Prolonged Phase Of Critical Illness Research Articles

Novel insights in endocrine and metabolic pathways in sepsis and gaps for future research.

Sepsis is defined as any life-threatening organ dysfunction caused by a dysregulated host response to infection. It remains an important cause of critical illness and has considerable short- and long-term morbidity and mortality. In the last decades, preclinical and clinical research has revealed a biphasic pattern in the (neuro-)endocrine responses to sepsis as to other forms of critical illness, contributing to development of severe metabolic alterations. Immediately after the critical illness-inducing insult, fasting- and stress-induced neuroendocrine and cellular responses evoke a catabolic state in order to provide energy substrates for vital tissues, and to concomitantly activate cellular repair pathways while energy-consuming anabolism is postponed. Large randomized controlled trials have shown that providing early full feeding in this acute phase induced harm and reversed some of the neuro-endocrine alterations, which suggested that the acute fasting- and stress-induced responses to critical illness are likely interlinked and benefical. However, it remains unclear whether, in the context of accepting virtual fasting in the acute phase of illness, metabolic alterations such as hyperglycemia are harmful or beneficial. When patients enter a prolonged phase of critical illness, a central suppression of most neuroendocrine axes follows. Prolonged fasting and central neuroendocrine suppression may no longer be beneficial. Although pilot studies have suggested benefit of fasting-mimicking diets and interventions that reactivate the central neuroendocrine suppression selectively in the prolonged phase of illness, further study is needed to investigate patient-oriented outcomes in larger randomized trials.

Chapter 29 - Endocrine interventions in the intensive care unit

Following the onset of any life-threatening illness that requires intensive medical care, alterations within the neuroendocrine axes occur which are thought to be essential for survival, as they postpone energy-consuming anabolism, activate energy-producing catabolic pathways, and optimize immunological and cardiovascular functions. The hormonal changes present in the acute phase of critical illness at least partially resemble those of the fasting state, and recent evidence suggests that they are part of a beneficial, evolutionary-conserved adaptive stress response. However, a fraction of patients who survive the acute phase of critical illness remain dependent on vital organ support and enter the prolonged phase of critical illness. In these patients, the hypothalamic-pituitary-peripheral axes are functionally suppressed, which may have negative consequences by which recovery may be hampered and the risk of morbidity and mortality in the long-term increased. Most randomized controlled trials of critically ill patients that investigated the impact on the outcome of treatment with peripheral hormones did not reveal a robust morbidity or mortality benefit. In contrast, small studies of patients in the prolonged phase of critical illness documented promising results with the infusion of hypothalamic-releasing hormones. The currently available data corroborate the need for well-designed and adequately powered RCTs to further investigate the impact of these releasing factors on patient-centered outcomes.

Anterior pituitary function in critical illness.

Critical illness is hallmarked by major changes in all hypothalamic–pituitary–peripheral hormonal axes. Extensive animal and human studies have identified a biphasic pattern in circulating pituitary and peripheral hormone levels throughout critical illness by analogy with the fasting state. In the acute phase of critical illness, following a deleterious event, rapid neuroendocrine changes try to direct the human body toward a catabolic state to ensure provision of elementary energy sources, whereas costly anabolic processes are postponed. Thanks to new technologies and improvements in critical care, the majority of patients survive the acute insult and recover within a week. However, an important part of patients admitted to the ICU fail to recover sufficiently, and a prolonged phase of critical illness sets in. This prolonged phase of critical illness is characterized by a uniform suppression of the hypothalamic–pituitary–peripheral hormonal axes. Whereas the alterations in hormonal levels during the first hours and days after the onset of critical illness are evolutionary selected and are likely beneficial for survival, endocrine changes in prolonged critically ill patients could be harmful and may hamper recovery. Most studies investigating the substitution of peripheral hormones or strategies to overcome resistance to anabolic stimuli failed to show benefit for morbidity and mortality. Research on treatment with selected and combined hypothalamic hormones has shown promising results. Well-controlled RCTs to corroborate these findings are needed.

Adrenocortical Stress Response during the Course of Critical Illness.

Critically ill patients have elevated plasma cortisol concentrations, in proportion to illness severity. This was traditionally attributed exclusively to a central activation of the hypothalamus-pituitary axis. However, low rather than high plasma ACTH concentrations have been reported in critically ill patients, with loss of diurnal ACTH and cortisol rhythm. Low ACTH together with high cortisol is referred to as "ACTH-cortisol dissociation." Although cortisol production is somewhat increased with inflammation, a reduced cortisol breakdown explains to a larger extent the hypercortisolism during critical illness. Inflammation-driven decrease in cortisol binding proteins further increase the active free cortisol fraction. Several drugs administered to ICU patients suppress plasma cortisol in a dose-dependent manner. Sustained low circulating ACTH might contribute to adrenal atrophy and dysfunction in the prolonged phase of critical illness. In the acute phase of sepsis or septic shock, a condition referred to as "relative adrenal insufficiency" has been suggested to ensue from glucocorticoid resistance and insufficiently elevated circulating cortisol to overcome such resistance, with pathological changes possibly occurring at every level of the HPA axis. However, it remains highly controversial whether tissue-specific glucocorticoid resistance is adaptive or maladaptive, how to diagnose "relative" adrenal insufficiency, and how it should be treated. Large RCTs, investigating the effect of 200 mg/d hydrocortisone treatment for sepsis or septic shock have shown conflicting, mainly negative, results. Not taking into account the reduced cortisol breakdown, which increases the risk of overdosing hydrocortisone, might have played a role. Further research on diagnostic, therapeutic and dosing aspects is urgently warranted. Compr Physiol 8:283-298, 2018.

Use of a Central Venous Line for Fluids, Drugs and Nutrient Administration in a Mouse Model of Critical Illness.

This protocol describes a centrally catheterized mouse model of prolonged critical illness. We combine the cecal ligation and puncture method to induce sepsis with the use of a central venous line for fluids, drugs and nutrient administration to mimic the human clinical setting. Critically ill patients require intensive medical support in order to survive. While the majority of patients will recover within a few days, about a quarter of the patients need prolonged intensive care and are at high risk of dying from non-resolving multiple organ failure. Furthermore, the prolonged phase of critical illness is hallmarked by profound muscle weakness, and endocrine and metabolic changes, of which the pathogenesis is currently incompletely understood. The most widely used animal model in critical care research is the cecal ligation and puncture model to induce sepsis. This is a very reproducible model, with acute inflammatory and hemodynamic changes similar to human sepsis, which is designed to study the acute phase of critical illness. However, this model is hallmarked by a high lethality, which is different from the clinical human situation, and is not developed to study the prolonged phase of critical illness. Therefore, we adapted the technique by placing a central venous catheter in the jugular vein allowing us to administer clinically relevant supportive care, to better mimic the human clinical situation of critical illness. This mouse model requires an extensive surgical procedure and daily intensive care of the animals, but it results in a relevant model of the acute and prolonged phase of critical illness.

On the Neuroendocrinopathy of Critical Illness. Perspectives for Feeding and Novel Treatments.

Typical for critical illnesses are substantial alterations within the hypothalamic-anterior pituitary-peripheral hormonal axes that are proportionate to the risk of poor outcome. These neuroendocrine responses to critical illness follow a biphasic pattern. The acute phase (first hours to days) is characterized by an increased release of anterior pituitary hormones, whereas altered target-organ sensitivity and hormone metabolism result in low levels of the anabolic peripheral effector hormones and contribute to the substantially elevated levels of the catabolic hormone cortisol. The prolonged phase of critical illness is hallmarked by a uniform suppression of the neuroendocrine axes, predominantly of central/hypothalamic origin, which contributes to the low (or insufficiently high in the case of cortisol) circulating levels of the target-organ hormones. Several of the acute-phase adaptations to critical illness are due to or accentuated by the concomitant fasting. Accepting the lack of macronutrients as well as the neuroendocrine responses to such fasting in the acute phase of critical illness has shown to beneficially affect outcome. In contrast, the neuroendocrine alterations that occur in the chronic phase of illness while patients are fully fed contribute to bone and skeletal muscle wasting and impose risk of adrenocortical atrophy. The combined administration of those hypothalamic releasing factors, which have been identified as suppressed or deficient during prolonged critical illness, may be a promising strategy to enhance recovery. The potential impact of treatment with such hypothalamic releasing factors on recovery from critical illness as well as on long-term rehabilitation should be investigated in future randomized controlled clinical trials.

MECHANISMS IN ENDOCRINOLOGY: New concepts to further unravel adrenal insufficiency during critical illness

The concept of 'relative' adrenal insufficiency during critical illness remains a highly debated disease entity. Several studies have addressed how to diagnose or treat this condition but have often yielded conflicting results, which further fuelled the controversy. The main reason for the controversy is the fact that the pathophysiology is not completely understood. Recently, new insights in the pathophysiology of the hypothalamic-pituitary-adrenal axis response to critical illness were generated. It was revealed that high circulating levels of cortisol during critical illness are explained more by reduced cortisol breakdown than by elevated cortisol production. Cortisol production rate during critical illness is less than doubled during the day but lower than in healthy subjects during the night. High plasma cortisol concentrations due to reduced breakdown in turn reduce plasma ACTH concentrations via feedback inhibition, which with time may lead to an understimulation and hereby a dysfunction of the adrenal cortex. This could explain the high incidence of adrenal insufficiency in the prolonged phase of critical illness. These novel insights have created a new framework for the diagnosis and treatment of adrenal failure during critical illness that has redirected future research.

Non-thyroidal illness in the ICU: a syndrome with different faces.

Critically ill patients typically present with low or low-normal plasma thyroxine, low plasma triiodothyronine (T3), increased plasma reverse T3 (rT3) concentrations, in the absence of a rise in thyrotropin (TSH). This constellation is referred to as nonthyroidal illness syndrome (NTI). Although it is long known that the severity of NTI is associated with risk of poor outcomes of critical illness, the causality in this association has not been well investigated. In this narrative review, the different faces of NTI during critical illness are highlighted. Acute alterations are dominated by changes in thyroid hormone binding, peripheral thyroid hormone uptake, and alterations in the expression and activity of the type-1 and type-3 deiodinases. It was recently shown that at least part of these acute changes are brought about by concomitant macronutrient restriction, and this part appears adaptive and beneficial. However, the face of the NTI in the prolonged phase of critical illness is different, when patients are fully fed but continue to depend on intensive medical care. In that prolonged phase of illness, hypothalamic thyrotropin releasing hormone (TRH) expression is suppressed and explains reduced TSH secretion and whereby reduced thyroidal hormone release. During prolonged critical illness, and in the presence of adequate nutrition, several tissue responses could be interpreted as compensatory to low thyroid hormone availability, such as increased expression of monocarboxylate transporters, upregulation of type-2 deiodinase activity, and increased sensitivity at the receptor level. Infusing hypothalamic releasing factors in these prolonged critically ill patients can reactivate the thyroid axis and induce an anabolic response. It is clear that the name "NTI" during critical illness refers to a syndrome with different faces. Tolerating the early "fasting response" to critical illness and its concomitant changes in thyroid hormone parameters appears to be wise and beneficial. This thus applies to the NTI present in the majority of the patients treated in intensive care units. However, the NTI that occurs in prolonged critically ill patients appears different with regard to both its causes and consequences. Future studies should specifically target this selected population of prolonged critically ill patients, and, after excluding iatrogic drug interferences, investigate the effect on outcome of treatment with hypothalamic releasing factors in adequately powered randomized controlled trials.

Chapter 8 - Hypothalamic–pituitary hormones during critical illness: a dynamic neuroendocrine response

Independent of the underlying condition, critical illness is characterized by a uniform dysregulation of the hypothalamic-pituitary-peripheral axes. In most axes a clear biphasic pattern can be distinguished. The acute phase of critical illness is characterized by low peripheral effector hormone levels such as T3, IGF-1 and testosterone, despite an actively secreting pituitary. The adrenal axis with high cortisol levels in the presence of low ACTH levels is a noteworthy exception. In the prolonged phase of critical illness, low peripheral effector hormone levels coincide with a uniform suppression of the neuroendocrine axes, predominantly of hypothalamic origin. The severity of the alterations in the different neuroendocrine axes is associated with a high risk of morbidity and mortality, but it remains unknown whether the observed changes are cause or consequence of adverse outcome. Several studies have identified therapeutic potential of hypothalamic releasing factors, but clinical outcome remains to be investigated with sufficiently powered randomized controlled trials.

Endocrine, Metabolic, and Morphologic Alterations of Adipose Tissue During Critical Illness*

Observational studies report lower mortality in obese than in lean critically ill patients, an association referred to as the "obesity paradox." This may suggest a possible protective role for adipose tissue during severe illness. Relevant publications were identified based on searches in PubMed and on secondary searches of their bibliographies. The endocrine functions of adipose tissue might play a role in the adaptation to critical illness. In the acute phase of illness, the anti-inflammatory adiponectin is reduced, whereas proinflammatory cytokine expression in adipose tissue is up-regulated. In the prolonged phase of critical illness, both adiponectin and anti-inflammatory cytokine production are increasing. Studies on the proinflammatory adipokine leptin during critical illness are inconsistent, possibly due to confounders such as gender, body mass index, and feeding. Morphologically, adipose tissue of critically ill patients reveals an increased number of newly differentiated, smaller adipocytes. Accentuated macrophage accumulation showing a phenotypic switch to M2-type suggests an adaptive response to the microenvironment of severe illness. Functionally, adipose tissue of critically ill patients develops an increased ability to store glucose and triglycerides. Endocrine, metabolic, and morphologic properties of adipose tissue change during critical illness. These alterations may suggest a possible adaptive, protective role in optimizing chances of survival. More research is needed to understand the exact role of adipose tissue in lean vs. obese critically ill patients, in order to understand how illness-associated alterations contribute to the obesity paradox.

Does critical illness cause reversible Cushing’s like syndrome? A case study of two case reports and review of the literature

An activation of the hypothalamic-pituitary-adrenal axis (HPA) and elevated cortisol levels are common during critical illness. Clinically evident Cushing’s syndrome, triggered by life threatening illness, has not been previously reported. We describe two patients with adrenocorticotropic hormone (ACTH)-dependent Cushing’s syndrome, which developed during the life threatening illness and later spontaneously remitted. The impact of the acute and prolonged phase of critical-illness on the function of HPA axis with its complex neuroimmunoendocrine dynamics has been reviewed. Key words: Adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome, hypothalamic-pituitary-adrenal axis, critical illness.

Hormonal and metabolic strategies to attenuate catabolism in critically ill patients

During the prolonged phase of critical illness, the ongoing hypermetabolic response leads to loss of lean tissue mass. Although the cachexia of prolonged illness is usually associated with low concentrations of anabolic hormones, most endocrine interventions attempting to correct the hormone balance have shown to be ineffective and their indiscriminate use is even harmful. Thus, a detailed understanding of the neuroendocrinology of the stress response is warranted, especially as the acute and chronic phases show remarkable differences. In the acute stress response, low circulating peripheral anabolic hormone levels, despite an actively secreting pituitary, are indicative of peripheral resistance to the anterior pituitary hormones. By contrast, the pulsatile secretion of anterior pituitary hormones is uniformly decreased in the prolonged phase of the disease, leading to proportionally reduced concentrations of peripheral anabolic hormones. As hypothalamic secretagogues can restore the pulsatile secretion of the anterior pituitary and increase peripheral target hormones, tissues are at least partially sensitive to the anterior pituitary hormones in this phase of illness. Therefore, a combination of hypothalamic secretagogues that reactivates the anterior pituitary to a greater extent could be a more physiological and effective strategy to induce anabolism in patients with prolonged critical illness.

The hypothalamic-pituitary-adrenal response to critical illness.

The maintenance of life depends on the capacity of the organism to sustain its equilibrium via allostasis'-the ability to achieve stability through change. Life-threatening disease induces acute adaptive responses specific to the stimulus and generalized responses when the disturbances are prolonged. These changes are associated with increased activity of the hypothalamic-pituitary-adrenal axis and may have survival value in preparing the body for fight or flight'. There is a shift towards an increase in glucocorticoid production and away from mineralocorticoid and androgen production, as well as an increase in the biological effects of glucocorticoids through an increased cortisol free fraction and an increased glucocorticoid receptor sensitivity. During the prolonged phase, there is a dissociation between high plasma cortisol and low adrenocorticotropin hormone levels, suggesting non-adrenocorticotropin hormone-mediated mechanisms for the regulation of the adrenal cortex. This hypercortisolism is in contrast to the very low dehydroepiandrosterone sulphate level, indicating an imbalance between the immunostimulatory and immunosuppressive adrenocortical hormones. The question is whether the total serum cortisol concentration represents sufficient glucocorticoid biological activity during the prolonged phase of critical illness.