Regulation of the somatotropic axis by intensive insulin therapy during protracted critical illness

The catabolic state of critical illness has been linked to the suppressed somatotropic GH-IGF-binding protein (IGFBP) axis. In critically ill patients it has been demonstrated that, compared with the conventional approach, which only recommended insulin therapy when blood glucose levels exceeded 12 mmol/liter, strict maintenance of blood glucose levels below 6.1 mmol/liter with intensive insulin therapy almost halved intensive care mortality, acute renal failure, critical illness polyneuropathy, and bloodstream infections. Poor blood glucose control in diabetes mellitus has also been associated with low serum IGF-I levels, which can be increased by insulin therapy. We hypothesized that intensive insulin therapy would improve the IGF-I axis, possibly contributing to the clinical correlates of anabolism. Therefore, this study of 363 patients, requiring intensive care for more than 7 d and randomly assigned to either conventional or intensive insulin therapy, examines the effects of intensive insulin therapy on the somatotropic axis. Contrary to expectation, intensive insulin therapy suppressed serum IGF-I, IGFBP-3, and acid-labile subunit concentrations. This effect was independent of survival of the critically ill patient. Concomitantly, serum GH levels were increased by intensive insulin therapy. The suppression of IGF-I in association with the increased GH levels suggests GH resistance induced by intensive insulin therapy, which was reflected by the decreased serum GH-binding protein levels. Intensive insulin therapy did not affect IGFBP-3 proteolysis, which was markedly higher in protracted critically ill patients compared with healthy controls. Also, intensive insulin therapy did not suppress the urea/creatinine ratio, a clinical correlate of catabolism. In conclusion, our data suggest that intensive insulin therapy surprisingly suppressed the somatotropic axis despite its beneficial effects on patient outcome. GH resistance accompanied this suppression of the IGF-I axis. To what extent and through which mechanisms the changes in the GH-IGF-IGFBP axis contributed to the survival benefit under intensive insulin therapy remain elusive.     

Contribution of circulating lipids to the improved outcome of critical illness by glycemic control with intensive insulin therapy

Compared with the conventional approach, which recommended only insulin therapy when blood glucose levels exceeded 12 mmol/liter, strict maintenance of blood glucose levels less than 6.1 mmol/liter with intensive insulin therapy has shown to reduce intensive care mortality, acute renal failure, critical illness polyneuropathy, and bloodstream infections in critically ill patients by about 40%. This study of 363 patients, requiring intensive care for more than 7 d and randomly assigned to either conventional or intensive insulin therapy, examines the effects of intensive insulin therapy on glucose and lipid homeostasis and their respective impact on the improved outcome. Intensive insulin therapy effectively normalized blood glucose levels within 24 h, both in survivors and nonsurvivors. Intensive insulin therapy also increased serum levels of low-density lipoprotein (P = 0.007) and high-density lipoprotein (P = 0.005), whereas it suppressed the elevated serum triglyceride concentrations (P < 0.0001). Multivariate logistic regression analysis, corrected for baseline univariate risk factors and the effect on inflammation, indicated that lipid rather than glucose control independently determined the beneficial effects of intensive insulin therapy on morbidity and mortality. In postmortem biopsies obtained from 74 patients who died in the intensive care unit, intensive insulin therapy increased mRNA levels of skeletal muscle glucose transporter 4 (P = 0.02) and hexokinase (P = 0.03), unlike those of hepatic glucokinase. In conclusion, our data suggest that intensive insulin therapy normalizes blood glucose levels through stimulation of peripheral glucose uptake and concomitantly partially restores the abnormalities in the serum lipid profile, which may have contributed significantly to the improved outcome of protracted critical illness.     

胰岛素强化治疗对高血糖危重症患者抢救成功率的影响

目的观察胰岛素强化治疗对高血糖危重症患者抢救成功率的影响，并探讨其可能的机制。方法将收入ICU监护病房的110例高血糖危重症患者随机分为胰岛素强化治疗组（血糖控制在4．4～6．1mmol／L）和胰岛素常规治疗组（血糖控制在8．0～11．1mmol／L）。观察两组患者并发症发生率、ICU停留时间、死亡率等，并于人院后24h、4天、10天通过EMSA、流式细胞仪和ELISA法对外周血单核细胞NF—kB活性、单核细胞HLA—DR表达及血浆CRP水平进行动态检测。结果（1）强化治疗组死亡率（19．6％VS27．8％，P〈0．05）明显低于常规治疗组。（2）强化治疗组人院后24h、4天、10天各时点NF—kB活性、CRP水平均显著低于常规治疗组（P〈0．05）。（3）强化治疗组HLA—DR表达显著高于常规治疗组（P〈0．05）。结论胰岛素强化治疗能降低高血糖危重症患者死亡率，缩短ICU停留时间，降低医疗费用等，这与胰岛素严格控制血糖能够改善机体免疫状态、减轻全身炎症反应有关。     

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.     

The response to short-term intensive insulin therapy in type 2 diabetes

Aim: Although a short course of intensive insulin therapy (IIT) can improve beta-cell function and glycaemic control in most patients with newly diagnosed type 2 diabetes (T2DM), the impact of this intervention in diabetes of longer duration has not been carefully studied. Thus, we sought to evaluate the effect of short-term IIT in patients with established T2DM.
Methods: Thirty-four patients, with diabetes of mean 5.9 ± 6.6 years duration, underwent 4–8 weeks of IIT, with 4-h meal test administered at baseline and at 1 day post-IIT. A positive clinical response was defined as fasting glucose < 7.0 mmol/l off any antidiabetic therapy at the latter test.
Results: A positive response was achieved in 68% (n = 23) of the subjects. At baseline meal test, the responders had lower glucose levels than the non-responders from 120 to 240 min (all timepoints p ≤ 0.0008) and higher late incremental area-under-the-C-peptide-curve (AUC_Cpep), particularly from 60 to 150 min (all p < 0.005). Beta-cell function (ratio of AUC_Cpep to AUC_gluc divided by HOMA-IR) was similar between the groups at baseline (median 54.1 vs. 51.3, p = 0.62) but after IIT was significantly higher in the responders (109.3 vs. 57.4, p = 0.009). At baseline, the strongest predictors of the change in beta-cell function were glucose levels between 180 and 240 min (all r = −0.5, p = 0.005) and incremental AUC_Cpep from 120 to 180 min (all r ≥ 0.66, p ≤ 0.0001), both reflecting late-phase insulin secretion.
Conclusions: The clinical response to short-term IIT is variable, consistent with the heterogeneity of T2DM. However, preserved late-phase insulin secretion may identify those patients who can benefit from this intervention with improved beta-cell function.     

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.     

Pressure response to carotid occlusion in diabetic rats: effect of insulin therapy

Bilateral carotid occlusion (BCO) in conscious rats has been used as a maneuver to increase the sympathetic drive, producing a hypertensive response characterized by two components: an initial peak, and a maintained response of lower intensity. Acute (10-15 days) or chronic (6-13 weeks) diabetes was induced in Wistar rats with streptozotocin (STZ, 50 mg/kg, i.v.) while time-control rats received vehicle. Insulin (9 IU/kg, s.c.) was applied daily to other diabetic groups. Blood glucose was monitored three days after the administration of STZ and immediately before the experiment. Blood glucose was elevated in diabetic rats, but normal in time-control or diabetic rats treated with insulin. Basal mean arterial pressure (MAP) was reduced in diabetic as compared to time-control rats. The initial peak of the hypertensive response to BCO was blunted in either acute or chronic diabetic rats, whereas the maintained response was unaffected. Treatment of diabetic rats with insulin prevented the decrease in basal MAP and the attenuation of the initial peak caused by BCO. The maintained response was similar to that of time-control or non-treated rats. These findings suggest an abnormality of the carotid afference of the baroreflex caused by chronic hyperglycemia, which was prevented by treatment with insulin.     

The intensive insulin therapy team

The use of a team approach to the management of patients using intensive insulin therapy (IIT) has been supported by policy/position statements of both the American Association of Diabetes Educators and the American Diabetes Association. A course designed and taught by a health care team within the Washington University Diabetes Research and Training Center was offered to 18 multidisciplinary health care teams desiring information about initiating IIT programs. Course outcomes demonstrated positive responses to the team approach to team education but raised questions about the actual composition and functioning of the health care "team." While a well-defined team with IIT knowledge and skills is essential for the development of a comprehensive and safe approach to IIT programs, it is not clear who should be offering these programs.     

Blood purification for critical illness: cytokines adsorption therapy

Blood purification therapies have been clinically applied to treat cytokine-induced pathological effects. The effects of broad-spectrum adsorption using Lixelle (beta2-microglobulin adsorption column; Kaneka Corporation, Osaka, Japan) for the condition of hypercytokinemia in vitro, in an animal model and in humans with sepsis were investigated. We found that Lixelle could selectively adsorb not only beta2-microglobulin but also cytokines composed of glycoproteins in vitro. In addition, Lixelle beads could adsorb not only endotoxin (ET) but also microbial fragments such as peptidoglycan (PG) which is a component of Gram-positive bacteria. Hypercytokinemic rats were connected to a direct hemoperfusion (DHP) system using a mini Lixelle column and time-course changes in plasma levels of inflammatory cytokines were examined. In addition, a Lixelle column was used in direct hemoperfusion in patients with systemic inflammatory response syndrome (SIRS), and the relationship between a decrease in cytokines and clinical course was examined. The increases in plasma levels of IL-6 and tumor necrosis factor-alpha (TNF-alpha) were significantly inhibited in the group treated with the Lixelle column in an animal model. In humans with sepsis, for IL-1beta, IL-1Ra, IL-6, IL-8, and TNF-alpha, the adsorbing rates in vivo before and after the use of the Lixelle column tended to decrease with time. However, the reduction rates at 5 min after the start were 31.4, 39.3, 36.4, 76.2 and 71.6%, respectively, and at 3 h after the start, the rates were 18.0, 17.7, 12.9, 31.8, and 32.9%, respectively. Clinically, their blood pressure increased and they recovered from shock status. These results suggest that SIRS and sepsis with hypercytokinemia can be treated with the DHP using the Lixelle column.     

强化胰岛素治疗对体外循环炎症反应的影响

目的探讨强化胰岛素治疗对体外循环(CPB)下心脏瓣膜置换术炎性反应的影响。方法 30例CPB下行心脏瓣膜置换术患者随机分为强化胰岛素组(强化组,n=15)和对照组(n=15)。强化组术中血糖控制在3.9~10.0 mmol/L,术后控制在4.4~8.3 mmol/L;对照组血糖11.1 mmol/L时给予胰岛素治疗。分别于麻醉诱导后(T0)、CPB开始(T1)、CPB结束即刻(T2)、6 h(T3)、24 h(T4)和48 h(T5)时点测定血浆白细胞介素(IL)-6、肿瘤细胞坏死因子(TNF)-α浓度,并记录术后临床情况。结果两组TNF-α、IL-6浓度在T2、T3、T4时点均明显高于T0时点(P0.05);在T2、T3、T4时点,强化组TNF-α、IL-6浓度明显低于对照组(P0.05);强化组呼吸机支持时间明显短于对照组(P0.05)。结论强化胰岛素治疗能降低TNF-α、IL-6浓度表达,缩短呼吸机支持时间,减弱CPB引起的炎性反应。     

Dehydroepiandrosterone sulphate in critical illness: effect of dopamine

OBJECTIVE As part of a study on the effect of dopamine therapy on pituitary dependent hormone secretion in critical illness, we documented the impact of this inotropic and vasoactive catecholamine on the serum concentrations of dehydroepiandrosterone sulphate (DHEAS). Concomitantly, serum levels of PRL and cortisol were determined. PATIENTS AND DESIGN In a prospective, randomized, controlled, open-labelled clinical study, 20 critically ill, adult polytrauma patients receiving dopamine treatment (5 μg/kg/ml i.v. for a median 109 hours (range 21–296 hours), were studied to evaluate the effect of dopamine withdrawal on serum concentrations of DHEAS, PRL and cortisol. The median age of the studied patients was 37 years (range 18–83 years) MEASUREMENTS Serum DHEAS and cortisol concentrations were measured by RIA and PRL by IRMA. The assessed serum samples were obtained at 0300h on each of two consecutive study nights. RESULTS Withdrawal of dopamine infusion was found to elicit a median 25% Increase of serum DHEAS concentrations within 24 hours whereas no significant change in DHEAS levels was observed when dopamine infusion was continued throughout both study nights (P= 0.01 continued vs interrupted dopamine). Prolactin levels were undetectable as long as dopamine was infused, and increased to a median of 317 IU/I after 24 hours of dopamine withdrawal (P = 0.0007). Elevated serum cortisol levels remained comparable with continued and interrupted dopamine infusion. CONCLUSIONS Dopamine infusion appears to suppress serum DHEAS concentrations in critically ill patients without affecting their elevated serum cortisol levels, suggesting a differential regulation of DHEAS and cortisol metabolism in critical illness. The lowering effect of dopamine on DHEAS levels could be linked to the concomitant suppression of circulating PRL. The simultaneous suppression of circulating PRL and DHEAS by dopamine infusion may be an iatrogenic factor maintaining or aggravating the anergic state of prolonged severe illness.     

Stress hyperglycemia in pediatric critical illness: the intensive care unit adds to the stress!

Stress hyperglycemia (SH) commonly occurs during critical illness in children. The historical view that SH is beneficial has been questioned in light of evidence that demonstrates the association of SH with worse outcomes. In addition to intrinsic changes in glucose metabolism and development of insulin resistance, specific intensive care unit (ICU) practices may influence the development of SH during critical illness. Mechanical ventilation, vasoactive infusions, renal replacement therapies, cardiopulmonary bypass and extracorporeal life support, therapeutic hypothermia, prolonged immobility, nutrition support practices, and the use of medications are all known to mediate development of SH in critical illness. Tight glucose control (TGC) to manage SH has emerged as a promising therapy to improve outcomes in critically ill adults, but results have been inconclusive. Large variations in ICU practices across studies likely resulted in inconsistent results. Future studies of TGC need to take into account the impact of commonly used ICU practices and, ideally, standardize protocols in an attempt to improve the accuracy of conclusions from such studies.     

门冬胰岛素和人胰岛素强化治疗内科危重症高血糖疗效比较

目的 比较门冬胰岛素和人胰岛素强化治疗内科危重症高血糖的有效性和安全性.方法 选取中南大学湘雅二医院老年病科符合全身炎症反应综合征诊断标准的内科危重患者186例,入组时空腹血糖水平为(10.8±2.3)mmoL/L,根据患者入组时恢复进食情况分为多次皮下注射胰岛素组(MDI,n=90)和持续皮下注射胰岛素组(CSⅡ,n=96),2组均随机分为门冬胰岛素和人胰岛素亚组.MDI组中门冬胰岛素和人胰岛素亚组分别为44、46例,CSⅡ组分别为46、50例.MDI组餐前大剂量采用门冬胰岛素或人胰岛素,基础量均采用甘精胰岛素,CSⅡ组餐前大剂量及基础量均采用门冬胰岛素或人胰岛素.根据多点指尖血糖监测结果调整胰岛素用量,强化胰岛素治疗疗程7 d,使血糖控制在4.4～8.3 mmol/L,7 d后改为常规胰岛素治疗,使血糖控制在4.4～11.1 mmol/L,观察各哑组患者基线及第7天日内平均血糖水平、日内血糖标准差、日内血糖极差(最高和最低血糖之差)、血清C反应蛋白(CRP)水平、急性生理与慢性疾病评分(APACHE Ⅱ),统计7 d内低血糖发生率、严重低血糖发生率、日平均胰岛素用量及28 d内各组死亡率.统计学分析采用t检验和x~2检验.结果 (1)MDI及CSⅡ组的门冬胰岛素亚组和人胰岛素亚组强化治疗各项指标差异无统计学意义.(2)强化治疗后第7天门冬胰岛素哑组较人胰岛素组日内平均血糖水平更低,MDI组:(6.2±1.3)mmol/L比(7.6±1.6)mmol/L;CSⅡ组:(6.0±1.2)mmol/L比(7.4±2.5)mmol/L,均P＜0.05.(3)门冬胰岛素亚组血糖标准差更小,MDI组:(1.54±0.27)mmol/L比(1.92±0.38)mmol/L;CSⅡ组:(1.24±0.27)mmol/L比(1.83±0.45)mmol/L,均P＜0.05.(4)门冬胰岛素亚组极差更小,MDI组:(3.0±0.5)mmoL/L vs(3.9±1.1)mmoL/L;CSⅡ组:(3.1±0.6)mmol/L vs(3.9±1.0)mmol/L,均P＜0.05.(5)门冬胰岛素业组7 d内日平均胰岛素用量更少,低血糖发生率及严重低血糖发生率更低.同时,门冬胰岛素亚组7 d内血清CRP?     

Corticosteroid therapy in critical illness due to seasonal and pandemic influenza

BACKGROUND:

Survey data suggest that Canadian intensivists administer corticosteroids to critically ill patients primarily in response to airway obstruction, perceived risk for adrenal insufficiency and hemodynamic instability.

OBJECTIVE:

To describe variables independently associated with systemic corticosteroid therapy during an influenza outbreak.

METHODS:

The present analysis was retrospective cohort study involving critically ill patients with influenza in two Canadian cities. Hospital records were reviewed for critically ill patients treated in the intensive care units (ICUs) of eight hospitals in Canada during the 2008 to 2009 and 2009 to 2010 influenza outbreaks. Abstracted data included demographic information, symptoms at disease onset, chronic comorbidities and baseline illness severity scores. Corticosteroid use data were extracted for every ICU day and expressed as hydrocortisone dose equivalent in mg. Multivariable regression models were constructed to identify variables independently associated with corticosteroid therapy in the ICU.

RESULTS:

The study cohort included 90 patients with a mean (± SD) age of 55.0±17.3 years and Acute Physiology and Chronic Health Evaluation II score of 19.8±8.3. Patients in 2009 to 2010 were younger with more severe lung injury but similar exposure to corticosteroids. Overall, 54% of patients received corticosteroids at a mean daily dose of 343±330 mg of hydrocortisone for 8.5±4.8 days. Variables independently associated with corticosteroid therapy in the ICU were history of airway obstruction (OR 4.8 [95% CI 1.6 to 14.9]) and hemodynamic instability (OR 4.6 [95% CI 1.2 to 17.8]).

CONCLUSION:

Observational data revealed that hemodynamic instability and airway obstruction were associated with corticosteroid therapy in the critical care setting, similar to a recent survey of stated practice. Efforts to determine the effects of corticosteroids in the ICU for these specific clinical situations are warranted.