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2025 PACUPrep BCCCP Preparatory Course Glycemic Control in the ICU Foundational Principles and Risk Factors of Dysglycemia in Critical Illness

Lesson 48, Topic 1

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Foundational Principles and Risk Factors of Dysglycemia in Critical Illness

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Dysglycemia in Critical Illness: Principles and Risk Factors

Dysglycemia in Critical Illness: Foundational Principles and Risk Factors

Learning Objective

Describe the epidemiology, pathophysiology, clinical presentation, and key risk factors of stress hyperglycemia and hypoglycemia in the ICU.

1. Epidemiology of Dysglycemia in the ICU

Dysglycemia—encompassing both stress-induced hyperglycemia and iatrogenic or spontaneous hypoglycemia—affects a majority of ICU patients and is an independent predictor of worse clinical outcomes, including mortality and morbidity.

1.1 Prevalence of Stress Hyperglycemia and Hypoglycemia

Stress hyperglycemia (blood glucose > 180 mg/dL) occurs in 40–70% of all ICU admissions.
Hypoglycemia (blood glucose < 70 mg/dL) complicates 15–20% of ICU stays, with severe episodes (< 40 mg/dL) occurring in 5–8% of patients, particularly those on insulin infusions.

Key Point: Uncovering Undiagnosed Diabetes

Routine measurement of hemoglobin A1c (HbA1c) on ICU admission uncovers previously undiagnosed diabetes in approximately 25% of patients presenting with stress hyperglycemia. This finding is critical for refining risk stratification, adjusting glycemic targets, and planning for long-term glycemic management post-discharge.

1.2 Association with Mortality and Morbidity

A mean glucose level exceeding 180 mg/dL is associated with a two- to three-fold increase in ICU mortality compared to normoglycemia.
Severe hypoglycemia (< 40 mg/dL) also doubles the risk of death and is linked to higher rates of cardiac arrhythmias and long-term neurocognitive injury in survivors.

Clinical Pearl: The Danger of Glycemic Variability

Glycemic variability—the amplitude of swings in blood glucose—is a stronger independent predictor of ICU mortality than mean glucose alone. A high coefficient of variation (>20%) signals instability and is associated with increased oxidative stress and endothelial damage. This underscores the importance of not just lowering glucose, but stabilizing it.

2. Pathophysiology Mechanisms

Critical illness unleashes a torrent of counter-regulatory hormones and inflammatory mediators. This neurohormonal storm drives profound insulin resistance, accelerates hepatic glucose production, and triggers systemic lipotoxicity, culminating in stress hyperglycemia.

Figure 1. Pathophysiology of Stress Hyperglycemia. Critical illness triggers a neurohormonal and inflammatory cascade that promotes insulin resistance, increases hepatic glucose production, and enhances lipolysis, collectively driving hyperglycemia and glycemic variability.

2.1 Counter-regulatory Hormones and Insulin Resistance

A surge of epinephrine, norepinephrine, cortisol, glucagon, and growth hormone directly antagonizes insulin’s action.
Pro-inflammatory cytokines like TNF-α and IL-6 impair insulin receptor signaling at the cellular level and can induce pancreatic β-cell dysfunction, blunting first-phase insulin release.

2.2 Hepatic Gluconeogenesis, Glycogenolysis, and Lipolysis

Cortisol and glucagon upregulate key enzymes (PEPCK, G6Pase), dramatically increasing hepatic glucose synthesis (gluconeogenesis).
Epinephrine stimulates rapid breakdown of liver glycogen stores (glycogenolysis) via β2-adrenergic pathways.
Unrestrained lipolysis liberates free fatty acids, which provide substrate for gluconeogenesis and can cause direct lipotoxic endothelial injury.

3. Influence of Premorbid Diabetes

A patient’s preexisting diabetic status significantly modifies the risk profile and clinical impact of dysglycemia in the ICU. Understanding this context is crucial for individualizing glycemic targets.

Clinical Nuance: Interpreting HbA1c in Acute Illness

While an admission HbA1c ≥ 6.5% reliably indicates chronic diabetes, its interpretation can be confounded in the critically ill. Factors such as red blood cell transfusions, hemolysis, and altered red cell turnover from acute kidney injury or hemorrhage can falsely lower the HbA1c value. In such cases, alternative markers of chronic glycemia like fructosamine or glycated albumin may offer a more accurate picture, though they are not yet in widespread clinical use.

3.1 Differential Outcomes Based on Diabetic Status

The harm associated with hyperglycemia and hypoglycemia differs between patients with and without diabetes. This necessitates a stratified approach to setting glycemic goals.

Differential Impact of Dysglycemia Based on Diabetic Status
Patient Population	Primary Glycemic Risk	Clinical Implication & Target Adjustment
Non-Diabetic Patients	Acute Hyperglycemia & Variability	Even moderate hyperglycemia is associated with a steep rise in mortality. Stricter control (e.g., 110–150 mg/dL) may be beneficial.
Diabetic (Good Control, HbA1c <7%)	Hyperglycemia & Iatrogenic Hypoglycemia	These patients are adapted to higher glucose levels but are still at risk. A standard target of 140–180 mg/dL is generally safe and effective.
Diabetic (Poor Control, HbA1c >8%)	Relative & Severe Hypoglycemia	Chronically adapted to high glucose; aggressive lowering increases hypoglycemia risk. A more lenient target (e.g., 160–200 mg/dL) is often safer.

Clinical Pearl: Avoid “Relative Hypoglycemia”

In patients with chronically poor diabetic control (e.g., HbA1c > 9%), a rapid drop in blood glucose to “normal” levels can trigger a counter-regulatory hormonal surge, paradoxically worsening outcomes. Set modestly higher glucose targets in this population to reduce the risk of both absolute and relative hypoglycemia.

4. Clinical Presentation and Complications

In the ICU, the classic symptoms of dysglycemia are often masked by sedation, mechanical ventilation, and underlying critical illness. Therefore, proactive monitoring is essential to detect its presence and prevent severe complications.

4.1 Neuroglycopenic and Autonomic Symptoms

Autonomic signs (often blunted): Tachycardia, diaphoresis, tremor.
Neuroglycopenic signs: Confusion, delirium, seizures, or focal neurologic deficits.
Crucial Point: Because sedation and intubation obscure these signs, routine blood glucose checks (every 1–2 hours) are mandatory for any patient on an intravenous insulin infusion.

4.2 Effects on Immune Function and Wound Healing

Hyperglycemia directly impairs immune cell function, including neutrophil chemotaxis, phagocytosis, and intracellular killing, increasing the risk of nosocomial infections.
Elevated glucose levels disrupt fibroblast activity and collagen synthesis. Maintaining tight glycemic control (< 150 mg/dL) has been shown to reduce surgical-site infections by up to 40%.

4.3 Organ Dysfunction and Metabolic Sequelae

Hyperglycemia: Can cause osmotic diuresis leading to dehydration and acute kidney injury, as well as increase the risk of myocardial arrhythmias and hepatic cholestasis.
Hypoglycemia: May lead to refractory hypotension, unmask underlying adrenal insufficiency, and contribute to long-term cognitive decline in ICU survivors.

Clinical Pearl: No “Safe” Hypoglycemia

There is no safe threshold for hypoglycemia in the critically ill. Even a single episode of mild hypoglycemia (blood glucose < 70 mg/dL) is associated with a doubling of ICU mortality. Prevention through careful protocol use and early detection via frequent monitoring are paramount.

5. Social Determinants and System Factors

Effective glycemic management extends beyond the bedside. Patient-level factors like medication access and health literacy, combined with institutional protocols and interdisciplinary teamwork, are critical determinants of success.

5.1 Medication Access, Health Literacy, and Adherence

Socioeconomic barriers and low health literacy contribute to poor glycemic control before admission and increase the risk of readmission after discharge.
Pharmacist-led medication reconciliation, provision of necessary supplies (e.g., glucose meters, insulin), and using teach-back education methods can significantly improve post-ICU outcomes.

5.2 Institutional Protocols and Interdisciplinary Communication

Standardized, validated insulin infusion algorithms that empower nurses with autonomy for titration and incorporate real-time decision support are proven to reduce glycemic excursions and medical errors.
Daily interdisciplinary rounds involving pharmacy, endocrinology (if available), and clinical nutrition promote a consistent, patient-centered approach to glycemic management.

Clinical Pearl: Empower the Bedside Nurse

The most effective glycemic control protocols are those that empower the bedside nurse. Clear, protocol-driven insulin titration guidelines allow for rapid adjustments to changing clinical conditions, reducing delays and improving patient safety. This approach minimizes glycemic variability and reduces the incidence of severe hypoglycemia.

References

Sreedharan R, Martini A, Das G, et al. Stress hyperglycemia in critical illness. World J Clin Cases. 2022;10(31):11260–11272.
Krinsley JS. Glycemic variability: a strong independent predictor of mortality in critically ill patients. Crit Care Med. 2008;36(11):3008–3013.
van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med. 2001;345(19):1359–1367.
Finfer S, Chittock DR, Su SY, et al; NICE-SUGAR Study Investigators. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009;360(13):1283–1297.
Moghissi ES, Korytkowski MT, DiNardo M, et al. American Association of Clinical Endocrinologists and American Diabetes Association consensus statement on inpatient glycemic control. Diabetes Care. 2009;32(6):1119–1131.
Finfer S, Liu B, Chittock DR, et al; NICE-SUGAR Study Investigators. Hypoglycemia and risk of death in critically ill patients. N Engl J Med. 2012;367(12):1108–1118.
Bellaver P, Schaeffer AF, Dullius DP, et al. Undiagnosed diabetes in the ICU: a secondary analysis of the GGM-MORE multicenter study. Sci Rep. 2019;9:18498.
Krinsley JS, Egi M, Kiss A, et al. Diabetic status and the relation between hyperglycemia and mortality in critical illness. Crit Care. 2013;17:R37.
Kanji S, Buffie J, Hutton B, et al. Reliability and validity of a new method for assessing the quality of glycemic control in critically ill patients. Crit Care Med. 2005;33(12):2778–2785.

2025 PACUPrep BCCCP Preparatory Course

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