The hypothalamic–pituitary–adrenal axis in critical illness

Hypothalamic-pituitary-adrenal (HPA) axis function is crucial to maintain and restore homeostasis. The HPA axis does not function in isolation. Rather, the HPA axis modulates and reacts to signals from endocrine, neural, and immune systems. Cortisol is the major glucocorticoid secreted by the human adrenal cortex. Its actions are largely mediated by the glucocorticoid receptor. The potent anti-inflammatory actions of glucocorticoids led to their use in critically ill patients. Metaanalyses of these early studies (before 1985) concluded that large glucocorticoid doses had no effect and were potentially detrimental. More recently, the pendulum has swung in the opposite direction based on the concept that critically ill patients may have relative adrenal insufficiency and/or acquired glucocorticoid resistance. However, inconsistent diagnostic criteria, heterogeneity of subjects, variable nutritional status, and pre-existing conditions preclude formulating definitive conclusions regarding glucocorticoid use among critically patients. Diagnosing adrenal insufficiency in the critically ill patient remains challenging. To resolve the issue, our challenge is to develop physiologically relevant tools to assess glucocorticoid action and GR function at the cellular level.     

Adrenal insufficiency in patients with decompensated cirrhosis

Adrenal reserve depletion and overstimulation of the hypothalamus-pituitary-adrenal(HPA) axis are causes for adrenal insufficiency(AI) in critically ill individuals. Cirrhosis is a predisposing condition for AI in cirrhotics aswell. Both stable cirrhotics and liver transplant patients(early and later after transplantation) have been reported to present AI. The mechanisms leading to reduced cortisol production in cirrhotics are the combination of low cholesterol levels(the primary source of cortisol), the increased cytokines production that overstimulate and exhaust HPA axis and the destruction of adrenal glands due to coagulopathy. AI has been recorded in 10%-82% cirrhotics depending on the test used to evaluate adrenal function and in 9%-83% stable cirrhotics. The similarity of those proportions support the assumption that AI is an endogenous characteristic of liver disease. However, the lack of a gold standard method for AI assessment and the limitation of precise thresholds in cirrhotics make difficult the recording of the real prevalence of AI. This review aims to summarize the present data over AI in stable, critically ill cirrhotics and liver transplant recipients. Moreover, it provides information about the current knowledge in the used diagnostic tools and the possible effectiveness of corticosteroids administration in critically ill cirrhotics with AI.     

Hypothalamic pituitary adrenal function during critical illness: limitations of current assessment methods

CONTEXT: Activation of the hypothalamic-pituitary-adrenal (HPA) axis represents one of several important responses to stressful events and critical illnesses. Despite a large volume of published data, several controversies continue to be debated, such as the definition of normal adrenal response, the concept of relative adrenal insufficiency, and the use of glucocorticoids in the setting of critical illness. OBJECTIVES: The primary objective was to review some of the modulating factors and limitations of currently used methods of assessing HPA function during critical illness and provide alternative approaches in that setting. DESIGN: This was a critical review of relevant data from the literature with inclusion of previously published as well as unpublished observations by the author. Data on HPA function during three different forms of critical illnesses were reviewed: experimental endotoxemia in healthy volunteers, the response to major surgical procedures in patients with normal HPA, and the spontaneous acute to subacute critical illnesses observed in patients treated in intensive care units. SETTING: The study was conducted at an academic medical center. PATIENTS/PARTICIPANTS: Participants were critically ill subjects. Intervention: There was no intervention. MAIN OUTCOME MEASURE: The main measure was to provide data on the superiority of measuring serum free cortisol during critical illness as contrasted to those of total cortisol measurements. RESULTS: Serum free cortisol measurement is the most reliable method to assess adrenal function in critically ill, hypoproteinemic patients. A random serum free cortisol is expected to be 1.8 microg/dl or more in most critically ill patients, irrespective of their serum binding proteins. Because the free cortisol assay is not currently available for routine clinical use, alternative approaches to estimate serum free cortisol can be used. These include calculated free cortisol (Coolens' method) and determining the free cortisol index (ratio of serum cortisol to transcortin concentrations). Preliminary data suggest that salivary cortisol measurements might be another alternative approach to estimating the free cortisol in the circulation. When serum binding proteins (albumin, transcortin) are near normal, measurements of total serum cortisol continue to provide reliable assessment of adrenal function in critically ill patients, in whom a random serum total cortisol would be expected to be 15 microg/dl or more in most patients. In hypoproteinemic critically ill subjects, a random serum total cortisol level is expected to be 9.5 microg/dl or more in most patients. Data on Cosyntropin-stimulated serum total and free cortisol levels should be interpreted with the understanding that the responses in critically ill subjects are higher than those of healthy ambulatory volunteers. The Cosyntropin-induced increment in serum total cortisol should not be used as a criterion for defining adrenal function, especially in critically ill patients. CONCLUSIONS: The routine use of glucocorticoids during critical illness is not justified except in patients in whom adrenal insufficiency was properly diagnosed or others who are hypotensive, septic, and unresponsive to standard therapy. When glucocorticoids are used, hydrocortisone should be the drug of choice and should be given at the lowest dose and for the shortest duration possible. The hydrocortisone dose (50 mg every 6 h) that is mistakenly labeled as low-dose hydrocortisone leads to excessive elevation in serum cortisol to values severalfold greater than those achieved in patients with documented normal adrenal function. The latter data should call into question the current practice of using such doses of hydrocortisone even in the adrenally insufficient subjects.     

2型糖尿病海马损伤与HPA轴功能紊乱

2型糖尿病患者出现下丘脑-垂体-肾上腺轴(HPA轴)功能紊乱,可能和海马损伤有关.一方面HPA轴功能紊乱可能通过引起海马胰岛素抵抗,突触可塑性改变,以及糖皮质激素受体紊乱影响海马功能及负反馈调节.另一方面,慢性应激所引起的海马损伤也可以导致HPA轴功能紊乱,从而形成恶性循环.本文就2型糖尿病患者HPA轴与海马损伤的关系作简要概述.     

重视老年重症患者的疾病复杂性

由于老化和多病、共病的存在,使得老年患者器官的储备能力下降,疾病复杂性增加,容易发生感染、营养不良、药物不良反应及器官功能损害,导致并发症及多器官功能障碍的发生率升高,病死率增加。因此,充分认识老年患者疾病的复杂性,积极采取应对措施,对改善老年危重患者的预后非常重要。     

Bad medicine: low-dose dopamine in the ICU

Low-dose dopamine administration (ie, doses < 5 microg/kg/min) has been advocated for 30 years as therapy in oliguric patients on the basis of its action on dopaminergic renal receptors. Recently, a large, multicenter, randomized, controlled trial has demonstrated that low-dose dopamine administered to critically ill patients who are at risk of renal failure does not confer clinically significant protection from renal dysfunction. In this review, we present the best evidence and summarize the effects of low-dose dopamine infusion in critically ill patients. We review the history and physiology of low-dose dopamine administration and discuss the reasons why dopamine is not clinically effective in the critically ill. In addition to the lack of renal efficacy, we present evidence that low-dose dopamine administration worsens splanchnic oxygenation, impairs GI function, impairs the endocrine and immunologic systems, and blunts ventilatory drive. We conclude that there is no justification for the use of low-dose dopamine administration in the critically ill.     

Hepatobiliary manifestations of critically ill and postoperative patients

Liver dysfunction is common in both the critically ill and postoperative patient. Metabolic derangements secondary to sepsis, poor hepatic perfusion, total parenteral nutrition, in addition to hemodynamic and anesthetic-induced changes that occur during surgery, can cause liver damage ranging from small self-limited abnormalities in liver chemistries to acute liver failure. Early recognition, supportive care, and effective treatment of the underlying disease process are crucial steps in managing liver disease in a critically ill patient.     

Vitamin D metabolism and deficiency in critical illness

Vitamin D deficiency is highly prevalent and has been associated with a diverse range of chronic medical conditions in the general population. In contrast, the prevalence, pathogenesis and significance of vitamin D deficiency have received little attention in acute medicine. Vitamin D deficiency is seldom considered and rarely corrected adequately, if at all, in critically ill patients. Recent recognition of the extra-skeletal, pleiotropic actions of vitamin D in immunity, epithelial function and metabolic regulation may underlie the previously under-recognized contribution of vitamin D deficiency to typical co-morbidities in critically ill patients, including sepsis, systemic inflammatory response syndrome and metabolic dysfunction. Improved understanding of vitamin D metabolism and regulation in critical illness may allow therapeutic exploitation of vitamin D to improve outcome in critically ill patients.     

食管超声心动图在重危心脏病人诊断治疗中的价值

目的　为评价食管超声心动图 (TEE)在重危心脏病人诊断治疗中的价值 ,对 3 7例收住监护病房的重症心血管病人进行了经胸超声心动图 (TTE)和TEE检查 ,其中男 2 5例 ,女 1 2例 ,平均年龄57( 1 9～ 85)岁。入选对象包括怀疑夹层动脉瘤 2 3例、心脏瓣膜功能异常 9例、感染性心内膜炎 3例 ,心内分流 2例。结果　所有病人均可耐受TEE检查 ,无并发症发生 ,TEE较TTE可提供更高的阳性诊断结果 ,阳性率分别为 65 0 %和 3 8 0 % ,在怀疑夹层动脉瘤者中 ,TEE检出夹层撕裂膜 1 4例 ;而TTE仅检出 7例 ,且图象欠清 ,检出部位有限。在 4例人工机械瓣膜功能异常者中 ,TEE发现瓣膜部位血栓形成 3例。结论　在对心脏大血管疾病的诊断中 ,TEE阳性诊断率高于TTE ,尤其在怀疑夹层动脉瘤及人工机械瓣膜病变时 ,应行TEE检查。即使在重危病人 ,TEE也是一种安全有效的诊断手段。     

Antibiotic dosing in multiple organ dysfunction syndrome

Although early and appropriate antibiotic therapy remains the cornerstone of success for the treatment of septic shock, few data exist to guide antibiotic dose optimization in critically ill patients, particularly those with multiple organ dysfunction syndrome (MODS). It is well known that MODS significantly alters the patient's physiology, but the effects of these variations on pharmacokinetics have not been reviewed concisely. Therefore, the aims of this article are to summarize the disease-driven variations in pharmacokinetics and pharmacodynamics and to provide antibiotic dosing recommendations for critically ill patients with MODS. The main findings of this review are that the two parameters that vary with greatest significance in critically ill patients with MODS are drug volume of distribution and clearance. Disease- and clinician-driven changes lead to an increased volume of distribution and lower-than-expected plasma drug concentrations during the first day of therapy at least. Decreased antibiotic clearance is common and can lead to drug toxicity. In summary, "front-loaded" doses of antibiotic during the first 24 h of therapy should account for the likely increases in the antibiotic volume of distribution. Thereafter, maintenance dosing must be guided by drug clearance and adjusted to the degree of organ dysfunction.     

Decreased beating rate variability of spontaneously contracting cardiomyocytes after co-incubation with endotoxin

Decreased heart rate variability (HRV) in critically ill patients indicates a poor prognosis. In heart failure patients, there is an elevated sympathetic tone, reflected by a dominance of sympathetic parameters in HRV, whereas in critically ill patients sympathetic and parasympathetic modulation of heart rate is attenuated despite increased catecholamine blood levels. Thus, autonomic dysfunction in the critically ill cannot be causally related to an impairment at the level of neural transmission, but may be due to a derangement of signal transduction at the effector cell level. On the basis of our working hypothesis that endotoxin may be involved in this blunting of effector cell response to nerval input, we studied the spontaneous beating of cardiomyocytes under the influence of endotoxin. Applying the clinically established indices of HRV to the analysis of beating rate variability (BRV) of neonatal rat cardiomyocytes in serum-free medium, a narrowing of their BRV by endotoxin is demonstrated. We propose that the narrowing of HRV in critically ill patients does not only reflect the altered input from the central or peripheral neurons, but rather a remodeling of the cardiac pacemaker cells by endotoxin and inflammatory mediators.     

综合医院危重症患者1735例死亡危险因素分析

目的探讨综合医院危重症患者死亡的危险因素,以提高诊治质量。方法回顾性分析2005年至2010年重症监护病房收治的1735例患者,其中198例于重症监护病房（ICU）死亡,135例出ICU后死亡,对198例患者各年龄段进行统计学分析,并调查疾病分布特点;对比ICU内、外器官功能衰竭数与死亡率,检验各种危险因素对死亡的影响。结果老年组死亡率明显高于非老年组,差异有统计学意义（P〈0.01）。随年龄增长,死亡率呈增高趋势;发生功能障碍器官数与死亡率密切相关,功能障碍器官数越多,死亡率越高;当有5个或5个以上器官发生功能障碍时,死亡率接近100%。当衰竭器官数≤3个时,ICU内死亡率明显低于ICU外死亡率（P〈0.01）。从器官功能障碍分布来看,心血管系统功能障碍发生率高达51.8%,死亡率却低;致死性最高的功能障碍器官是：血液（59.3%）、肾（58.7%）;ICU内、外致死的障碍功能器官不同。结论降低危重症患者死亡率首先要降低≥60岁老年人的死亡率,明确原发病和受损器官,积极控制疾病向多器官功能衰竭的发展,保护重要脏器功能在危重症患者治疗中占重要地位。     

Intestinal alkaline phosphatase is a gut mucosal defense factor maintained by enteral nutrition

Under conditions of starvation and disease, the gut barrier becomes impaired, and trophic feeding to prevent gut mucosal atrophy has become a standard treatment of critically ill patients. However, the mechanisms responsible for the beneficial effects of enteral nutrition have remained a mystery. Using in vitro and in vivo models, we demonstrate that the brush-border enzyme, intestinal alkaline phosphatase (IAP), has the ability to detoxify lipopolysaccharide and prevent bacterial invasion across the gut mucosal barrier. IAP expression and function are lost with starvation and maintained by enteral feeding. It is likely that the IAP silencing that occurs during starvation is a key component of the gut mucosal barrier dysfunction seen in critically ill patients.     

The role of endocrine mechanisms in ventilator-associated lung injury in critically ill patients

The critically ill subjects are represented by a?heterogeneous group of patients suffering from a?life-threatening event of different origin, e.g. trauma, cardiopulmonary failure, surgery or sepsis. The majority of these patients are dependent on the artificial lung ventilation, which means a?life-saving chance for them. However, the artificial lung ventilation may trigger ventilation-associated lung injury (VALI). The mechanical ventilation at higher volumes (volutrauma) and pressure (barotrauma) can cause histological changes in the lungs including impairments in the gap and adherens junctions and desmosomes. The injured lung epithelium may lead to an impairment of the surfactant production and function, and this may not only contribute to the pathophysiology of VALI but also to acute respiratory distress syndrome. Other components of VALI are atelectrauma and toxic effects of the oxygen. Collectively, all these effects may result in a?lung inflammation associated with a?subsequent profibrotic changes, endothelial dysfunction, and activation of the local and systemic endocrine responses such as the renin-angiotensin system (RAS). The present review is aimed to describe some of the pathophysiologic aspects of VALI providing a?basis for novel therapeutic strategies in the critically ill patients. Keywords: critically ill patients, lung ventilation, inflammation, endothelial dysfunction, endocrine response, renin angiotensin system, glucocorticoids.     

Cost considerations in sedation, analgesia, and neuromuscular blockade in the intensive care unit

Sedation of critically ill patients is a costly endeavor. Costs of commonly used intensive care unit (ICU) sedatives range from pennies to more than $500 per day. Although the agents account for some of this expense, complications related to the use of these drugs in the ICU produce even greater costs. Prolongation of mechanical ventilation and length of stay are some of the common complications resulting from non-ideal use of these drugs. Sedative agents also impair neurological evaluation in many critically ill patients, which may mask detection of acute delirium resulting from intercurrent illness or intracranial catastrophes and can lead to excessive diagnostic testing. Opiates may result in gastrointestinal dysfunction with resulting malnutrition and perhaps bacterial translocation and sepsis. Neuromuscular blocking agents may cause prolonged paralysis and disability in critically ill patients who receive them. Simple dosing strategies based on pharmacological principles may decrease the incidence of these costly problems.     

Interleukin-10 haplotype associated with increased mortality in critically ill patients with sepsis from pneumonia but not in patients with extrapulmonary sepsis

STUDY OBJECTIVE: To test the hypothesis that haplotypes of the interleukin (IL)-10 gene are associated with clinical outcomes, comparing critically ill patients with sepsis from pneumonia vs those with extrapulmonary sepsis. DESIGN: Genetic association study. SETTING: Medical/surgical ICUs in a tertiary-care, university-affiliated teaching hospital. PATIENTS: Of 550 white patients with sepsis, 158 had pneumonia as the principle cause of their sepsis and 392 had an extrapulmonary source of sepsis. MEASUREMENTS: Haplotypes of the IL-10 gene were defined by measurement of haplotype tag single-nucleotide polymorphisms (SNPs). Primary outcome was 28-day survival. Secondary outcomes were days alive and free of organ dysfunction. RESULTS: Three SNPs in the IL-10 gene (-592 C/A, +734 G/T, and +3367 G/A) identified four major haplotypes: CGG, AGG, CTA, and CTG. Patients with pneumonia who carried one or two copies of the CGG haplotype had greater 28-day mortality (51.4%) than patients who did not carry this haplotype (29.1%, p = 0.007). Carriers of CGG had significantly more cardiovascular dysfunction (and use of vasopressors), renal dysfunction (and requirement of dialysis), hepatic dysfunction, and hematologic dysfunction (p < 0.05 in each case). In contrast, in patients with an extrapulmonary source of infection there was no significant association of the CGG haplotype (or any measured IL-10 genotype) with 28-day mortality or organ dysfunction. CONCLUSIONS: The IL-10 haplotype - 592C/734G/3367G is associated with increased mortality and organ dysfunction in critically ill patients with pulmonary sepsis but not in similarly ill patients with extrapulmonary sepsis. Therefore, polymorphisms within the IL-10 gene may be predictors of outcome in patients with sepsis from pneumonia.     

合并糖尿病危重症患者的营养支持护理探讨

目的探究合并糖尿病危重症患者的营养支持护理的临床效果。方法选取从2017年2月—2019年3月收治于该院的80例合并糖尿病危重症患者作为研究对象,对ICU心肺功能损害危重症合并糖尿病患者进行治疗,患者进入医院的第2天便给予患者提供充足营养支持,选择4个主要时间点,对患者血糖和营养情况进行观察和记录。结果治疗后,持续性营养支持可以保证患者血糖数值恢复到原本水平,血糖控制效果显著提升,并未出现任何不良反应,治疗前后血糖数值的对比差异有统计学意义(P<0.05);患者血红蛋白和血白蛋白水平始终保持稳定状态,所有患者均未出现营养不良状况,同时未出现营养支持和血糖控制等其他并发症。结论对合并糖耐病危重症患者提供充足肠内营养支持,可以是瑞代营养液以及胰岛素等,可以有效控制患者血糖水平,同时可以改善患者代谢状态,防止患者治疗期间出现不良反应,效果更加理想,安全可靠。     

Modulation of polymorphonuclear leukocyte apoptosis in the critically ill by removal of cytokines with continuous hemodiafiltration

Delay of polymorphonuclear leukocyte (PMN) apoptosis caused by hypercytokinemia is considered to be a potential cause of tissue damage and resultant organ failure. We evaluated whether continuous hemodiafiltration using a polymethylmethacrylate membrane hemofilter (PMMA-CHDF), which can remove cytokines in the circulating blood, can modulate apoptosis in peripheral blood neutrophils and thereby reduce tissue damage and organ dysfunction in 25 critically ill patients. Following the completion of a 3-day PMMA-CHDF session, serum cytokine levels were significantly decreased and the percentage of apoptotic PMNs was significantly increased. A significant correlation was observed between the PMMA-CHDF-induced increase in the percentage of apoptotic PMNs and the degree of decrease in the serum interleukin-6 level. A significant correlation was also found between the increase in the percentage of apoptotic PMNs and improvement in sequential organ failure assessment score following PMMA-CHDF. These results suggest that PMMA-CHDF in critically ill patients with hypercytokinemia and concomitant delay in apoptosis of PMNs can alleviate the delay of PMN apoptosis through the removal of serum cytokines and thus may result in avoidance of organ dysfunction.     

Probiotic/Synbiotic Therapy for Treating Critically Ill Patients from a Gut Microbiota Perspective

The gut is an important target organ for stress caused by severe insults such as sepsis, trauma, burn, shock, bleeding and infection. Severe insult to the gut is considered to have an important role in promoting infectious complications and multiple organ dysfunction syndrome. These are sequelae of interactions between deteriorated intestinal epithelium, the immune system and commensal bacteria. The gut is the “motor” of multiple organ failure, and now it is recognized that gut dysfunction is a causative factor in disease progression. The gut flora and environment are significantly altered in critically ill patients, and the number of obligate anaerobes is associated with prognosis. Synbiotic therapy is a combination of probiotics and prebiotics. Probiotic, prebiotic and synbiotic treatment has been shown to be a promising therapy to maintain and repair the gut microbiota and gut environment. In the critically ill, such as major abdominal surgery, trauma and ICU patients, synbiotic therapy has been shown to significantly reduce septic complications. Further basic and clinical research would clarify the underlying mechanisms of the therapeutic effect of probiotic/synbiotic treatment and define the appropriate conditions for use.