Hyperglycemia in Critically Ill Patients: Current Approaches and Management Strategies

Pathophysiology of Hyperglycemia in Critically Ill Patients

Mechanisms of hyperglycemia production. Glucose homeostasis is primarily regulated by insulin, a hormone secreted by the pancreas that stimulates glycolysis, glycogenesis, lipogenesis, and protein synthesis while inhibiting gluconeogenesis. In critical illness, insulin resistance develops due to increased counter-regulatory hormone activity (cortisol, glucagon, catecholamines), leading to hyperglycemia. To compensate, the pancreas increases insulin secretion, but persistent resistance can result in pancreatic beta-cell dysfunction and elevated circulating glucose levels (20, 21).

Hyperglycemia contributes to metabolic dysregulation, systemic inflammation, and vascular complications. It is associated with the development of dyslipidemia, nephropathy, retinopathy, cardiovascular disease, cataracts, and infections, further exacerbating the patient’s condition (22).

Stress hyperglycemia. Critically ill patients without prior diabetes may develop stress hyperglycemia, a condition characterized by elevated blood glucose levels (>10.0 mmol/l or 180 mg/dl) due to insulin resistance and decreased insulin secretion. This response is triggered by the activation of the hypothalamic-pituitary-adrenal axis, which increases cortisol release, stimulating gluconeogenesis while inhibiting glucose utilization (23). Additionally, counter-regulatory hormones such as glucagon, catecholamines, and growth hormone contribute to lipolysis, proteolysis, and further glucose production, ultimately leading to deficient glucose uptake in peripheral tissues and increased free fatty acid levels (24).

Three key conditions recognized as triggers for stress hyperglycemia in critically ill patients include severe sepsis, systemic inflammatory response syndrome (SIRS), and head trauma. Despite impaired tissue oxygenation, persistent glycolysis serves as an energy source, a phenomenon known as the Warburg effect, which plays a central metabolic role in these conditions (24).

Stress hyperglycemia is strongly associated with increased in-hospital mortality (25, 26). However, its effects may be mitigated through a personalized approach, including targeted nutrient supplementation to support metabolic balance in critically ill patients (27-29).

Hyperglycemia and oxidative stress. Hyperglycemia induces oxidative stress by increasing reactive oxygen species (ROS) production, leading to cellular damage. This imbalance between ROS accumulation and the body’s detoxification mechanisms exacerbates insulin resistance, inflammation, and endothelial dysfunction, further impairing patient recovery (28, 29).

Under normal physiological conditions, three primary ROS are produced: superoxide, hydrogen peroxide, and nitric oxide. These reactive species interact to form highly active compounds such as singlet oxygen, hydroxyl radicals, and peroxynitrites, which can damage proteins, lipids, and DNA (4, 30, 31).

The interplay between dyslipidemia, obesity, oxidative stress, inflammation, and diabetes is evident in adipose tissue, which contains macrophages and stromal cells that produce adipokines to regulate carbohydrate metabolism and insulin resistance. Moreover, diabetes significantly increases cardiovascular risk, negatively impacting the prognosis of ICU patients (32).

Hyperglycemia and inflammation. Elevated glucose levels stimulate pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), perpetuating systemic inflammation and contributing to immune dysregulation. Poor glucose control is associated with increased levels of these inflammatory markers, creating a chronic inflammatory state that may promote tumor development (33).

The role of hypoxia-inducible factor-1 alpha (HIF-1α) in hyperglycemia-induced inflammation has been noted, linking metabolic stress to oxidative stress. Studies indicate that hyperglycemia combined with hypoxia stimulates HIF-1α expression, further exacerbating inflammation (34).

Another mechanism through which hyperglycemia promotes low-grade chronic inflammation, particularly in individuals with metabolic syndrome and untreated diabetes, involves the release of pro-inflammatory cytokines in response to the scavenging of haptoglobin (Hb)- hemoglobin (Hp) complexes via CD163 in M(IFNγ) cells. This process, normally protective against vascular damage, is converted into an inflammatory response under hyperglycemic conditions (35).

Counter-regulatory hormones. Under conditions of stress, as well as under conditions of hypoglycemia, counter-regulatory hormones are released. They have insulin-antagonistic effects for the liver, as well as for the peripheral tissues. These counter-regulatory hormones are glucagon, cortisol, adrenaline and growth hormone (36).

Glucagon is recognized to be important in glucose homeostasis and in diabetes pathophysiology. Its main role is to stimulate hepatic glucose production, but it also stimulates ketogenesis, working concurrently with insulin to maintain a balance (37). The mechanism of hyperglycemia production is presented in Figure 1.

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Figure 1.

Hyperglycemia production mechanism. HHS: Hyperosmolar hyperglycemic state.

Hyperglycemia in Diabetic ICU Patients

Increased insulin requirements. Critically ill diabetic patients experience heightened insulin resistance, necessitating higher insulin doses. However, excessive insulin administration must be carefully managed to prevent hypoglycemia. Increased insulin resistance in these patients is linked to greater inflammation, disease severity, and impaired glucose tolerance, potentially leading to insulin saturation and worsening hyperglycemia (38).

While higher insulin doses are often required, their use should be carefully controlled, as excessively high doses can increase the risk of hypoglycemia and prolong the time needed to achieve target glucose levels. Balancing insulin therapy is essential to minimize risks and optimize glycemic control in critically ill diabetic patients (39).

Hypoglycemia risks. Strict glucose control in critically ill patients increases the risk of hypoglycemia, which is independently associated with higher mortality. Hypoglycemia is classified by severity based on blood glucose levels, with intensive glucose management in the ICU often leading to moderate or severe hypoglycemic episodes (40).

Severe hypoglycemia, defined as a blood glucose level below 2.2 mmol/l (40 mg/dl), significantly increases the risk of death within 90 days for ICU patients. Additionally, patients experiencing multiple hypoglycemic episodes (at least three), whether severe or moderate (2.2-3.3 mmol/l or 40-60 mg/dl), have an elevated mortality risk beyond 90 days. Therefore, careful monitoring and individualized glucose management are essential to achieving glycemic control while minimizing hypoglycemia-related complications (41). Diabetic ketoacidosis and hyperosmolar hyperglycemic state. Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are acute, life-threatening complications of DM that require immediate recognition and aggressive management. Both conditions result from severe insulin deficiency but differ in their clinical presentation, pathophysiology, and associated risks (42).

DKA is characterized by hyperglycemia, metabolic acidosis (due to ketone accumulation), and dehydration (43). It primarily affects individuals with type 1 diabetes but can also occur in type 2 diabetes under extreme stress or infection. DKA presents with symptoms such as polyuria, polydipsia, nausea, vomiting, abdominal pain, and altered mental status (44). The major biochemical features include elevated blood glucose levels (>13.9 mmol/l or 250 mg/dl), arterial pH <7.3, and serum bicarbonate <18 mEq/l. Despite its severity, DKA has a relatively low mortality rate (<1%) when promptly treated with fluid resuscitation, insulin therapy, and electrolyte correction (45, 46).

Hyperosmolar hyperglycemic state (HHS), on the other hand, predominantly affects older individuals with type 2 diabetes and is often precipitated by infections, cardiovascular events, or noncompliance with diabetes treatment (47). Unlike DKA, HHS is marked by extreme hyperglycemia (>33.3 mmol/l or >600 mg/dl), profound dehydration, and hyperosmolarity (>320 mOsm/kg), without significant ketone production (48). Neurological symptoms, such as confusion, seizures, or coma, are more common in HHS due to severe dehydration and increased serum osmolality. HHS has a significantly higher mortality rate (~17%), primarily due to delayed diagnosis, severe dehydration, and underlying comorbidities (49).

Management considerations. Fluid resuscitation: Rapid intravenous fluid replacement is essential for both conditions, with a focus on restoring intravascular volume and correcting dehydration. Insulin therapy: In DKA, continuous intravenous insulin infusion is necessary to suppress ketogenesis, whereas in HHS, insulin is initiated cautiously to prevent rapid osmotic shifts. Electrolyte replacement: Potassium, phosphate, and bicarbonate imbalances must be closely monitored and corrected as needed. Addressing underlying causes: Identifying and treating precipitating factors such as infections, myocardial infarction, or medication noncompliance is crucial to prevent recurrence (50, 51).

Given the higher mortality rate associated with HHS, early detection and aggressive treatment are critical in improving patient outcomes. A multidisciplinary approach involving endocrinologists, critical care specialists, and nursing staff ensures optimal management and reduces complications in patients with DKA and HHS (50, 51).

Electrolyte imbalances and dehydration. Diabetic patients in the ICU frequently develop a range of electrolyte imbalances, including hyponatremia, hypernatremia, hypokalemia, hyperkalemia, hypomagnesemia, hypocalcemia, hypercalcemia, and hypophosphatemia. These imbalances significantly contribute to morbidity and mortality, necessitating careful monitoring and targeted treatment based on their underlying physiopathological mechanisms (52).

Proper hydration plays a crucial role in glycemic control, particularly in patients with pre-existing metabolic syndrome. DM increases the risk of dehydration through excessive urinary water loss due to glucosuria and osmotic diuresis. Hyperglycemia further exacerbates dehydration by shifting water from the intracellular to the extracellular space, altering osmolality and blood volume regulation. In severe cases, prolonged glucosuria leads to increased vasopressin secretion, resulting in a chronic hyperosmolar hypovolemic state. Close monitoring and timely intervention are essential to prevent complications arising from dehydration and electrolyte disturbances in critically ill diabetic patients (53). The particularities of hyperglycemia in DM patients hospitalized in the ICU are presented in Figure 2.

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Figure 2.

Particularities of hyperglycemia in diabetes mellitus (DM) patients hospitalized in intensive care unit (ICU). DM: Diabetes mellitus; ICU: intensive care unit; DKA: diabetic ketoacidosis; HHS: hyperosmolar hyperglycemic state.

Hyperglycemia in Non-diabetic ICU Patients

Insulin therapy for stress hyperglycemia. Current guidelines for managing stress hyperglycemia in critically ill patients vary, with recommended blood glucose targets ranging from 7.7 to 11.1 mmol/l (139-200 mg/dl). The American College of Physicians (2011) suggests maintaining glucose levels within this range, while the American Diabetes Association (2012) recommends a slightly stricter target of 7.7-9.9 mmol/l (139-179 mg/dl). In contrast, the Medical Society of the Care of the Critically Ill proposes a lower range of 5.5-8.3 mmol/l (99-149 mg/dl). However, studies indicate that stringent glycemic control does not significantly reduce mortality and may increase the risk of hypoglycemia, particularly in patients with stroke or heart failure (54-56).

Insulin therapy plays a crucial role in stress hyperglycemia management by reducing morbidity, preventing new kidney injuries, shortening mechanical ventilation time, and decreasing ICU stay duration. Despite these benefits, its impact on overall mortality remains unclear (57).

For critically ill patients, continuous insulin infusion is typically used following a structured protocol (57-61). Recommended insulin administration rates are included in Table II. Given the variability in guideline recommendations and patient responses, individualized insulin therapy remains essential to balance glucose control while minimizing hypoglycemia risks.

Increased mortality in newly diagnosed hyperglycemic patients. Non-diabetic patients with acute hyperglycemia have worse outcomes than known diabetics, possibly due to a lack of metabolic adaptation and increased cardiovascular stress. The particularities of hyperglycemia in non-diabetic patients hospitalized in the ICU are presented in Figure 3.

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Figure 3.

Particularities of hyperglycemia in non-diabetic patients hospitalized in intensive care unit (ICU). ICU: Intensive care unit.

Glycemic Management in ICU

Glycemic targets. International guidelines recommend maintaining blood glucose levels between 7.8 and 10.0 mmol/l (140-180 mg/dl) for critically ill patients (62, 63). Different organizations provide slightly varying recommendations, with some advocating for stricter control in selected patients. However, maintaining blood glucose below 6.1 mmol/l (110 mg/dl) or above 10.0 mmol/l (180 mg/dl) has been associated with increased risks of hypoglycemia and hyperglycemia-related complications (64). Careful attention should be paid to glycemic variability and preventing hypoglycemia, especially when blood glucose drops below 3.9 mmol/l (70 mg/dl) (65). The recommended glycemic targets for ICU patients according to international guidelines (61-67) are described in Table III.

Continuous insulin infusion protocols. Protocols such as the Yale continuous insulin infusion protocol recommend (68-72) initiating insulin infusion when blood glucose exceeds 10.0 mmol/l (180 mg/dl) (73). The target range is typically 6.6-8.8 mmol/l (120-160 mg/dl), with infusion rates adjusted based on glucose response and hypoglycemia risk (74). Insulin administration is calculated based on the patient’s initial blood glucose level, with incremental adjustments made according to predefined algorithms (75). Monitoring should initially be performed hourly, then spaced to every two to four hours once glucose levels stabilize (76). Additional factors, such as underlying conditions, concurrent medications, and nutritional status, should also be considered in glycemic management. The recommendations of international associations regarding glycemic levels in ICU patients are presented in Table IV.

Postoperative hyperglycemia management. Postoperative ICU patients with hyperglycemia require close monitoring to prevent complications. Regular insulin with blood glucose checks every 1-2 hours is recommended. Transitioning from continuous intravenous insulin infusion to long- or intermediate-acting subcutaneous insulin should be done cautiously once the patient is hemodynamically stable and has maintained stable glucose levels with minimal variability for at least 6-8 hours. To prevent rebound hyperglycemia or hypoglycemia, a 2-3 hour overlap between intravenous and subcutaneous insulin is essential due to the short half-life of IV insulin and the delayed onset of subcutaneous insulin. Careful glycemic management in the postoperative setting helps improve recovery and reduce complications associated with hyperglycemia in critically ill patients (77-81).

Glucose Monitoring in ICU

Arterial vs. capillary monitoring. Arterial blood glucose monitoring is generally more accurate in critically ill patients, as capillary glucose readings can be influenced by conditions such as hypoperfusion, subcutaneous edema, hypoxemia, anemia, and renal failure. Capillary monitoring requires minimal blood volume and does not need specialized expertise, but its accuracy can be compromised under specific clinical conditions. Conversely, arterial blood sampling, while more invasive, provides reliable glucose readings and allows simultaneous measurement of electrolytes, hemoglobin, and blood gases. The choice between arterial and capillary monitoring should be guided by the patient’s condition and clinical needs (82).

Continuous glucose monitoring (CGM). CGM presents a promising alternative for glucose monitoring in critically ill patients, offering real-time data and reducing the need for frequent blood sampling. Although CGM has demonstrated feasibility and reliability, challenges remain, including accuracy concerns and potential failures in detecting hypoglycemia or hyperglycemia, particularly in critically ill patients. Additionally, CGM primarily measures interstitial glucose levels rather than blood glucose, introducing a lag that may delay therapeutic adjustments. Despite these limitations, CGM can help reduce glycemic variability and provide early alerts for abnormal glucose levels, improving patient outcomes (83).

AI-driven biosensors. Artificial intelligence (AI)-integrated biosensors represent a significant advancement in continuous glucose monitoring, offering predictive analytics and personalized diabetes management. These biosensors analyze glucose trends in real time, allowing for proactive adjustments in treatment and reducing the risk of glycemic fluctuations. AI-driven monitoring enhances accuracy and may improve early detection of complications such as diabetic retinopathy and macular edema. However, barriers to widespread adoption include high costs, the need for further validation, and potential patient discomfort with device wearability. Continued advancements in AI-based glucose monitoring systems hold promise for revolutionizing diabetes care in ICU settings (84-86).

Intensive vs. conventional glycemic control. Multiple studies, including the 2009 NICE-SUGAR trial, have demonstrated that intensive glycemic control (4.4-6.1 mmol/l or 80-110 mg/dl) in critically ill patients increases mortality, primarily due to the increased risk of severe hypoglycemia. In the NICE-SUGAR study, which included 6104 patients, those undergoing intensive glycemic control had a significantly higher incidence of severe hypoglycemia (272 episodes compared to 16 in the conventional control group), contributing to increased mortality at 90 days (87).

A 2012 meta-analysis of 22 randomized controlled trials involving 13,978 participants further supported these findings, showing that strict glycemic control increased the risk of severe hypoglycemia by 5-fold without significantly reducing sepsis or the need for dialysis. While intensive glycemic control in surgical ICU patients was associated with a reduced risk of sepsis, no significant mortality benefit was observed (88).

Similarly, a 2021 randomized study assessed whether targeting a patient’s pre-admission blood glucose level improved survival compared to maintaining blood glucose levels below 10.0 mmol/l (180 mg/dl). The study found no survival advantage for critically ill patients subjected to intensive glycemic control (89).

A 2024 systematic review reinforced these concerns, highlighting a higher incidence of hypoglycemia and an increased risk of death in patients not receiving parenteral nutrition. In response to this growing evidence, the 2024 Society of Critical Care Medicine Guidelines now recommend against intensive glycemic control (4.4-7.7 mmol/l or 80-139 mg/dl) and instead endorse conventional glucose control (7.8-11.1 mmol/l or 140-200 mg/dl) to minimize the risk of hypoglycemia in critically ill patients (71).

As a result, conventional glycemic control (7.8-10.0 mmol/l or 140-180 mg/dl) is now considered the standard of care in ICU settings, prioritizing patient safety and reducing complications associated with excessive insulin administration.

Evidence from literature. The main findings of the systematic reviews, from the specialized literature, which focused on blood glucose monitoring in patients with diabetes in intensive care units, are shown in Table V.

In recent years, the frequency of DM in the extra-hospital and intra-hospital environment has increased, and a much greater increase is expected in the future, a fact that must arouse special interest among medical personnel for the timely discovery of this chronic pathology (56, 90-92).

Hyperglycemia hides some complex production mechanisms and acts on a multitude of organs, eventually taking over the entire body through its manifestations. This can occur even in healthy patients before hospitalization (stress hyperglycemia). At the same time, it is recognized for its implications both in oxidative stress and in the occurrence and maintenance of chronic inflammation (93).

The control of hyperglycemia in critically ill patients must be carried out in accordance with the body’s needs, implicitly by increasing insulin doses. This action can lead to hypoglycemic episodes that are threatening for the patient’s already precarious condition, increasing mortality (60).

There are two entities of diabetes complications that support the poor evolution of the patient: diabetic ketoacidosis and hypersomolar hyperglycemic state. They influence mortality in different percentages and the management must be prompt because they have negative implications on different organs.

The therapeutic approach must not lose sight of the hydro-electrolytic balance.

Also, in this type of patients, episodes of hypoglycemia are common, but their frequency is lower and glycemic control strategies should be revised to avoid both hypoglycemia and hyperglycemia.

Postoperatively, there is a need for intensive surveillance of the critically ill hyperglycemic patient with the transition from intravenous insulin infusion to long- or intermediate-acting insulin done at the appropriate time.

There are several ways to monitor blood glucose in the critically ill patient. The classic monitoring methods that have been mentioned are arterial and capillary glucose monitoring, respectively continuous glucose monitoring.

The strong point of the study consists in the extensive presentation of the implications of hyperglycemia in the critically ill patients in the intensive care units, and especially the ways in which it influences the evolution of the disease and the health status in this category of patients. A thorough review of the presentation, along with an explanation of the mechanisms behind hyperglycemia and the specific care considerations for critically ill patients. Another strength point of the study lies in the exposure of the treatment protocols that we find in the treatment of hyperglycemia. A limitation of the study could be the performance of a narrative review compared to a meta-analysis; however, as it is an extensive narrative review, it provides a broad view of the complex topic of hyperglycemia in the critically ill.