 3-year-old girl Clin Pediatr (Phila) 1989;28(12):

571–4

16 Lee TG, Ha CK, Lim BH Thyroid storm presenting

as status epilepticus and stroke Postgrad Med J

1997;73(855):61

17 Lichstein DM, Arteaga RB Rhabdomyolysis

associ-ated with hyperthyroidism Am J Med Sci 2006;332:

103–5

18 Ko GT, Chow CC, Yeung VT, et al Thyrotoxic

peri-odic paralysis in a Chinese population QJM

1996;89(6):463

19 Dias Da Silva MR, Cerutti JM, Arnaldi LA, et al A

mutation in the KCNE3 potassium channel gene is

associated with susceptibility to thyrotoxic

hypoka-lemic periodic paralysis J Clin Endocrinol Metab

2002;87(11):4881–4

20 Marino M, Ricciardi R, Pinchera A, et al Mild clinical expression of myasthenia gravis associated with autoimmune thyroid diseases J Clin Endocrinol Metab 1997;82(2):438–43

21 Bhattacharyya A, Wiles PG Thyrotoxic crisis senting as acute abdomen J R Soc Med 1997;90(12): 681–2

pre-22 Das G, Kreiger M Treatment of thyrotoxic storm with intravenous administration of propranolol Ann Intern Med 1969;70:985

23 Perrild H, Hansen JM, Skovsted L, et al Different effects of propranolol, alprenolol, sotalol, atenolol and metoprolol on serum T3 and serum rT3 in hyper-thyroidism Clin Endocrinol (Oxf) 1983;18(2): 139–42

24 Feely J, Forrest A, Gunn A, et al Propranolol dosage

in thyrotoxicosis J Clin Endocrinol Metab 1980; 51(3):658–61

25 Brunette DD, Rothong C Emergency department management of thyrotoxic crisis with esmolol Am J Emerg Med 1991;9(3):232–4

26 Shenfield GM, Thompson J, Horn DB Plasma and urinary digoxin in thyroid dysfunction Eur J Clin Pharmacol 1977;12(6):437–43

27 Chaudhury S, Ismail-Beigi F, Gick GG, et al Effect of thyroid hormone on the abundance of Na,K-adenosine triphosphatase alpha-subunit messenger ribonucleic acid Mol Endocrinol 1987;1(1):83–9

28 Perret G, Yin YL, Nicolas P, et al Amiodarone decreases cardiac beta-adrenoceptors through an antagonistic effect on 3,5,3’ triiodothyronine J Car-diovasc Pharmacol 1992;19(4):473–8

29 Boehm TM, Burman KD, Barnes S, et al Lithium and iodine combination therapy for thyrotoxicosis Acta Endocrinol (Copenh) 1980;94(2):174–83

30 Bartalena L, Brogioni S, Grasso L, et al Treatment of amiodarone-induced thyrotoxicosis, a difficult chal-lenge: results of a prospective study J Clin Endocri-nol Metab 1996;81(8):2930–3

31 Nicoloff JT, LoPresti JS Myxedema coma A form of decompensated hypothyroidism Endocrinol Metab Clin North Am 1993;22(2):279–90

32 Mintzer MJ Hypothyroidism and hyperthyroidism

in the elderly J Fla Med Assoc 1992;79(4):231–5

33 Dutta P, Bhansali A, Masoodi SR, et al Predictors of outcome in myxoedema coma: a study from a tertiary care centre Crit Care 2008;12(1):R1

34 Streeten DH, Anderson Jr GH, Howland T, et al Effects of thyroid function on blood pressure Recog-nition of hypothyroid hypertension Hypertension 1988;11(1):78–83

35 Shenoy MM, Goldman JM Hypothyroid opathy: echocardiographic documentation of revers-ibility Am J Med Sci 1987;294(1):1–9

cardiomy-36 Behnia M, Clay AS, Farber MO Management of myxedematous respiratory failure: review of ventila-tion and weaning principles Am J Med Sci 2000; 320(6):368–73

37 Iwasaki Y, Oiso Y, Yamauchi K, et al tion of plasma vasopressin in myxedema J Clin Endocrinol Metab 1990;70(2):534–9

Osmoregula-659.e2 Thyroid emergencies

38 Hylander B, Rosenqvist U Treatment of myxoedema

coma – factors associated with fatal outcome Acta

Endocrinol (Copenh) 1985;108(1):65–71

39 Wartofsky L Myxedema coma In: Braverman LE,

Utiger RD, editors The Thyroid Phiadelphia:

Lippincott-Raven; 1996 p 871

40 Rodriguez I, Fluiters E, Perez-Mendez LF, et al

Factors associated with mortality of patients with

myxoedema coma: prospective study in 11 cases

treated in a single institution J Endocrinol 2004;

180(2):347–50

41 Smallridge RC Metabolic and anatomic thyroid

emergencies: a review Crit Care Med 1992;20(2):

276–91

42 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(7):3202–11

43 De Groot LJ Dangerous dogmas in medicine: the nonthyroidal illness syndrome J Clin Endocrinol Metab 1999;84(1):151–264

44 Chopra IJ, Solomon DH, Hepner GW, et al ingly low free thyroxine index and usefulness of reverse triiodothyronine measurement in nonthyroi-dal illnesses Ann Intern Med 1979;90(6):905–12

Mislead-45 Chopra IJ Clinical review 86: Euthyroid sick drome: is it a misnomer? J Clin Endocrinol Metab 1997;82(2):329–34

syn-46 Utiger RD Altered thyroid function in nonthyroidal illness and surgery To treat or not to treat? N Engl J Med 1995;333(23):1562–3