Towards a feasible algorithm for tight glycaemic control in critically ill patients: a systematic review of the literature

Introduction  

Tight glycaemic control is an important issue in the management of intensive care unit (ICU) patients. The glycaemic goals described by Van Den Berghe and colleagues in their landmark study of intensive insulin therapy appear difficult to achieve in a real life ICU setting. Most clinicians and nurses are concerned about a potentially increased frequency of severe hypoglycaemic episodes with more stringent glycaemic control. One of the steps we took before we implemented a glucose regulation protocol was to review published trials employing insulin/glucose algorithms in critically ill patients.     

Implementation and evaluation of the SPRINT protocol for tight glycaemic control in critically ill patients: a clinical practice change

Introduction  

Stress-induced hyperglycaemia is prevalent in critical care. Control of blood glucose levels to within a 4.4 to 6.1 mmol/L range or below 7.75 mmol/L can reduce mortality and improve clinical outcomes. The Specialised Relative Insulin Nutrition Tables (SPRINT) protocol is a simple wheel-based system that modulates insulin and nutritional inputs for tight glycaemic control.     

Nurse-led implementation of an insulin-infusion protocol in a general intensive care unit: improved glycaemic control with increased costs and risk of hypoglycaemia signals need for algorithm revision

Background  

Strict glycaemic control (SGC) has become a contentious issue in modern intensive care. Physicians and nurses are concerned about the increased workload due to SGC as well as causing harm through hypoglycaemia. The objective of our study was to evaluate our existing degree of glycaemic control, and to implement SGC safely in our ICU through a nurse-led implementation of an algorithm for intensive insulin-therapy.     

Efectividad de un protocolo basado en la evidencia para el control de la hiperglucemia por estrés en cuidados intensivos

Aim

To assess the effectiveness of the implementation of a protocol for glycaemic control in critical care, in terms of maintenance of a pre-established target of blood glucose level, reduction of hyperglycaemia and prevention of severe hypoglycaemia.

Is there more to glycaemic control than meets the eye?

Tight glycaemic control has emerged as a major focus in critical care. However, the struggle to repeat, improve and standardize the results of the initial landmark studies is ongoing. The prospective computerized glycaemic control study by Shulman et al. highlights two emerging and often overlooked aspects of intensive insulin therapy protocols beyond simple glycaemic performance. First, the clinical ergonomics and ability to integrate into the critical care unit workflow must be considered as they may impact results and definitely affect uptake. Second, the real lessons of any protocol's performance are likely to be best realized by comparison with other results, a task that is very difficult without a consensus method of reporting that allows such comparisons across studies. Embracing these issues will take the field closer to accepted, repeatable approaches to tight glycaemic control.     

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.     

A systematic review on quality indicators for tight glycaemic control in critically ill patients: need for an unambiguous indicator reference subset

Introduction  

The objectives of this study were to systematically identify and summarize quality indicators of tight glycaemic control in critically ill patients, and to inspect the applicability of their definitions.     

Uncertainties in the measurement of blood glucose in paediatric intensive care: implications for clinical trials of tight glycaemic control

Purpose  

In preparation for a tight glycaemic control (TGC) clinical trial we assessed the agreement between methods used to measure blood glucose in critically ill children.     

Optimal glycemic control in neurocritical care patients: a systematic review and meta-analysis

Introduction

Hyper- and hypoglycemia are strongly associated with adverse outcomes in critical care. Neurologically injured patients are a unique subgroup, where optimal glycemic targets may differ, such that the findings of clinical trials involving heterogeneous critically ill patients may not apply.

Methods

We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing intensive insulin therapy with conventional glycemic control among patients with traumatic brain injury, ischemic or hemorrhagic stroke, anoxic encephalopathy, central nervous system infections or spinal cord injury.

Results

Sixteen RCTs, involving 1248 neurocritical care patients, were included. Glycemic targets with intensive insulin ranged from 70-140 mg/dl (3.9-7.8 mmol/L), while conventional protocols aimed to keep glucose levels below 144-300 mg/dl (8.0-16.7 mmol/L). Tight glycemic control had no impact on mortality (RR 0.99; 95% CI 0.83-1.17; p = 0.88), but did result in fewer unfavorable neurological outcomes (RR 0.91; 95% CI 0.84-1.00; p = 0.04). However, improved outcomes were only observed when glucose levels in the conventional glycemic control group were permitted to be relatively high [threshold for insulin administration > 200 mg/dl (> 11.1 mmol/L)], but not with more intermediate glycemic targets [threshold for insulin administration 140-180 mg/dl (7.8-10.0 mmol/L)]. Hypoglycemia was far more common with intensive therapy (RR 3.10; 95% CI 1.54-6.23; p = 0.002), but there was a large degree of heterogeneity in the results of individual trials (Q = 47.9; p<0.0001; I² = 75%). Mortality was non-significantly higher with intensive insulin in studies where the proportion of patients developing hypoglycemia was large (> 33%) (RR 1.17; 95% CI 0.79-1.75; p = 0.44).

Conclusions

Intensive insulin therapy significantly increases the risk of hypoglycemia and does not influence mortality among neurocritical care patients. Very loose glucose control is associated with worse neurological recovery and should be avoided. These results suggest that intermediate glycemic goals may be most appropriate.     

Effect of Intensive Insulin Therapy Using a Closed-Loop Glycemic Control System in Hepatic Resection Patients: A prospective randomized clinical trial

OBJECTIVE

Intensive insulin therapy (IIT) reduces morbidity and mortality in patients in surgical intensive care units. The aim of this study is to assess the effect of IIT using a closed-loop system in hepatectomized patients.

RESEARCH DESIGN AND METHODS

Patients were randomly assigned to receive IIT using a closed-loop system: an artificial pancreas (AP group) or conventional insulin therapy using the sliding-scale method (SS group).

RESULTS

The incidence of surgical-site infection in the AP group was significantly lower than that in the SS group. The length of hospitalization required for patients in the AP group was significantly shorter than that in the SS group.

CONCLUSIONS

Total hospital costs for patients in the AP group were significantly lower than for patients in the SS group. IIT using a closed-loop system maintained near-normoglycemia and contributed to a reduction in the incidence of SSI and total hospital costs due to shortened hospitalization.Large randomized trials in which the use of tight blood glucose control with intensive insulin therapy (IIT) was compared with standard blood glucose control in surgical intensive care unit (ICU) patients have demonstrated that strict control of postoperative blood glucose levels not only significantly reduced patient mortality but also reduced morbidity (1,2). These results helped initiate several short-lived multicenter randomized control studies designed to evaluate the benefit of tight glycemic control with IIT (3,4). Unfortunately, however, these clinical trials were stopped early, mainly because of the high incidence of hypoglycemia (10–17%) induced by IIT (5).Considering the frequency of the use of IIT in patients undergoing surgical treatment in the ICU, we conducted a prospective randomized controlled trial to evaluate the postoperative condition of the patients and the effect of a closed-loop artificial pancreas (6–9) on tight glycemic control during IIT in hepatectomized patients.     

Evaluation of factors related to glycaemic control among South Korean patients with type 2 diabetes

Aims

To examine specific self‐care behaviours, depression, and diabetes‐related stress among South Korean patients with type 2 diabetes and to evaluate whether these factors are related to glycaemic control.

Methods

This cross‐sectional study included 171 patients with type 2 diabetes who visited an endocrinology clinic. A structured questionnaire and electronic medical records were used to collect data regarding self‐care behaviours, depression, diabetes‐related distress, and glycaemic control between May 2015 and July 2015.

Results

Compared with the group with good glycaemic control, the group with poor glycaemic control had significantly lower values for medication adherence and significantly greater values for regimen‐related distress. Depression was not significantly associated with glycaemic control. In logistic regression analysis, only medication adherence was independently associated with glycaemic control.

Conclusions

Medication adherence should be continuously emphasized and monitored in clinical practice to effectively manage glycaemic control among patients with type 2 diabetes. Furthermore, consideration of diabetes‐related distress may help improve glycaemic control among patients with type 2 diabetes.     

The metrics of glycaemic control in critical care

Introduction  

Trials of tight glucose control have compared measures of central tendency, such as average blood glucose, and yielded conflicting results. Other metrics, such as standard deviation, reflect different properties of glucose control and are also associated with changes in outcome. It is possible, therefore, that the conflicting results from interventional studies arise from effects on glycaemic control that have not been reported.     

A randomized controlled trial comparing a computer-assisted insulin infusion protocol with a strict and a conventional protocol for glucose control in critically ill patients

Purpose

The objective of this study is to evaluate blood glucose (BG) control efficacy and safety of 3 insulin protocols in medical intensive care unit (MICU) patients.

Methods

This was a multicenter randomized controlled trial involving 167 MICU patients with at least one BG measurement ≥150 mg/dL and one or more of the following: mechanical ventilation, systemic inflammatory response syndrome, trauma, or burns. The interventions were computer-assisted insulin protocol (CAIP), with insulin infusion maintaining BG between 100 and 130 mg/dL; Leuven protocol, with insulin maintaining BG between 80 and 110 mg/dL; or conventional treatment—subcutaneous insulin if glucose >150 mg/dL. The main efficacy outcome was the mean of patients' median BG, and the safety outcome was the incidence of hypoglycemia (≤40 mg/dL).

Results

The mean of patients' median BG was 125.0, 127.1, and 158.5 mg/dL for CAIP, Leuven, and conventional treatment, respectively (P = .34, CAIP vs Leuven; P < .001, CAIP vs conventional). In CAIP, 12 patients (21.4%) had at least one episode of hypoglycemia vs 24 (41.4%) in Leuven and 2 (3.8%) in conventional treatment (P = .02, CAIP vs Leuven; P = .006, CAIP vs conventional).

Conclusions

The CAIP is safer than and as effective as the standard strict protocol for controlling glucose in MICU patients. Hypoglycemia was rare under conventional treatment. However, BG levels were higher than with IV insulin protocols.     

Optimal blood glucose control in severely burned patients: a long way to go,but one step closer

Over the past years there has been a significant decrease in mortality and morbidity in patients suffering from severe burns due to improved burn wound management and approaches in critical care. Survival is no longer the exception, but unfortunately death still occurs. One of the key elements concerning state-of-the-art burn care is blood glucose control and insulin therapy; it is well known that burn-induced hyperglycaemia is associated with adverse clinical outcomes. However, controversy for insulin therapy and tight glycaemic control in critically ill and burn patients exists. The increased incidence of hypoglycaemia is the dominant argument against this treatment, because hypoglycaemia is also associated with an increased risk for death in critically ill patients. Taking all current data together, insulin therapy appears both a friend and a foe in the treatment of ICU patients. In order to overcome the limits of tight glycaemic control resulting from hypoglycaemic episodes, current efforts have been directed towards the development of protocols allowing for implementation of clinically feasible and safe guidelines. Among the strategies addressing this problem are closed loop techniques, which are supported by studies demonstrating their capability of exerting tight glycaemic control without the risk of developing hypoglycaemic episodes. Although closed loop techniques have become readily available, we require further evidence to ensure their safety in various ICU environments, notably in ICUs dealing with burn patients. Nonetheless, it is important to emphasise that glycaemic control and adequate insulin therapy are crucial factors for the final outcome (survival) and require our attention.     

Glycaemic control in Australia and New Zealand before and after the NICE-SUGAR trial: a translational study

Introduction

There is no information on the uptake of Intensive Insulin Therapy (IIT) before the Normoglycemia in Intensive Care Evaluation and Surviving Using Glucose Algorithm Regulation (NICE-SUGAR) trial in Australia and New Zealand (ANZ) and on the bi-national response to the trial, yet such data would provide important information on the evolution of ANZ practice in this field. We aimed to study ANZ glycaemic control before and after the publication of the results of the NICE-SUGAR trial.

Methods

We analysed glucose control in critically ill patients across Australia and New Zealand during a two-year period before and after the publication of the NICE-SUGAR study. We used the mean first day glucose (Glu₁) (a validated surrogate of ICU glucose control) to define practice. The implementation of an IIT protocol was presumed if the median of Glu₁ measurements was <6.44 mmol/L for a given ICU. Hypoglycaemia was categorised as severe (glucose ≤2.2 mmol/L) or moderate (glucose ≤3.9 mmol/L).

Results

We studied 49 ICUs and 176,505 patients. No ICU practiced IIT before or after NICE-SUGAR. Overall, Glu₁ increased from 7.96 (2.95) mmol/L to 8.03 (2.92) mmol/L (P <0.0001) after NICE-SUGAR. Similar increases were noted in all patient subgroups studied (surgical, medical, insulin dependent diabetes mellitus, ICU stay >48/<48 hours). The rate of severe and moderate hypoglycaemia before and after NICE-SUGAR study were 0.59% vs. 0.55% (P =0.33) and 6.62% vs. 5.68% (P <0.0001), respectively. Both crude and adjusted mortalities declined over the study period.

Conclusions

IIT had not been adopted in ANZ before the NICE-SUGAR study and glycaemic control corresponded to that delivered in the control arm of NICE-SUGAR trial. There were only minor changes in practice after the trial toward looser glycaemic control. The rate of moderate hypoglycaemia and mortality decreased along with such changes.     

Transition from intravenous to subcutaneous insulin: effectiveness and safety of a standardized protocol and predictors of outcome in patients with acute coronary syndrome

OBJECTIVE

The study objectives were 1) to assess the effectiveness and safety of a standardized protocol for the transition to subcutaneous insulin and oral feeding in diabetic or hyperglycemic patients with acute coronary syndrome (ACS) who were receiving intravenous insulin and glucose at the time of the transfer from the intensive cardiac care unit to a general ward and 2) to identify predictors of transition outcome.

RESEARCH DESIGN AND METHODS

This was a prospective observational study. The protocol specifies that patients receive a 100% of their daily subcutaneous insulin requirement from the first day of oral feeding, calculated from the intravenous insulin rate during the final 12 h divided into two: 50% basal and 50% prandial.

RESULTS

In 142 patients (93 male, 49 female, age range 47–88 years, 135 with known diabetes) the first day after transition, 44.8% of blood glucose (BG) measurements were within the strict range of 100–140 mg/dL before meals and 100–180 mg/dL after meals, and 70.8% were within the broader ranges of 80–160 mg/dL and 80–200 mg/dL, respectively. Pre- or postprandial hypoglycemia (BG <70 mg/dL) occurred in 11 patients (7.7%) on the first day and in 38 patients (26.8%) on the first 3 days after transition. Old age, high doses of intravenous insulin, and wide BG variations in the 24 h before insulin infusion was stopped were predictive of poor BG control after transition.

CONCLUSIONS

This study shows the effectiveness and safety of a standardized protocol for the transition from intravenous to subcutaneous insulin in patients with ACS when regular oral feeding was resumed.In critically ill patients with diabetes or hyperglycemia who are admitted to intensive care units, intravenous infusion of insulin is the recommended treatment (1–6). During the postacute phase, many guidelines and recommendations suggest switching to subcutaneous insulin when patients begin eating regular meals and are moved to a lower-intensity care setting (1–6).There are few observational and intervention studies on the procedure for the transition from intravenous to subcutaneous insulin, and almost all concerned patients who had undergone operation and took little if any food (7–11). The transition is delicate because of the patients’ clinical condition and the organizational context in which they are transferred from an intensive care unit to a general ward. The few studies that have examined the course of blood glucose (BG) after interruption of intravenous insulin have documented inadequate control in the absence of a standardized transition protocol (9,12). In addition, the literature reporting the predictors of optimal transition is scarce and refers mainly to patients postsurgery (7,9,10).The objectives of this prospective observational study were to

1. assess the effectiveness and safety of a standardized protocol for conversion from intravenous to subcutaneous insulin therapy in patients with acute coronary syndrome (ACS) during the transfer from the intensive cardiac care unit (ICCU) to the general ward; and
2. identify predictive factors of transition outcome.

     

Oatmeal interventions in severe insulin resistance on the intensive care unit: A case report

ObjectivesTo report on the potential effectiveness of hypocaloric, plant-based short-term dietary oatmeal interventions in the treatment of insulin resistance in critically ill patients on the intensive care unit.Clinical features and outcomeA 67-year-old female with type 2 diabetes was admitted to our hospital with suspected pneumonia. The patient developed acute hypoxemic respiratory failure and was diagnosed with pneumogenic sepsis requiring invasive ventilation and an immediate transfer to our medical intensive care unit. Within 48 h the patient developed severe to extreme insulin resistance and required more than 200 units of insulin per day.Based on the “Noorden diet” described in 1903, a modified hypocaloric (700 kcal) and plant-based dietary oatmeal intervention was performed to “break” insulin resistance and to improve glycaemic control. For two days, the patient received a low-fat diet that restricted carbohydrates to whole-grain oats (180 g) and included small amounts of vegetables (60 g). Enteral feeding was done via nasogastric tube. During and after the intervention, glycaemic control improved significantly. A significant reduction in total daily insulin requirements was achieved during and after the intervention.ConclusionsHypocaloric, plant-based short-term dietary oatmeal interventions significantly reduced mean blood glucose levels and mean required daily insulin doses in a critically ill and septic patient on the intensive care unit.     

Tight glycaemic control by an automated algorithm with time-variant sampling in medical ICU patients

OBJECTIVE: Tight glycaemic control (TGC) in critically ill patients improves clinical outcome, but is difficult to establish The primary objective of the present study was to compare glucose control in medical ICU patients applying a computer-based enhanced model predictive control algorithm (eMPC) extended to include time-variant sampling against an implemented glucose management protocol. DESIGN: Open randomised controlled trial. SETTING: Nine-bed medical intensive care unit (ICU) in a tertiary teaching hospital. PATIENTS AND PARTICIPANTS: Fifty mechanically ventilated medical ICU patients. INTERVENTIONS: Patients were included for a study period of up to 72 h. Patients were randomised to the control group (n = 25), treated by an implemented insulin algorithm, or to the eMPC group (n = 25), using the laptop-based algorithm. Target range for blood glucose (BG) was 4.4-6.1 mM. Efficacy was assessed by mean BG, hyperglycaemic index (HGI) and BG sampling interval. Safety was assessed by the number of hypoglycaemic-episodes < 2.2 mM. Each participating nurse filled-in a questionnaire regarding the usability of the algorithm. MEASUREMENTS AND MAIN RESULTS: BG and HGI were significantly lower in the eMPC group [BG 5.9 mM (5.5-6.3), median (IQR); HGI 0.4 mM (0.2-0.9)] than in control patients [BG 7.4 mM (6.9-8.6), p < 0.001; HGI 1.6 mM (1.1-2.4), p < 0.001]. One hypoglycaemic episode was detected in the eMPC group; no such episodes in the control group. Sampling interval was significantly shorter in the eMPC group [eMPC 117[Symbol: see text]min (+/- 34), mean (+/- SD), vs 174 min (+/- 27); p < 0.001]. Thirty-four nurses filled-in the questionnaire. Thirty answered the question of whether the algorithm could be applied in daily routine in the affirmative. CONCLUSIONS: The eMPC algorithm was effective in maintaining tight glycaemic control in severely ill medical ICU patients.     

Evaluation of an intensive insulin protocol for septic patients in a medical intensive care unit

OBJECTIVE: Intensive insulin therapy to normalize blood glucose may improve outcome in intensive care unit patients. We prospectively evaluated the implementation of an intensive insulin protocol in medical intensive care patients to identify and overcome obstacles that this complex therapy creates. DESIGN: This prospective, quality assessment study was designed to establish a standard protocol for glucose control in critically ill patients. SETTING: The study took place in the medical intensive care unit at the Medical University of South Carolina, a tertiary care center. PATIENTS: Patients diagnosed with sepsis and two consecutive blood glucose measurements of >120 mg/dL were included in the study. INTERVENTIONS: The protocol, targeting blood glucose of 80-120 mg/dL, was a multidisciplinary initiative involving extensive education of house staff before subject enrollment. Based on predefined criteria, patients were monitored daily for glycemic control, inclusion criteria, and protocol adherence. Protocol improvements were assessed at 6 and 12 months via nursing surveys. MEASUREMENTS AND MAIN RESULTS: Seventy patients receiving insulin infusion for >8 hrs were included in data analysis, accounting for 4,920 glucose readings. Eighty-six hypoglycemic events were recorded, with the number of events decreasing from 7.6% to 0.3% by the final version of the protocol. Average duration on protocol was 6 days, and average time to target range was 5.4 hrs. Identifiable causes of hypoglycemia and survey results led to four protocol revisions by study completion. CONCLUSIONS: In comparison to studies suggesting that normoglycemia is an easily achievable goal, our protocol often recorded glucose values <80 mg/dL, although values <60 mg/dL were rare and usually due to protocol violations. In the interval before automated glucose-sensing insulin infusion devices become available for the intensive care unit, the current protocol is available to assist others in achieving target glucose levels shown to improve mortality rate in an intensive care unit population.     

A review of the use of insulin protocols to maintain normoglycaemia in high dependency patients

Aim. This paper critically examines the evidence base for and issues involved in the introduction of an insulin protocol to maintain normoglycaemia in patients within a medical/surgical high dependency ward. Background. A growing body of evidence has linked hyperglycaemia to worsened clinical outcomes. This has led to intravenous insulin protocols becoming a new standard of care in intensive care units. However, the use and benefits of insulin protocols within high dependency units have not yet been addressed in the literature. Methods. The literature was examined for the 10‐year period up to January 2005. The databases searched were MEDLINE, OVID, CINHAL, the British Nursing Index, the EBSCO collection, the COCHRANE library, the Department of Health, and guidelines within the Scottish Intercollegiate Guidelines Network and National Institute for Clinical Excellence using the key words insulin, protocol, hyperglycaemia, critical care, intensive care and high dependency. Results. The literature reports that both medical and surgical intensive care patients treated with intravenous insulin protocols to maintain normoglycaemia experienced significantly reduced mortality and morbidity. Resulting hypoglycaemic episodes were limited with no incidence of patient deterioration. A review of published intravenous insulin protocols used in intensive care settings revealed their safe and effective use in nurse to patient ratios similar to those present in high dependency units. Conclusions. In the light of this evidence, it would seem safe and ethically correct to enable high dependency patients to benefit from this cheap intervention. An insulin protocol tailored for the glycaemic control of high dependency patients has been suggested, although it may have to be commenced in conjunction with other fluid and nutrition protocols to safeguard the risk of hypoglycaemic events. Further research into the safety and benefit of insulin protocols in high dependency populations is required. Relevance to clinical practice. The stress of critical illness often leads to hyperglycaemia, which is linked to worsened clinical outcomes. Both medical and surgical intensive care patients treated with intravenous insulin protocols to maintain normoglycaemia experienced significantly reduced mortality and morbidity. This paper identifies that, to date, no research into the benefits of glycaemic control in high dependency populations has been published. The case for the introduction of insulin protocols into high dependency units is therefore examined and an insulin protocol suggested.