Relationship of continuous infusion lorazepam to serum propylene glycol concentration in critically ill adults

OBJECTIVES: The primary objective was to evaluate the relationship between high-dose lorazepam and serum propylene glycol concentrations. Secondary objectives were a) to document the occurrence of propylene glycol accumulation associated with continuous high-dose lorazepam infusion; b) to assess the relationship between lorazepam dose, serum propylene glycol concentrations, and propylene glycol accumulation; and c) to assess the relationship between the osmol gap and serum propylene glycol concentrations. DESIGN: Prospective, observational study. SETTING: Tertiary care, medical intensive care unit. PATIENTS: Nine critically ill adults receiving high-dose lorazepam (> or =10 mg/hr) infusion. INTERVENTIONS: Cumulative lorazepam dose (mg/kg) and the rate of infusion (mg.kg(-1).hr(-1)) were monitored from initiation of lorazepam infusion until 24 hrs after discontinuation of the high-dose lorazepam infusion. Serum osmolarity was collected at 48 hrs into the high-dose lorazepam infusion and daily thereafter. Serum propylene glycol concentrations were drawn at 48 hrs into the high-dose lorazepam infusion, and the presence of propylene glycol accumulation, as evidenced by a high anion gap (> or =15 mmol/L) metabolic acidosis with elevated osmol gap (> or =10 mOsm/L), was assessed at that time. MEASUREMENTS AND MAIN RESULTS: The mean cumulative high-dose lorazepam received and mean high-dose lorazepam infusion rate were 8.1 mg/kg (range, 5.1-11.7) and 0.16 mg.kg(-1).hr (-1)(range, 0.11-0.22), respectively. A significant correlation between high-dose lorazepam infusion rate and serum propylene glycol concentrations was observed (r =.557, p =.021). Osmol gap was the strongest predictor of serum propylene glycol concentrations (r =.804, p =.001). Propylene glycol accumulation was observed in six of nine patients at 48 hrs. No significant correlation between duration of lorazepam infusion and serum propylene glycol concentrations was observed (p =.637). CONCLUSION: Propylene glycol accumulation, as reflected by a hyperosmolar anion gap metabolic acidosis, was observed in critically ill adults receiving continuous high-dose lorazepam infusion for > or =48 hrs. Study findings suggest that in critically ill adults with normal renal function, serum propylene glycol concentrations may be predicted by the high-dose lorazepam infusion rate and osmol gap.     

Lowering of glucose in critical care: a randomized pilot trial

BACKGROUND: Similar to cardiac surgery patients, medical-surgical critically ill patients may benefit from intensive insulin therapy. The objectives of this pilot trial were to evaluate the feasibility of a randomized trial of intensive insulin therapy with respect to (a) achieving target glucose values in the 2 ranges of 5 to 7 and 8 to 10 mmol/L and (b) uncovering problems with the protocol in anticipation of a larger trial. SETTING: The trial was conducted in a 15-bed medical-surgical university-affiliated intensive care unit (ICU). METHODS: We included patients older than 18 years, expected to be in ICU for more than 72 hours, with a glucose value of more than 10 mmol/L within 48 hours of ICU admission. Exclusion criteria were diabetic ketoacidosis, severe hepatic failure or hepatic resection, pancreatitis, glucose of less than 2.2 mmol/L on admission to hospital, insulin infusion on admission to ICU, planned withdrawal of life support, and inability to obtain informed consent. Patients underwent concealed random allocation to a target glucose range of 5 to 7 or 8 to 10 mmol/L using pretested algorithms of insulin infusions. Dedicated glucometer measurement of arterial glucose values was calibrated daily to values measured in the laboratory. RESULTS: We enrolled 20 patients with a mean (SD) Acute Physiology and Chronic Health Evaluation (APACHE) II score of 32 (10.2); 14 were insulin-dependent pre-ICU, and all were medical admissions. Mean glucose values were different in the 2 groups (7.1 +/- 2.6 vs 9.4 +/- 2.1 mmol/L, P < .001). Although the intensive insulin therapy group had more glucose measurements performed than the control group, a similar proportion of values were within the target range (682 [42.4%] of 1607 values in the 5- to 7-mmol/L range; 250 [38.7%] of 660 values in the 8- to 10-mmol/L range, P = .35). Glucose values of less than 2.5 mmol/L developed 7 times in 5 patients, 4 of whom were in the intensive insulin therapy group; however, no adverse consequences were documented. As expected, there were no differences in clinically important outcomes. CONCLUSIONS: In this pilot trial of ICU patients with high illness severity, glucose values were in the 2 target ranges only 40% of the time, using well-accepted initiation and maintenance insulin infusion algorithms. A large randomized trial of glycemic control is feasible in this population to examine clinically important outcomes, but will require refined insulin algorithms and more comprehensive behavior change strategies to achieve target values.     

危重病患者抢救中胰岛素强化治疗的探讨

目的观察胰岛素强化治疗能否改善重症监护室（ICU）危重患者的预后。方法将116例危重患者随机分为传统治疗组（CT组）和胰岛素强化治疗组（IT组），每4h监测1次床旁血糖。当CT组血糖＞11．9mmol／L时，皮下注射中性可溶性胰岛素控制血糖在10．0～11．1mmol／L；当IT组血糖＞6．1mmol／L时，皮下注射胰岛素控制血糖在4．4～6．1mmol／L。记录患者ICU住院时间、使用呼吸机时间、气管插管或气管套管留置时间、每日早6时平均血糖、每日提供的平均热量、每日胰岛素用量、每日简化治疗干预评分系统-28（TISS-28）评分、人白细胞DR抗原（HLA—DR）、CD4^＋／CD8^＋，死亡、低血糖、肾功能损害（血肌酐＞221／μmol／L）和高胆红素血症（总胆红素＞34．2μmol／L）、输红细胞及发热（口温＞38．5℃）例数。结果CT组病死率（44．83％）远远高于IT组（12．07％），差异有显著性（P＜O．01）；患者ICU住院时间、使用呼吸机时间、气管插管留置时间、每日早6时平均血糖、每日TISS-28评分均明显高于IT组（P＜0．05或P＜0．01）；每日胰岛素用量、HLADR、CD4^＋／CD8^＋均明显低于IT组（P＜0．05或P＜0．01）。两组并发症比较，CT组患者发生肾功能损害、输注红细胞及发热例数均明显高于IT组（P均＜0．01）。结论胰岛素强化治疗控制危重患者血糖在4．4～6．1mmol／L水平确能降低患者的病死率。     

强化胰岛素治疗危重病患者40例

目的观察强化胰岛素治疗在危重病患者中的临床疗效。方法80例危重病患者随机分为两组,治疗组（40例）给予强化胰岛素治疗,使血糖维持在4．4—6．1mmol／L;对照组（40例）给予常规胰岛素治疗,使血糖控制在10．0—11．1mmol／L。观察两组患者使用抗生素的天数、使用呼吸机的天数、血透发生率、院内感染发生率及病死率。结果治疗组中使用抗生素天数（15±5）d,使用呼吸机天数（6±4）d,需行血透6例（15．0％）,院内感染6例（15．0％）,病死率17．5％,均明显低于对照组,P〈0．05,差异有统计学意义。结论对于危重病患者,当出现应激性高血糖时,强化胰岛素治疗可改善危重病患者的预后,降低其病死率。     

An insulin infusion protocol in critically ill cardiothoracic surgery patients

BACKGROUND: Critically ill cardiothoracic patients are prone to hyperglycemia and an increased risk of surgical site infections postoperatively. Aggressive insulin treatment is required to achieve tight glycemic control (TGC) and improve outcomes. OBJECTIVE: To examine and report on the performance of an insulin infusion protocol to maintain TGC, defined as a blood glucose level of 80-150 mg/dL, in critically ill cardiothoracic surgical patients. METHODS: A nurse-driven insulin infusion protocol was developed and initiated in postoperative cardiothoracic surgical intensive care patients with or without diabetes. In this before-after cohort study, 2 periods of measurement were performed: a 6-month baseline period prior to the initiation of the insulin infusion protocol (control group, n = 174) followed by a 6-month intervention period in which the protocol was used (TGC group, n = 168). RESULTS: Findings showed percent and time of blood glucose measurements within the TGC range (control 47% vs TGC 61%; p = 0.001), AUC of glucose exposure >150 mg/dL versus time for the first 24 hours of the insulin infusion (control 28.4 vs TGC 14.8; p < 0.001), median time to blood glucose <150 mg/dL (control 9.4 h vs TGC 2.1 h; p < 0.001), and percent blood glucose <65 mg/dL as a marker for hypoglycemia (control 9.8% vs TGC 16.7%; NS). CONCLUSIONS: An insulin infusion protocol designed to achieve a goal blood glucose range of 80-150 mg/dL efficiently and significantly improved TGC in critically ill postoperative cardiothoracic surgery patients without significantly increasing the incidence of hypoglycemia.     

胰岛素泵和多次胰岛素皮下注射治疗老年危重症高血糖的有效性和安全性比较

目的 比较持续皮下注射胰岛素(CSII,即胰岛素泵)和多次皮下注射胰岛素(MDI)强化治疗改善老年危重症高血糖的有效性和安全性.方法 选择本院老年危重病患者94例,入组时空腹血糖为(10.3±2.5)mmol/L;随机分为CSII组(46例)和MDI组(48例),两组均注射可溶性人胰岛素,连续治疗7 d,观察两组血糖控制情况、7 d内日平均胰岛素用量、低血糖发生率.第7日血清C-反应蛋白(CRP)、肿瘤坏死因子-a(TNF-a)、白细胞介素-6(IL-6)水平、急性生理学与慢性健康状况评分系统Ⅱ(APACHE Ⅱ)评分以及28 d病死率.结果 与MDI组比较,CSII组血糖控制更好,血糖控制良好率[76.1%(35/46)比33.3%(16/48)3及血糖控制尚可率更高[21.7%(10/46)比14.6%(7/48)3,而控制差的更低[2.2%(1/46)比52.1%(25/48)];低血糖发生率更低(10.9%(5/46)比22.9%(11/48)],7 d内日平均胰岛素用量更少[(40.1±6.3)U/d比(46.2±7.1)U/d];血清TNF-a[(11.54±2.7)μg/L比(19.8±4.2)μg/L]、IL-6水平[(78.3±5.1)μg/L比(141.4±6.2)μg/L]、CRP水平[(53.1±3.3)mg/L比(72.1±4.0)mg/L3明显低于MDI组;APACHE Ⅱ评分明显低于MDI组[(6.0±1.4)分比(11.6±1.0)分];CSII组28 d病死率低于MDI组(4.3%(2/46)比16.7%(8/48)3;差异均有统计学意义(P均<0.05).结论 胰岛素泵较多次皮下注射治疗可更好地控制危重症高血糖,减轻炎症反应及改善短期预后.     

Metabolic inefficacy of a short-term low-dose insulin regimen in critically ill patients: a randomized, placebo-controlled trial

OBJECTIVE: Hyperglycemia and protein catabolism frequently occur in critically ill patients and both are associated with increased complication rates. These metabolic alterations can be improved by insulin administered exogenously. Since a wide range of insulin dosages have been used, this randomized, placebo-controlled, investigator-blinded, clinical study tests the hypothesis that a low-dose insulin regimen improves hyperglycemia and protein catabolism in critically ill medical patients. PATIENTS AND METHODS: The day after their admission to a medical intensive care unit, forty consecutive, critically ill medical patients were randomized for receiving either a low-dose insulin regimen (i.e. 1 IU/h) (treatment group, n = 20) or placebo (control group, n = 20) continuously over 24 hours. The primary endpoint was the efficacy of the low-dose insulin regimen to decrease serum glucose concentrations; the secondary endpoint was its influence on protein catabolism. Serum glucose concentrations and protein catabolism, which was assessed by the urea nitrogen appearance rate, were determined at baseline and at 8 and 24 hours thereafter. Serum insulin concentrations were measured at baseline and after 24 hours. RESULTS: After 24 hours the low-dose insulin regimen increased serum insulin concentrations compared with baseline (16.8+/-13.3 microU/ml and 11.5+/-16.9 microU/ml, respectively; p<0.05). Hyperglycemia and the urea nitrogen appearance rate did not change within the two groups of patients and there was no difference between the groups at the different time points. CONCLUSIONS: Administration of the low-dose insulin regimen was safe. However, the short-term low-dose insulin regimen was inefficient in influencing mild hyperglycemia and protein catabolism in critically ill medical patients.     

持续皮下胰岛素输注与多次皮下胰岛素注射在2型糖尿病围手术期血糖控制疗效观察

目的 比较2型糖尿病围手术期应用持续皮下胰岛素输注(CSII)和多次皮下胰岛素注射(MSII)的血糖控制效果.方法 将外科疾病合并2型糖尿病患者180例随机分为2组,98例为CSII组(持续皮下胰岛素输注诺和灵R),82例为MSII组(多次皮下注射诺和灵R和诺和灵N,所用剂量根据患者不同情况而定),观察2组患者治疗前后不同时点的血糖变化、血糖达标时间、平均胰岛素用量、低血糖发生率、术后切口感染率及住院天数的变化.结果 CSII组治疗后各时点血糖控制及其其他相关指标均优于MSII组,即CSII组治疗后空腹血糖[(4.8±1.6)mmol/L]控制效果优于MSII组[(6.4±2.1)mmol/L](t=7.74,P<0.05);早餐后2 h血糖控制效果[(7.6±2.3)mmol/L]优于MSII组[(9.3±2.4)mmol/L](t=7.72,P<0.05);血糖迭标时间[(4.1±2.9)d]明显短于MSII组[(6.9±2.0)d](t=2.81,P<0.05);平均胰岛素用量[(40.7±10.3)U]明显少于MSII组[(63.2±17.0)U](t=3.57,P<0.05);低血糖发生率(9.20%)较MSII组(3.05%)低(χ~2=4.92,P<0.05);CSII组切口感染率(0.0%)较MSII组(10.9%)低(χ~2=4.18,P<0.05);住院天数[(15.3±7.2)d]明显短于MSII组[(22.5±9.7)d](t=3.12,P<0.05).结论 2型糖尿病患者在围手术期应用持续皮下胰岛素输注控制血糖迅速、有效、安全.     

Intensive insulin therapy: enhanced Model Predictive Control algorithm versus standard care

Objective  To investigate the effectiveness of an enhanced software Model Predictive Control (eMPC) algorithm for intravenous insulin infusion, targeted at tight glucose control in critically ill patients, over 72 h, in two intensive care units with different management protocols. Design  Comparison with standard care in a two center open randomized clinical trial. Setting  Two adult intensive care units in University Hospitals. Patients and participants  Thirty-four critically ill patients with hyperglycaemia (glucose >120 mg/dL) or already receiving insulin infusion. Interventions  Patients were randomized, within each ICU, to intravenous insulin infusion advised by eMPC algorithm or the ICU’s standard insulin infusion administration regimen. Measurements and results  Arterial glucose concentration was measured at study entry and when advised by eMPC or measured as part of standard care. Time-weighted average glucose concentrations in patients receiving eMPC advised insulin infusions were similar [104 mg/dL (5.8 mmol/L)] in both ICUs. eMPC advised glucose measurement interval was significantly different between ICUs (1.1 vs. 1.8 h, P < 0.01). The standard care insulin algorithms resulted in significantly different time-weighted average glucose concentrations between ICUs [128 vs. 99 mg/dL (7.1 vs. 5.5 mmol/L), P < 0.01]. Conclusions  In this feasibility study the eMPC algorithm provided similar, effective and safe tight glucose control over 72 h in critically ill patients in two different ICUs. Further development is required to reduce glucose sampling interval while maintaining a low risk of hypoglycaemia. An erratum to this article can be found at     

危重症病人应激性高血糖短期胰岛素强化治疗的临床护理

目的:探讨短期胰岛素强化治疗对危重病人预后的影响,并分析相关护理问题。方法:选择入住ICU、既往无糖尿病史的危重病人108例,随机分为治疗组和对照组各54例。治疗组给予7 d的短期强化胰岛素治疗,随后给予常规的血糖控制;对照组则一直给予常规的血糖控制。强化胰岛素治疗控制血糖在4.4～8.3 mmol/L,常规血糖控制在4.4～11.1 mmol/L。结果:治疗组ICU住院时间、机械通气天数、院内感染发生率、多器官功能障碍综合征(MODS)发生率及病死率均明显低于对照组(P<0.05),两组低血糖的发生率差异比较无统计学意义(P>0.05)。结论:短期胰岛素强化治疗能有效控制重症病人的应激性高血糖,改善预后,实施过程中要做好病人血糖动态监测工作,减少低血糖的发生率。     

Rarity of a marked "dawn phenomenon" in diabetic subjects treated by continuous subcutaneous insulin infusion

We assessed the quality of overnight glycemic control and the frequency of the "dawn phenomenon" (nadir-0800 h glycemic increase) in 41 insulin-dependent diabetic patients treated by continuous subcutaneous insulin infusion (CSII). Mean plasma glucose levels were near-normal during the 24 h and, in particular, constant throughout the night. In a subset of six patients overnight plasma free insulin concentrations were also constant during CSII. The majority of profiles (88%) showed a glucose nadir from 2.0 to 5.9 mmol/L (most frequently at 0600 h) and had an 0800 h value from 2.0 to 6.9 mmol/L (92%). A large proportion (46%) of profiles showed a zero or negative nadir-0800 h glycemic increase. In 22 patients with three or more profiles recorded at the same basal insulin infusion rate, only one of 103 profiles had a fasting glycemic increase greater than an arbitrary value of 5.0 mmol/L (5.3), although many patients exhibited small dawn glycemic increases (e.g., 14 of 22 had a mean increase of from 0 to 2 mmol/L). In 12 subjects a 15% reduction in basal insulin infusion rate increased the mean +/- SEM dawn glycemic increase from 0.58 +/- 0.25 mmol/L to 2.7 +/- 0.76 mmol/L (P less than 0.025) as well as significantly increasing the nocturnal nadir and 0800 h plasma glucose concentrations. Thus, a marked dawn phenomenon is rare when a single but adequate basal infusion rate is used for CSII, and this questions the need in the majority of patients for preprogrammable pumps with nocturnal infusion rate changes.     

甘精胰岛素治疗老年危重患者合并高血糖40例临床分析

目的探讨甘精胰岛素对老年危重患者合并高血糖的临床疗效。方法选择老年危重患者合并高血糖患者78例，随机分为2组，治疗前两组患者24h血糖为（13．8±4．5vs13．8±4．2）mmol／L，治疗组（n=40）采用甘精胰岛素作为基础治疗药物，对照组（n=38）采用中性低精蛋白锌人胰岛素作为基础治疗药物。可进食患者餐前追加短效胰岛素。血糖控制目标为5．0～8．0mmol／L。结果治疗组1，3，5d的平均血糖较对照组降低，分别为（12．2±1．4vs13．5±3．8）mmol／L，P〈0．01，（8．3±0．6VS9．5±0．8）mmol／L，P〈0．01，（5．8±0．2vs6．4±0．6）mmol／L，P〈0．05。7d及以后，两组间血糖无统计学差异。结论以甘精胰岛素为基础胰岛素的治疗方案能有效控制老年危重合并高血糖患者的血糖水平，有确切临床意义，值得临床推广使用。     

重症患者应激性高血糖短期胰岛素强化治疗方案的探讨

目的 探讨短期胰岛素强化治疗对重症患者应激性高血糖的调控及临床转归的影响.方法 选择入住ICU既往无糖尿病史的危重患者186例,随机分为4d组、7d组和对照组,每组各62例.分别给予4d、7d的短期强化胰岛素治疗,随后给予常规的血糖控制,对照组则一直给予常规的血糖控制.强化胰岛素治疗控制血糖在4.4～8.3mmol/L,常规血糖控制在4.4～11.1mmol/L.结果 在强化胰岛素治疗停止后第8～14d,4d组、7d组的平均血糖水平明显较对照组低,同期每天胰岛素用量也明显低于对照组(P<0.01);4d组、7d组的ICU住院时间、机械通气天数、院内感染发生率、MODS发生率及病死率均明显低于对照组(P<0.05或P<0.01),而4d组的ICU住院时间、机械通气天数均较7d组高(P<0.05).结论 在危重病人中,采用7d短期胰岛素强化治疗,能有效控制重症患者的应激性高血糖,改善预后,又减少了低血糖的发生率.     

Outcome benefit of intensive insulin therapy in the critically ill: Insulin dose versus glycemic control

OBJECTIVES: Maintenance of normoglycemia with insulin reduces mortality and morbidity of critically ill patients. Here we report the factors determining insulin requirements and the impact of insulin dose vs. blood glucose control on the observed outcome benefits. DESIGN: A prospective, randomized, controlled trial. SETTING: A 56-bed predominantly surgical intensive care unit in a tertiary teaching hospital. PATIENTS AND INTERVENTION: A total of 1,548 patients were randomly assigned to either strict normalization of blood glucose (80-110 mg/dL) with insulin infusion or the conventional approach, in which insulin is only given to maintain blood glucose levels at 180-200 mg/dL. MEASUREMENTS AND MAIN RESULTS: It was feasible and safe to achieve and maintain blood glucose levels at <110 mg/dL by using a titration algorithm. Stepwise linear regression analysis identified body mass index, history of diabetes, reason for intensive care unit admission, at-admission hyperglycemia, caloric intake, and time in intensive care unit as independent determinants of insulin requirements, together explaining 36% of its variation. With nutritional intake increasing from a mean of 550 to 1600 calories/day during the first 7 days of intensive care, normoglycemia was reached within 24 hrs, with a mean daily insulin dose of 77 IU and maintained with 94 IU on day 7. Insulin requirements were highest and most variable during the first 6 hrs of intensive care (mean, 7 IU/hr; 10% of patients required >20 IU/hr). Between day 7 and 12, insulin requirements decreased by 40% on stable caloric intake. Brief, clinically harmless hypoglycemia occurred in 5.2% of intensive insulin-treated patients on median day 6 (2-14) vs. 0.8% of conventionally treated patients on day 11 (2-10). The outcome benefits of intensive insulin therapy were equally present regardless of whether patients received enteral feeding. Multivariate logistic regression analysis indicated that the lowered blood glucose level rather than the insulin dose was related to reduced mortality (p <.0001), critical illness polyneuropathy (p <.0001), bacteremia (p =.02), and inflammation (p =.0006) but not to prevention of acute renal failure, for which the insulin dose was an independent determinant (p =.03). As compared with normoglycemia, an intermediate blood glucose level (110-150 mg/dL) was associated with worse outcome. CONCLUSION: Normoglycemia was safely reached within 24 hrs and maintained during intensive care by using insulin titration guidelines. Metabolic control, as reflected by normoglycemia, rather than the infused insulin dose, was related to the beneficial effects of intensive insulin therapy.     

Decision support for optimized blood glucose control and nutrition in a neurotrauma intensive care unit: preliminary results of clinical advice and prediction accuracy of the Glucosafe system

Assessment of glycemic control with model-based decision support ("Glucosafe") in neurotrauma intensive care patients in an ongoing randomized controlled trial with a blood glucose (BG) target of 5-8 mmol/L. Assessment of BG prediction accuracy of the model and assessment of the effect that two potential model extensions would have on prediction accuracy in this trial. In the intervention group insulin infusion rates and nutrition are varied based on Glucosafe's decision support. In the control group, the caloric target is 25-30 kcal/kg per day and insulin is regulated according to department rules. BG concentrations, insulin infusion rates, and feed rates are compared from the data of 12 consecutive patients. BG measurements are predicted retrospectively and the mean relative prediction error is calculated using (1) the current model from the trial, (2) the current model modified by using a BG-dependent variable endogenous insulin appearance rate, (3) the current model modified by a patient-specific carbohydrate absorption factor. BG control was improved by Glucosafe. 76 % of BG measurements in Glucosafe patients were in the 5-8 mmol/L band (Controls: 51 %). BG means (log-normal) ± SD were 7.0 ± 1.19 mmol/L in Glucosafe patients compared to 8.0 ± 1.24 mmol/L in controls (P = 0.05). Mean caloric intake was 93.5 ± 15 % of resting energy expenditure in Glucosafe patients (Controls: 129 ± 29 %). The BG-dependent variable insulin appearance rate had no measurable effect on prediction accuracy. The patient-specific carbohydrate absorption factor improved prediction accuracy significantly (P = 0.001). Glucosafe advice reduces hyperglycemia in neurotrauma intensive care patients. Further parameterization can improve model prediction accuracy.     

Standardization of intravenous insulin therapy improves the efficiency and safety of blood glucose control in critically ill adults

Objective Aggressive glycemic control improves mortality and morbidity in critically ill adults, however implementation of such a strategy can be logistically difficult. This study evaluates the efficiency and safety of a nurse-managed insulin protocol in critically ill adults.Design Combined retrospective-prospective before-after cohort study.Setting Twenty-one bed, medical/surgical ICU in a tertiary care hospital.Patients Two cohorts of 50 consecutive ICU patients requiring insulin infusions.Intervention Patients in the control cohort received insulin infusions titrated according to target blood glucose ranges and sliding scales at the physicians discretion. Patients in the interventional cohort received an insulin infusion adjusted using a standardized protocol targeting a blood glucose of 4.5–6.1 mmol/l (81–110 mg/dl).Measurements and main results Efficiency was measured by comparing the time to reach, and the time spent within, the target range between cohorts. Safety was assessed by comparing the incidence of severe hypoglycemia, the frequency of rescue dextrose administration and the cumulative time that the infusion was held for hypoglycemia between cohorts. Patients in the interventional cohort reached their target more rapidly (11.3±7.9 vs 16.4±12.6 h; p=0.028) and maintained their blood glucose within the target range longer (11.5±3.7 vs 7.1±5.0 h/day; p<0.001) than controls. The standardized protocol yielded a four-fold reduction in the incidence of severe hypoglycemia (4 vs 16%; p=0.046) and reduced the median frequency of dextrose rescue therapy (0 [0–0.91] vs 0.17 [0–1.2] episodes/patient per day; p=0.01) as compared to controls.Conclusion Standardization of intensive insulin therapy improves the efficiency and safety of glycemic control in critically ill adults.     

Insulin sensitivity of glucose and fat metabolism in severe sepsis

In order to quantify the changes in insulin sensitivity, particularly of endogenous glucose production and fat metabolism, in patients with severe sepsis, a prospective study was conducted in five normal subjects and in five patients with severe sepsis hospitalized in an intensive care unit. The responses of endogenous glucose production, glucose utilization, plasma fatty acids and ketone body concentrations to progressive increase in plasma insulin levels (exogenous insulin infusion rates of 0, 0.5, 1 and 2 m-units x min(-1) x kg(-1)) were measured using the isoglycaemic clamp technique. Total glucose turnover was determined with D-[6,6-(2)H(2)]glucose. In each group, plasma glucose was maintained at basal levels (control subjects, 4.32+/-0.22 mmol x l(-1); patients with sepsis, 7.10+/-2.29 mmol x l(-1); P<0.05). Plasma insulin concentrations were comparable in the two groups at an insulin infusion rate of 0.4 m-unit x min(-1) x kg(-1) for controls and 0.5 m-unit x min(-1) x kg(-1) for patients with sepsis, but differed following infusion at 2 m-unit x min(-1) x kg(-1) (control subjects, 102+/-13.4 m-units x l(-1); patients with sepsis, 124.8+/-19.7 m-units x l(-1); P<0.05). Endogenous glucose production was completely suppressed in control subjects by the first insulin infusion (0.4 m-unit x min(-1) x kg(-1)), but was only suppressed during infusion at 1 m-unit x min(-1) x kg(-1) insulin in patients with sepsis. The glucose utilization rate increased significantly with exogenous insulin infusion in control subjects, but did not increase in patients with sepsis. Plasma non-esterified (free) fatty acid and ketone body levels were significantly decreased in both groups by the infusion of exogenous insulin, but the sensitivity of lipolysis was impaired in patients with sepsis. In conclusion, sepsis impaired to a varying extent the action of insulin on endogenous glucose production, glucose utilization, lipolysis and ketogenesis. Whole-body glucose uptake was the most affected, with a total lack of response to the elevated insulin levels obtained in this study. Suppression of endogenous glucose production and lipolysis could only be achieved with higher doses of insulin than those required in normal subjects.     

Short-term infusions of insulin, triacylglycerol and glucose do not cause acute increases in plasminogen activator inhibitor-1 concentrations in man

1. To investigate the acute effects of insulin and triacylglycerol ('triglyceride') on circulating plasminogen activator inhibitor-1 concentrations, seven healthy volunteers were studied during hyperinsulinaemic clamps in the presence of euglycemia (mean glucose concentration 5 mmol/l) and hyperglycaemia (mean glucose concentration 9 mmol/l) with and without triacylglycerol infusions. 2. During euglycemia, plasma insulin levels rose from baseline values [median (range)] of 13 (6.6-20.6) m-units/l to 89 (74-105) m-units/l and 99 (74-109) m-units/l after 1 and 2 h of insulin infusion, respectively. Concentrations of plasminogen activator inhibitor-1 fell from 27.5 (10-47) ng/ml to 25.0 (14.5-55) ng/ml and 15.5 (11.5-28.5) ng/ml (P less than 0.02) over the same time. 3. During hyperglycaemia, plasma insulin concentrations were 12.1 (9.3-17.1) m-units/l at the run-in period and rose to 87 (73-112) m-units/l and 91 (84-97) m-units/l after 1 and 2 h of insulin infusion, respectively. Concentrations of plasminogen activator inhibitor-1 again showed a gradual fall from 24.7 (22-50) ng/ml to 14 (8.3-25.5) ng/ml and 13 (6.0-35.0) ng/ml (P less than 0.02) over the same period. 4. Infusion of Intralipid in the presence of hyperinsulinaemia with either euglycemia or hyperglycaemia was associated with a similar fall in concentrations of plasminogen activator inhibitor-1 over the study period. 5. The results from this study indicate that short-term increases in insulin, glucose or triacylglycerol do not cause acute increases in plasma concentrations of plasminogen activator inhibitor-1.     

Comparison of plasma glucose and plasma free insulin during CSII and intensified conventional insulin therapy

The plasma glucose and plasma free insulin profiles of six totally insulin-dependent diabetic patients were compared during periods of 4 days in hospital under a conventional insulin therapy (ICIT) comprising 4 daily injections of regular insulin and under continuous subcutaneous insulin infusion (CSII). Two profiles of prandial insulin administration with CSII were compared: a rectangular (R) and an exponential wave (E) in which 50% of the dose was given rapidly followed by an exponential decrease. In both cases, the basal infusion rate was increased by 30-50% between 5 a.m. and 8 a.m. Mean circadian blood glucose was equally good with ICIT: R and E: 7.0 +/- 0.9, 7.3 +/- 1.0, and 7.1 +/- 1.0 mmol/L, respectively. In five patients, fasting plasma glucose was higher with ICIT than with R and E (12.7 +/- 1.8 versus 6.9 +/- 1.0 and 6.8 +/- 0.8 mmol/L, respectively; t test: P less than 0.05; Wilcoxon: P = 0.06). Mean plasma free insulin level was significantly higher (t test: P less than 0.005; Wilcoxon: P less than 0.05) with ICIT (0.46 +/- 0.04 nmol/L) than with R (0.37 +/- 0.04 nmol/L) or E (0.36 +/- 0.05 nmol/L), although the daily doses were similar. In conclusion, CSII leads to a better glycemic control than ICIT, since it appears to prevent the morning rise of blood glucose.