Hyperosmolar Hyperglycaemic State

Also known as: HHS, HONK, Hyperosmolar non-ketotic coma

Hyperosmolar hyperglycaemic state is a life-threatening complication of, most often, type 2 diabetes, characterised by profound hyperglycaemia, marked hyperosmolality and severe volume depletion, without significant ketoacidosis. Residual endogenous insulin is sufficient to suppress ketogenesis but insufficient to control glucose.

It differs from diabetic ketoacidosis in several ways that matter for management: onset is slower (days to weeks rather than hours), fluid deficits are much larger (often 100–220 mL/kg, or 8–15 litres), glucose and osmolality are higher, ketosis and acidosis are absent or mild, and mortality is considerably higher — in the region of 5–20%, compared with under 1% for diabetic ketoacidosis.

It is frequently the first presentation of previously undiagnosed diabetes, and is usually precipitated by infection, myocardial infarction, stroke, medication non-adherence, or drugs including steroids and thiazides.

Diagnostic features (per Joint British Diabetes Societies guidance):

Marked hyperglycaemia, typically above 30 mmol/L
Serum osmolality above 320 mOsm/kg, calculated as (2 × Na) + glucose + urea
Hypovolaemia, often severe
No significant ketonaemia (ketones below 3 mmol/L) and no significant acidosis (pH above 7.3, bicarbonate above 15 mmol/L)

Investigations:

Glucose, blood ketones, venous blood gas, U&E, osmolality (calculated and measured), FBC, CRP
Sodium requires careful interpretation: hyperglycaemia lowers measured sodium through osmotic dilution, so a corrected sodium should be calculated. A measured sodium that is already high indicates severe water deficit
Potassium, which may be normal or high initially despite a large total body deficit, and will fall with treatment
Identify the precipitant actively: septic screen including cultures and chest imaging, ECG and troponin (myocardial infarction is common and may be silent), and neurological assessment for stroke
Monitor osmolality, glucose, sodium and potassium at least hourly initially
Assess for complications: venous thromboembolism risk is markedly elevated in this hyperviscous, dehydrated state, and arterial thrombosis and foot ulceration also occur

The governing principle is gradual correction. Rapid shifts in osmolality risk cerebral oedema and central pontine myelinolysis, and the physiology has adapted over days rather than hours.

Fluid:

0.9% sodium chloride is the fluid of choice, and fluid replacement alone will lower glucose substantially before any insulin is given
Aim for a positive balance of 3–6 litres by 12 hours, with full replacement of the estimated deficit over 24–48 hours, not faster
Target a fall in glucose of no more than 4–6 mmol/L per hour
Sodium may rise initially as glucose falls, and this is expected rather than alarming; a rise of more than 10 mmol/L in 24 hours, or a failure of osmolality to fall, warrants review. Consider 0.45% saline only if osmolality is not declining despite adequate positive fluid balance

Insulin:

Do not start insulin immediately unless significant ketonaemia is present. This is the key difference from diabetic ketoacidosis management: starting insulin early causes a rapid fluid shift into cells and can precipitate cardiovascular collapse
Start a fixed-rate insulin infusion at 0.05 units/kg/hour only once glucose is no longer falling with fluid alone, or if ketones are raised from the outset
Target a gradual glucose fall, aiming for around 10–15 mmol/L in the first 24 hours rather than normalisation

Potassium:

Replace as in diabetic ketoacidosis, anticipating a fall once insulin is started, and monitoring hourly initially

Alongside:

Treat the precipitant, which is essential and often the determinant of outcome
Prophylactic low molecular weight heparin for all patients unless contraindicated, given the high thrombotic risk, and continued for the duration of admission
Foot protection and pressure area care, since these patients are often immobile and neuropathic
Nutritional and diabetes specialist nurse input, with education and a clear plan for ongoing diabetes management, since many patients are newly diagnosed

Referral: diabetes team for all cases; critical care for reduced consciousness, haemodynamic instability, or severe hyperosmolality.

Clinical toolsCalculators

BMI GCS EDD Parkland Formula

Corrected Sodium Corrected Calcium Anion Gap Creatinine Clearance Insulin Calculations qSOFA Wells PE Wells DVT CHA₂DS₂-VASc HAS-BLED CURB-65 Centor/McIsaac

Phaeochromocytoma

Also known as: Pheochromocytoma

Phaeochromocytoma is a catecholamine secreting tumor arising from chromaffin cells of the adrenal medulla.

When an analogous tumor arises from extra-adrenal sympathetic paraganglia rather than the adrenal medulla itself, it is termed a paraganglioma, and the two are often considered together given their shared biology and clinical presentation.

A meaningful proportion of cases, more than historically appreciated, arise in the context of an underlying hereditary syndrome, including multiple endocrine neoplasia type 2, von Hippel-Lindau syndrome, neurofibromatosis type 1, and hereditary paraganglioma syndromes from succinate dehydrogenase gene mutations, which is why genetic counseling and testing is now recommended for essentially all patients diagnosed with a phaeochromocytoma or paraganglioma, regardless of whether an obvious family history is present.

The classic presentation is paroxysmal, with episodic symptoms from a surge of catecholamine release, though a substantial proportion of patients have persistent, sustained hypertension rather than a purely episodic pattern, and a smaller proportion are entirely asymptomatic, with the tumor identified incidentally on imaging performed for another reason.

The classic paroxysmal triad consists of episodic headache, sweating, and palpitations, often accompanied by a sense of anxiety or impending doom, pallor, and a significant surge in blood pressure during the episode. Episodes may be triggered by specific factors, including certain medications, abdominal palpation, or, notably, induction of anesthesia, which is part of why the diagnosis should be actively considered and excluded before any planned surgery on a patient with an incidentally discovered adrenal mass.

Hypertension, whether paroxysmal or sustained, is a near universal feature and is often resistant to standard antihypertensive therapy, which should prompt consideration of a secondary cause, including phaeochromocytoma, particularly in a younger patient or one with other suggestive features.

Biochemical testing is the first step and should precede any imaging, since imaging findings, particularly incidentally discovered adrenal masses, are common in the general population and non-specific without biochemical confirmation of catecholamine excess.

Plasma free metanephrines or 24 hour urinary fractionatedmetanephrines are the preferred initial tests, offering high sensitivity for catecholamine excess, since metanephrines are continuously produced within the tumor regardless of the episodic nature of catecholamine release itself, making them more reliable than measuring catecholamines directly, which can be normal between paroxysmal episodes.

Certain medications and circumstances can cause false positive results, and a careful review of medications (including certain antidepressants and other agents affecting catecholamine metabolism or measurement) and consideration of the testing conditions (ideally with the patient supine and rested, avoiding caffeine and strenuous exercise beforehand) is important when interpreting borderline results.

Once biochemical confirmation is obtained, CT or MRI of the abdomen localizes the tumor, with MRI often preferred, particularly in younger patients given the avoidance of radiation, and given its good sensitivity for adrenal and extra-adrenal disease. MIBG scintigraphy or, increasingly, PET imaging with specific tracers, provides functional confirmation and is particularly useful for localizing extra-adrenal paragangliomas or identifying metastatic disease, which occurs in a meaningful minority of cases and cannot be reliably predicted from histology alone.

Genetic testing, as noted above, is recommended for essentially all confirmed cases, given the substantial proportion of hereditary disease and the implications for the patient's own surveillance for other syndrome associated tumors as well as for family screening.

Differentials include other causes of paroxysmal hypertension and episodic symptoms, including panic disorder (see that entry), hyperthyroidism, and, importantly, other causes of an incidentally discovered adrenal mass without catecholamine excess (adrenal adenoma, adrenal cortical carcinoma, metastasis), which is why biochemical exclusion of a phaeochromocytoma is a standard part of the workup for any incidentally discovered adrenal mass.

Surgical resection is the definitive treatment and offers the potential for cure in localized disease, but must never be undertaken without adequate preoperative alpha blockade, given the risk of a catastrophic hypertensive crisis if the tumor is manipulated during surgery before adrenergic blockade is established.

Alpha blockade, typically with phenoxybenzamine or a selective alpha-1 blocker such as doxazosin, is started at least one to two weeks before planned surgery and titrated to achieve adequate blood pressure control, alongside a liberalized salt and fluid intake to counteract the volume contraction that chronic catecholamine excess causes, given the risk of significant hypotension once the tumor is removed and the catecholamine surge ceases.

Beta blockade is added only after adequate alpha blockade has been established, never before, since beta blockade in the presence of unopposed alpha adrenergic stimulation can precipitate a severe hypertensive crisis from unopposed vasoconstriction, an important and specific sequencing principle in the preoperative preparation of these patients.

Intraoperative and immediate postoperative management requires close hemodynamic monitoring, given the potential for significant blood pressure swings both during tumor manipulation and immediately after its removal.

Metastatic or unresectable disease is managed with a combination of continued alpha and beta blockade for symptom and blood pressure control, alongside systemic therapy directed at the tumor itself, which may include MIBG targeted radionuclide therapy for MIBG avid disease, or chemotherapy, guided by specialist endocrine oncology input.

Lifelong follow up, including periodic biochemical testing, is recommended after resection given the risk of recurrence or metachronous disease, particularly in patients with an identified hereditary syndrome.

Referral: endocrinology for diagnosis and perioperative medical management; endocrine surgery for resection; genetic counseling for all confirmed cases given the substantial hereditary component.

Hyperosmolar Hyperglycaemic State

Overview

Diagnosis

Management

Overview

Clinical Features

Diagnosis

Management