Disorders of body water homeostasis

Disorders of body fluids are among the most commonly encountered problems in the practice of clinical medicine. This is in large part because many different disease states can potentially disrupt the finely balanced mechanisms that control the intake and output of water and solute. It therefore behoves clinicians treating such patients to have a good understanding of the pathophysiology, the differential diagnosis and the management of these disorders. Because body water is the primary determinant of the osmolality of the extracellular fluid, disorders of body water homeostasis can be divided into hypo-osmolar disorders, in which there is an excess of body water relative to body solute, and hyperosmolar disorders, in which there is a deficiency of body water relative to body solute. The classical hyperosmolar disorder is diabetes insipidus (DI), and the classical hypo-osmolar disorder is the syndrome of inappropriate antidiuretic hormone secretion (SIADH). This chapter first reviews the regulatory mechanisms underlying water and sodium metabolism, the two major determinants of body fluid homeostasis. The major disorders of water metabolism causing hyperosmolality and hypo-osmolality, DI and SIADH, are then discussed in detail, including the pathogenesis, differential diagnosis and treatment of these disorders.     

Relationship of baseline glucose homeostasis to hyperglycemia during medical critical illness

STUDY OBJECTIVE: To elucidate the relationship of baseline glucose control and acute stimuli with hyperglycemia during medical critical illness. DESIGN: Prospective cohort study. SETTING: Medical ICU (MICU) of a university affiliated hospital. PATIENTS: Convenience sample of 100 medical patients meeting criteria for severity of illness and anticipated length of stay and not admitted to the hospital for diabetic ketoacidosis or a hyperglycemic hyperosmolar state. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients were categorized as having normal, abnormal, or unevaluable baseline glucose control based on history and glycosylated hemoglobin (HbA1c). Data collection included blood glucose measurements within 120 h of MICU admission, and dosing of norepinephrine, corticosteroids, propofol, and carbohydrates. Average blood glucose and times over glycemic thresholds were calculated using linear interpolation. Hyperglycemia (glucose > 110 mg/dL) was pervasive in all groups. Among the 51 patients with normal baseline glucose control, HbA1c was correlated with hyperglycemic time (p < 0.01, R(2) = 0.15). Multiple regression found HbA1c, age, corticosteroid dose, and carbohydrate administration independently associated with hyperglycemic time (p < 0.05 for each, total R(2) = 0.49) in these patients, while body mass index, APACHE (acute physiology and chronic health evaluation) II, norepinephrine dose, propofol dose, gender, and sepsis were not associated with time > 110 mg/dL. Among normal subjects, HbA1c was independently predictive of peak and average glucose, and the fraction of time glucose was > 150 mg/dL and > 200 mg/dL (p < 0.05 for each). Patients with abnormal baseline glucose control had significantly more hyperglycemia than patients with normal baseline control. CONCLUSIONS: Even in patients without evidence of abnormal glucose homeostasis at baseline, hyperglycemia is common during critical illness. Time exposure to hyperglycemia is correlated with acute stressors and baseline glucose regulation, as characterized by HbA1c. Patients with low HbA1c levels are less disposed to hyperglycemia during severe illness than patients with higher, but still normal, HbA1c.     

Disorders of calcium homeostasis

To ensure a multitude of essential cellular functions, the extracellular concentration of calcium is maintained within a narrow physiological range. This depends on integrated regulation of calcium fluxes with respect to the intestine, kidneys and bone. The precise regulation of serum calcium is controlled by calcium itself, through a calcium receptor and several hormones, the most important of which are parathyroid hormone and 1,25(OH)(2) vitamin D. This balance can be disturbed by mutations in the calcium-sensing receptor, inappropriately high or low levels of parathyroid hormone, resistance to parathyroid hormone effects, insufficient intake or production of 1,25(OH)(2) vitamin D and inactivation of the vitamin D receptor. Mineral homeostasis is moreover influenced by many other systemic factors (e.g. sex steroid, thyroid and glucocorticoid hormones) or humoral factors (e.g. cytokines and growth factors). A specific example is the major abnormalities of mineral homeostasis in case of malignancy by excessive production of parathyroid hormone-related peptide resulting in hypercalcaemia. Several new drugs have been developed based on factors in this axis, including calcimimetics, calcilytics, vitamin D analogues and parathyroid hormone-related peptide inhibitors.     

Secretin as a neurohypophysial factor regulating body water homeostasis

Hypothalamic magnocellular neurons express either one of the neurohypophysial hormones, vasopressin or oxytocin, along with different neuropeptides or neuromodulators. Axonal terminals of these neurons are generally accepted to release solely the two hormones but not others into the circulation. Here, we show that secretin, originally isolated from upper intestinal mucosal extract, is present throughout the hypothalamo–neurohypophysial axis and that it is released from the posterior pituitary under plasma hyperosmolality conditions. In the hypothalamus, it stimulates vasopressin expression and release. Considering these findings together with our previous findings that show a direct effect of secretin on renal water reabsorption, we propose here that secretin works at multiple levels in the hypothalamus, pituitary, and kidney to regulate water homeostasis. Findings presented here challenge previous understanding regarding the neurohypophysis and could provide new concepts in treating disorders related to osmoregulation.     

The hypothalamic-pituitary-adrenal axis in critical illness.

The hypothalamic-pituitary-adrenal response to stress is a dynamic process. The homeostatic corrections that have emerged in the course of human evolution to cope with the catastrophic events during critical illness involve a complex multisystem endeavor. Although the repertoire of endocrine changes has been probed in some detail, discerning the vulnerabilities and failures of this system is far more challenging. One of the most controversially debated topics in the current literature is the characterization and optimal treatment of allegedly inadequate adaptations of the hypothalamic-pituitary-adrenal axis during critical illness. This outline attempts to touch briefly some of the debated issues, stir the discussion, and thereby contribute to resolving the dispute.     

Catecholamines and vasopressin during critical illness.

This article summarizes the effects of catecholamines and vasopressin on the cardiovascular system, focusing on their metabolic and immunologic properties. Particular attention is dedicated to the septic shock condition.     

Polyarticular heterotopic ossification complicating critical illness.

A patient with generalized heterotopic ossification (HO) complicating critical illness due to necrotizing pancreatitis is described; data on two other cases with HO are briefly presented. The clinical features, prevention and therapy of HO are discussed. The effect of surgical therapy of the HO in our three patients was good.     

Disorders of calcium and magnesium homeostasis

The components of calcium and magnesium balance and the factors responsible for the maintenance of the serum concentration of these cations are reviewed. Within this framework, the causes and treatment of disturbances of the serum concentration are discussed. Hypercalcemia is usually a reflection of increased bone resorption and/or gut absorption with the kidney playing a secondary role. Hypocalcemia is usually due to either a disturbance in the parathyroid hormone-adenylate cyclase system or a disturbance in vitamin D metabolism. As vitamin D is required for expression of the action of PTH at bone and as PTH is a prime regulator of vitamin D metabolism, the absence of either component results in important disturbances in calcium balance. In contrast to calcium homeostasis, the kidney plays a major role in the determination and regulation of serum magnesium. The major causes of hypermagnesemia therefore are associated with loss of renal function, and hypomagnesemia is frequently due to renal magnesium wasting.     

Endocrine evaluation of patients with critical illness.

Prolonged critical illness has a high morbidity and mortality. The acute and chronic phases of critical illness are associated with distinct endocrine alterations. The acute neuroendocrine response to critical illness involves an activated anterior pituitary function. In prolonged critical illness, however, a reduced pulsatile secretion of anterior pituitary hormones and the so-called "wasting syndrome" occur. The impaired pulsatile secretion of GH, thyrotropin and gonadotropin can be re-amplified by relevant combinations of releasing factors, which also substantially increase circulating levels of IGF-1, GH-dependent IGFBPs, thyroxin, tri-iodothyronine and testosterone. Anabolism is clearly re-initiated at the time GH secretagogues, thyrotropin-releasing hormone and gonadotropin-releasing hormone are coadministered but the effect on survival remains unknown. A lethal outcome of critical illness is predicted by a high serum concentration of IGFBP-1, pointing to impaired insulin effect rather than pituitary function, and survival was recently shown to be dramatically improved by strict normalization of glycemia with exogenous insulin. In addition to the illness-induced endocrine alterations, patients may have pre-existing central or peripheral endocrine diseases, either previously diagnosed or unknown. Hence, endocrine function testing in a critically ill patient represents a major challenge and the issue of treatment remains controversial. The recent progress in knowledge of the neuroendocrine response to critical illness and its interrelation with peripheral hormonal and metabolic alterations during stress, allows for potential new therapeutic perspectives to safely reverse the wasting syndrome and improve survival.     

Skeletal muscle in critical illness

Summary Skeletal muscle protein breakdown is a dominant feature of critical illness and is believed to be a useful biological response to injury. However the loss of muscle is accompanied by some major difficulties in medical management and complications for the patient. Protein turnover is difficult to study and the catabolic state is resistant to treatment, whether by nutritional or other strategies. This article provides an overview of the current physiological knowledge in this area, questions the usefulness of the catabolic response and highlights some new research worthy of further investigation. Received: 24 September 1998 Accepted: 20 April 1999     

Pituitary-thyroid axis in critical illness

Severe nonthyroidal illness has been claimed to cause secondary hypothyroidism. We reevaluated this concept measuring serum free T4 and free T3 by an ultrafiltration method and serum TSH by an ultrasensitive technique (detection limit, and serum TSH by an ultrasensitive technique (detection limit, 0.05 mU/L). Forty-five critically ill patients suffering from hepatic coma (n = 10), terminal cancer (n = 9), stroke (n = 8), and respiratory insufficiency not treated (n = 7) and treated (n = 11) with dopamine were studied. The mortality rate was 80%. No patients received glucocorticoids, and only patients in the last group received dopamine. Serum total as well as free thyroid hormone index values were grossly reduced in the majority of the patients. The 34 patients not receiving dopamine in general had normal values of serum free T4 (32 of 34) and free T3 (31 of 34), measurable TSH (33 of 34), and detectable TSH responses to iv TRH (33 of 34). In contrast, the dopamine-treated patients had reduced serum free T4 and TSH levels compared to normal subjects (P less than 0.05), as well as reduced TSH responses to TRH (P less than 0.01). Serum free T4 and free T3 were below the normal range in 3 patients and 1 patient, respectively, and serum TSH was below the detection limit in 2 patients. We conclude that critically ill patients with nonthyroidal illness not receiving dopamine have normal pituitary-thyroid function, whereas dopamine induces some degree of secondary hypothyroidism.     

Airway management in critical illness

Airway management in the ICU can be complicated due to many factors including the limited physiologic reserve of the patient. As a consequence, the likelihood of difficult mask ventilation and intubation increases. The incidence of failed airways and of cardiac arrest related to airway instrumentation in the ICU is much higher than that of elective intubations performed in the operating room. A thorough working knowledge of the devices available for the management of the difficult airway and recommended rescue strategies is paramount in avoiding bad patient outcomes. In this review, we will provide a conceptual framework for airway assessment, with an emphasis on assessment of the patient with limited cervical spine movement or injury and of morbidly obese patients. Furthermore, we will review the devices that are available for airway management in the ICU, and discuss controversies surrounding interventions like cricoid pressure and the use of muscle relaxants in the critically ill patient. Finally, strategies for the safe extubation of patients with known difficult airways will be provided.     

The dynamic neuroendocrine response to critical illness.

The severity of striking alterations in the hypothalamic-anterior pituitary-peripheral hormone axes, which are the hallmark of severity of critical illness, is associated with a high risk for morbidity and mortality. Most attempts to correct the hormone balance are ineffective or harmful because of lack of pathophysiologic understanding. Extensive research has provided more insight in the biphasic neuroendocrine response to critical illness: the acute phase is characterized by an actively secreting pituitary but low peripheral effector hormone levels. In contrast, in prolonged critical illness, uniform suppression of the neuroendocrine axes, predominantly of hypothalamic origin, contributes to low serum levels of the respective target-organ hormones.     

Endocrine aspects of critical illness

Metabolic disorders and endocrine changes are common and relevant in critically ill patients. Thereby, endocrinopathies, electrolyte or metabolic derangements may either pre-exist or develop, and left unattended, may lead to significant morbidity and mortality. The homeostatic corrections which have emerged in the course of human evolution to cope with the catastrophic events during critical illness involve a complex multisystem endeavour, of which the endocrine contribution is an integral component. Although the repertoire of endocrine changes has been probed in some detail, discerning the vulnerabilities and failures of this system is far more challenging. The ensuing endocrine topics illustrate some of the current issues reflecting attempts to gain an improved insight and clinical outcome for critical illness. Disturbances in glucose and cortisol homeostasis during critical illness are two controversially debated topics in the current literature. The term "hormokine" encompasses the cytokine like behaviour of hormones during inflammation and infections. The concept is based on an ubiquitous expression of calcitonin peptides during sepsis. Adrenomedullin, another member of the calcitonin peptide superfamily, was shown to complement and improve the current prognostic assessment in lower respiratory tract infections. Procalcitonin is the protopye of "hormokine" mediators circulating procalcitonin levels increase several 10,000-fold during sepsis improve the clinical assessment especially of respiratory tract infections and sepsis safely and markedly reduces antibiotic usage in non-bacterial respiratory tract infections and meningitis. Adrenomedullin, another member of the calcitonin peptide superfamily, was shown to complement and improve the current prognostic assessment in lower respiratory tract infections. Hormokines are not only biomarkers of infection. Hormokines are also pivotal inflammatory mediators. Like all mediators, their role during systemic infections is basically beneficial, possibly to combat invading microbes. Yet, with increasing levels they can become harmful for their host. Multiple mechanisms of action were proposed. In several animal models the modulation and neutralization of hormokines during infection was shown to improve survival and thus might open new treatment options for severe infections, especially of the respiratory tract.