Martin Cuesta

The contribution of undiagnosed adrenal insufficiency to euvolaemic hyponatraemia: results of a large prospective single-centre study

The syndrome of inappropriate antidiuresis (SIAD) is the commonest cause of hyponatraemia. Data on SIAD are mainly derived from retrospective studies, often with poor ascertainment of the minimum criteria for the correct diagnosis. Reliable data on the incidence of adrenal failure in SIAD are therefore unavailable. The aim of the study was to describe the aetiology of SIAD and in particular to define the prevalence of undiagnosed adrenal insufficiency.

Increased Population Risk of AIP-related Acromegaly and Gigantism in Ireland.

The aryl hydrocarbon receptor interacting protein (AIP) founder mutation R304* (or p.R304*; NM_003977.3:c.910C>T, p.Arg304Ter) identified in Northern Ireland (NI) predisposes to acromegaly/gigantism; its population health impact remains unexplored. We measured R304* carrier frequency in 936 Mid Ulster, 1,000 Greater Belfast (both in NI) and 2,094 Republic of Ireland (ROI) volunteers and in 116 NI or ROI acromegaly/gigantism patients. Carrier frequencies were 0.0064 in Mid Ulster (95%CI = 0.0027–0.013; P = 0.0005 vs. ROI), 0.001 in Greater Belfast (0.00011–0.0047) and zero in ROI (0–0.0014). R304* prevalence was elevated in acromegaly/gigantism patients in NI (11/87, 12.6%, P < 0.05), but not in ROI (2/29, 6.8%) versus non‐Irish patients (0–2.41%). Haploblock conservation supported a common ancestor for all the 18 identified Irish pedigrees (81 carriers, 30 affected). Time to most recent common ancestor (tMRCA) was 2550 (1,275–5,000) years. tMRCA‐based simulations predicted 432 (90–5,175) current carriers, including 86 affected (18–1,035) for 20% penetrance. In conclusion, R304* is frequent in Mid Ulster, resulting in numerous acromegaly/gigantism cases. tMRCA is consistent with historical/folklore accounts of Irish giants. Forward simulations predict many undetected carriers; geographically targeted population screening improves asymptomatic carrier identification, complementing clinical testing of patients/relatives. We generated disease awareness locally, necessary for early diagnosis and improved outcomes of AIP‐related disease.

Adipsic diabetes insipidus in adult patients

IntroductionAdipsic diabetes insipidus (ADI) is a very rare disorder, characterized by hypotonic polyuria due to arginine vasopressin (AVP) deficiency and failure to generate the sensation of thirst in response to hypernatraemia. As the sensation of thirst is the key homeostatic mechanism that prevents hypernatraemic dehydration in patients with untreated diabetes insipidus (DI), adipsia leads to failure to respond to aquaresis with appropriate fluid intake. This predisposes to the development of significant hypernatraemia, which is the typical biochemical manifestation of adipsic DI.MethodsA literature search was performed to review the background, etiology, management and associated complications of this rare condition.ResultsADI has been reported to occur in association with clipping of an anterior communicating artery aneurysm following subarachnoid haemorrhage, major hypothalamic surgery, traumatic brain injury and toluene exposure among other conditions. Management is very difficult and patients are prone to marked changes in plasma sodium concentration, in particular to the development of severe hypernatraemia. Associated hypothalamic disorders, such as severe obesity, sleep apnoea and thermoregulatory disorders are often observed in patients with ADI.ConclusionThe management of ADI is challenging and is associated with significant morbidity and mortality. Prognosis is variable; hypothalamic complications lead to early death in some patients, but recent reports highlight the possibility of recovery of thirst.

The syndrome of inappropriate antidiuresis (SIAD)

Hyponatraemia is the commonest electrolyte disturbance encountered in clinical practice and the syndrome of inappropriate antidiuresis (SIADH) is the most frequent underlying disorder. There is a well-recognized relationship between hyponatraemia and increased morbidity and mortality, though it is unknown whether SIADH confers the same mortality as other causes of hyponatraemia. SIADH is the biochemical manifestation of a wide variety of diseases, and the pathophysiology of SIADH is sometimes multiple. There have been significant advances in the treatment of SIADH over the last 10 years, in particular since the introduction of the vasopressin-2 receptor antagonists, which provide a potent, disease-specific tool which targets the underlying pathophysiology of SIADH. The mechanisms and the evidence base recommendations of the available therapies for SIADH are discussed in this article. The various guidelines and recommendations for treatment of hyponatraemia all emphasise that fluid restriction is first line therapy for SIADH, but we feel that it is ineffective or unfeasible in many patients. A number of key points relevant to the use of fluid restriction are presented in the manuscript. The clinical efficacy of tolvaptan in SIADH supported by good quality randomized, placebo controlled, clinical trials. However, the cost of the therapy and the need for long term safety data may limit its widespread use. Finally, new recommendations for the management of acute hyponatraemia, with a focus on the use of bolus therapy with 3% hypertonic sodium chloride is described.

Symptoms of gonadal dysfunction are more predictive of hypopituitarism than nonspecific symptoms in screening for pituitary dysfunction following moderate or severe traumatic brain injury

The economic and logistic burden of screening for hypopituitarism following moderate/severe traumatic brain injury (TBI) is considerable. A key recommendation in published guidelines is to prioritize for screening those patients with symptoms suggestive of pituitary dysfunction. The purpose of this study was to evaluate the utility of targeted screening for hypopituitarism in long‐term survivors after moderate/severe TBI using referrals on the basis of symptoms.

Diagnosis and treatment of hyponatraemia in neurosurgical patients.

Hyponatraemia is the most common electrolyte imbalance in neurosurgical patients. Acute hyponatraemia is particularly common in neurosurgical patients after any type of brain insult, including brain tumours and their treatment, pituitary surgery, subarachnoid haemorrhage or traumatic brain injury. Acute hyponatraemia is an emergency condition, as it leads to cerebral oedema due to passive osmotic movement of water from the hypotonic plasma to the relatively hypertonic brain which ultimately is the cause of the symptoms associated with hyponatraemia. These include decreased level of consciousness, seizures, non-cardiogenic pulmonary oedema or transtentorial brain herniation. Prompt treatment is mandatory to prevent such complications, minimize permanent brain damage and therefore permit rapid recovery after brain insult. The infusion of 3% hypertonic saline is the treatment of choice with different rates of administration based on the severity of symptoms and the rate of drop in plasma sodium concentration. The pathophysiology of hyponatraemia in neurotrauma is multifactorial; although the syndrome of inappropriate antidiuresis (SIADH) and central adrenal insufficiency are the commonest causes encountered. Fluid restriction has historically been the classical treatment for SIADH, although it is relatively contraindicated in some neurosurgical patients such as those with subarachnoid haemorrhage. Furthermore, many cases admitted have acute onset hyponatraemia, who require hypertonic saline infusion. The recently developed vasopressin receptor 2 antagonist class of drug is a promising and effective tool but more evidence is needed in neurosurgical patients. Central adrenal insufficiency may also cause acute hyponatraemia in neurosurgical patients; this responds clinically and biochemically to hydrocortisone. The rare cerebral salt wasting syndrome is treated with large volume normal saline infusion. In this review, we summarize the current evidence based on the clinical presentation, causes and treatment of different types of hyponatraemia in neurosurgical patients.

The relevance of hyponatraemia to perioperative care of surgical patients

BACKGROUND Hyponatraemia is the most common electrolyte disturbance in hospitalized patients. There is an increasing awareness of the impact of hyponatraemia on the perioperative management of surgical patients. METHODS We performed a literature review. We have included relevant data from different surgical disciplines for analysis. In this review we discuss the differential diagnosis of hyponatraemia, and explain the specific relevance of hyponatraemia to pre-, peri- and post-operative care. RESULTS Hyponatraemia is common during the preoperative period and is associated with an increase in subsequent peri-operative complications, such as wound infection, pneumonia, higher mortality rate and higher direct and indirect costs. Furthermore, data shows poorer surgical outcomes when plasma sodium concentration drops. Careful preoperative evaluation of the hyponatraemic patient enables assessment of surgical risk and individualization of the management of hyponatraemia. CONCLUSIONS We outline a practical guide to the assessment of the cause of hyponatraemia, which dictates the correct management of hyponatraemia and the correct selection of perioperative fluids. Finally, for the therapeutic role of the new vasopressin antagonist drugs in the treatment of surgical hyponatraemia is discussed in two illustrative surgical clinical cases.

Reference Change Values for Sodium Are Ignored by the American and European Treatment Guidelines for Hyponatremia.

Updated revised expert panel recommendations on the evaluation and treatment of hyponatremia were published in the United States in 2013 (1). In 2014, a separate set of guidelines were issued by a group representing the European Society of Intensive Care Medicine, the European Society of Endocrinology, and the European Renal Association–European Dialysis and Transplant Association represented by European Renal Best Practice (2). The recommended rates of correction of chronic hyponatremia from the US group are 4–8 mmol/L per day for patients at low risk of osmotic demyelinating syndrome (ODS)4 and 4–6 mmol/L per day if that risk is high. The limits not to exceed are 8 mmol/L in any 24-h period when the ODS risk is high, and when the ODS risk is low, 10–12 mmol/L in any 24-h period and 18 mmol/L in any 48-h period. If 8 mmol/L is exceeded in a 24-h period, there should be no active therapeutic intervention for the next 24 h (1). Regarding frequency of sodium analysis, serum sodium should be measured at 4- to 6-h intervals until mildly hyponatremic concentrations ≥125 mmol/L have been reached. The section on counteracting overcorrection of chronic hyponatremia by >6–8 mmol/L in the first 24 h of therapy discusses the uses of 2–4 μg desmopressin with repeated 3-mL/kg infusions of 5% dextrose in water administered over 1 h combined with the measurement of serum sodium after each infusion, i.e., hourly until the therapeutic target for the patient has been reached when the starting serum sodium is <120 mmol/L. When using vasopressin receptor antagonists (vaptans) and when treating diuretic-induced hyponatremia, measurements of serum sodium are set at a 6- to 8-h minimum until a stable sodium value >125 mmol/L has been reached. When diuretics have caused hyponatremia-induced seizures, hypertonic saline is recommended to raise the …

Heterogenous patterns of recovery of thirst in adult patients with adipsic diabetes insipidus

BACKGROUND The natural history of adipsic diabetes insipidus (ADI) is not well described, and reports of recovery of thirst are rare. DESIGN AND METHODS Case histories presentation. ADI was identified by demonstrating absent thirst and arginine vasopressin (AVP) responses to hypertonic saline infusion. RESULTS Twelve patients with ADI were identified (craniopharyngioma 5, anterior communicating artery aneurysm (ACOM) repair 4, congenital 1, neurosarcoidosis 1, prolactinoma 1). Three patients died. Six patients had permanent ADI. Three patients had recovery of thirst, with a heterogenous pattern of recovery. In the first case, ADI had developed after clipping of an ACOM aneurysm. Ten years after surgery; he sensed the return of thirst; repeated hypertonic saline infusion showed recovery of thirst and AVP secretion. In the second case, a 41-year-old female with an intrasellar craniopharyngioma developed post-operative ADI with persistent hypernatremia. Two years post-operatively, she complained of thirst, and hypertonic saline infusion showed normalization of thirst but absent AVP responses, confirming recovery of thirst, but with persistent diabetes insipidus (DI). In the third case, a 29-year-old Caucasian had craniotomy and radiotherapy for craniopharyngioma and developed ADI post-operatively. Eight years post-op, she presented with thirst, seizures and pNa of 112 mmol/l. Hypertonic saline infusion showed persistent DI but thirst responses typical of compulsive water drinking; she has had recurrent hyponatraemia since then. CONCLUSIONS We report that 3/12 patients with ADI recovered thirst after longstanding adipsia with heterogenous pattern of recovery. Both the mortality of 25% and the recovery rate of 25% should be considered when planning long-term surveillance.

Mortality rates are lower in SIAD, than in hypervolaemic or hypovolaemic hyponatraemia: Results of a prospective observational study

Hyponatraemia is associated with increased mortality, but the mortality associated specifically with SIAD is not known. We hypothesized that mortality in SIAD was elevated, but that it was less than in hypervolaemic (HEN) or hypovolaemic (HON) hyponatraemia.