Metabolic Crisis in Neurocritical Care: Definition, Classification, and Bundle of Therapeutic Interventions for the Acute and Hyperacute Stages

Keywords

metabolic crisis - neurocritical care - neurotrauma - acute neurological injuries - bundle approach

Introduction

Metabolic crisis is a serious condition that can occur in patients with acute neurological injuries, such as traumatic brain injury, stroke, and subarachnoid hemorrhage. It refers to a state of severe metabolic disturbance in which the supply and demand of energy substrates are not balanced. This metabolic dysfunction is best described as a decrease in oxidative metabolism[1] [2] with an alteration in glucose metabolism[3] [4] and has been demonstrated in both experimental[3] [5] and human brain injury.[6] [7] This imbalance can lead to a cascade of detrimental effects that exacerbate the initial neurological injury and can result in poor patient outcomes.

This critical care aspect must be recognized and treated as it can significantly affect patient prognosis and recovery. The extent of secondary brain damage may depend on the nature and length of the metabolic disturbance, and an extended metabolic crisis may increase the risk of complications like infections and organ failure.[8] Improved patient outcomes and better chances of recovery are possible with effective management.[9] Carre et al compared post-traumatic metabolic disturbances with an iceberg ([Fig. 1]).[10] All medical professionals understand what ischemia is and how to avoid or treat ischemic events. The iceberg's submerged portion poses a real threat. The metabolic crisis may be a sneaky manifestation of energetic post-traumatic disturbances that are challenging to diagnose, treat, and understand.

Fig. 1 The iceberg of metabolic disturbance.

The purpose of this review is to provide an overview of metabolic crisis in neurocritical care, including its definition, classification, and bundle of therapeutic interventions for the acute and hyperacute stages. This review aims to provide clinicians with a comprehensive understanding of the metabolic crisis and equip them with the knowledge and tools to effectively manage this complex condition in their patients.

Definition of Metabolic Crisis in Neurocritical Care

Explanation of Metabolic Crisis

In neurocritical care, a metabolic crisis denotes a serious disruption of the delicate equilibrium of energy metabolism within the central nervous system (CNS). The brain heavily depends on a consistent and sufficient supply of glucose and oxygen to meet its high energy requirements. A metabolic crisis results when this equilibrium is disturbed, either as a result of a decreased energy supply or an increased demand.[11]

Ischemia, which is characterized by inadequate blood flow to the brain, is one of the main causes of metabolic crisis.[11] It may be caused by conditions like ischemic stroke, cerebral artery vasospasm, or generalized cerebral hypoperfusion. Due to the limitation of delivery of oxygen and glucose due to ischemia the brain cells cannot produce adenosine triphosphate (ATP), the molecule necessary for cellular energy.[12] A decrease in ATP-dependent processes and a resulting energy deficit compromise cellular metabolism and normal neuronal function.

Another factor that causes metabolic crisis is hypoxia, which is a condition of decreased oxygen availability.[13] Brain cells in hypoxic environments receive insufficient oxygen, which impairs their oxidative metabolism and lowers their ability to produce ATP.[13] The insufficient supply of ATP impairs crucial cellular processes, compromising the integrity and functionality of neurons.

The CNS may experience a metabolic crisis as a result of seizures, especially status epilepticus (prolonged or recurrent seizures). The demand for energy and metabolic substrates increases noticeably during seizures due to the spike in neuronal activity.[14] Large amounts of glucose and oxygen are consumed during prolonged, excessive electrical discharges, depleting the energy stores required for ongoing normal cellular functions.[14] Long-lasting seizures can trigger a metabolic crisis by depleting energy reserves and upsetting the delicate balance between energy supply and demand.

A metabolic crisis in neurocritical care can also be caused by systemic metabolic disturbances. The body's endocrine system and conditions like severe hypoglycemia, hyperglycemia, electrolyte imbalances, acid–base disturbances, thyroid storm, and electrolyte disorders can all affect how the brain uses its energy.[15] The energy crisis can be made worse by these systemic abnormalities, which can have a direct impact on glucose transport, oxygenation, and cellular metabolism in the brain.

In general, a metabolic crisis in neurocritical care refers to a variety of pathological processes that disturb the delicate equilibrium between cerebral energy demand and supply. Brain health and function may be significantly impacted by the resulting impairment in cellular metabolism and neuronal function. Understanding the underlying causes of the metabolic crisis is crucial for effective management and the implementation of timely interventions to restore metabolic homeostasis in the CNS.

Neurological Consequences of Metabolic Crisis

Metabolic crisis poses a serious threat to the CNS's effectiveness and integrity. The brain is extremely dependent on a steady supply of oxygen and glucose to meet its metabolic needs. When the availability of these substrates is compromised, the brain's pathways for energy production are upset, which leads to the accumulation of toxic metabolites and the impairment of cellular functions. Neuronal injury, cerebral edema,[16] oxidative stress,[17] mitochondrial dysfunction,[18] excitotoxicity,[19] and other issues that can harm brain tissue and result in neurological dysfunction can be brought on by a lack of energy.

Importance of Early Detection and Intervention

To effectively manage the metabolic crisis in neurocritical care, early detection and prompt intervention are essential. If a metabolic crisis is not treated, the effects could be severe and even irreversible. It is crucial to promptly identify the symptoms and signs of metabolic crisis, including altered mental status, seizures, focal neurological deficits, and indications of systemic metabolic abnormalities.[20] The goals of prompt intervention are to address the underlying cause, restore metabolic balance in the brain, and stop further neuronal damage.[21] This could entail focusing on treatments like improving cerebral perfusion, treating underlying metabolic issues, ensuring proper oxygenation and ventilation, and administering neuroprotective drugs. Healthcare providers can potentially lessen the severity of brain damage and enhance patient outcomes in the acute and hyperacute stages of metabolic syndrome by starting the proper interventions at an early stage.

Classification of Metabolic Crisis in Neurocritical Care

Based on the underlying pathophysiological mechanisms and metabolic disturbances present, metabolic crises in neurocritical care can be divided into various types. For accurate diagnosis and focused management strategies, it is crucial to comprehend these various types. Commonly recognized metabolic crisis types include the following:

• 1. Hypoglycemic crisis: Metabolic crisis in neurocritical care refers to a state of severe metabolic derangement that can occur in critically ill patients, particularly those with diabetes. One significant aspect of the metabolic crisis is the hypoglycemic crisis, which is characterized by a measurable decrease in blood glucose levels below the normal range. This condition poses a serious threat to patients, as it can lead to significant morbidity and mortality if left untreated.[22]

Hypoglycemia is a common and important complication in the context of intensive insulin therapy for critically ill patients.[23] Unfortunately, it has often received less attention compared with other acute complications such as diabetic ketoacidosis and hyperosmolar non-ketotic coma.[22] However, recent studies and emerging evidence have highlighted the grave concerns associated with hypoglycemia, both in the short term and long term.[22]

If left untreated, hypoglycemia can result in permanent brain damage and an increased risk of mortality.[23] Critically ill patients with diabetes who experience severe hypoglycemia are particularly vulnerable, as they face a higher likelihood of major macrovascular events or death within the following 12 months.[24] Alarming data from the T1D Exchange registry revealed that over 10% of adult patients reported at least one episode of severe hypoglycemia in the past year.[24]

The ratio of systemic blood glucose level to cerebrospinal fluid glucose is a key concept that can be attributed to the complex nature of hypoglycemia in neurocritical. The normal ratio is close to 0.6; hence, with a blood glucose level of 100 mg/dL, the brain glucose may be around 60 mg/dL which is a low level in any acute neurological crisis.

Multiple factors can contribute to hypoglycemia in critically ill patients, including underlying diseases, malnutrition, infections, variations in glucose measurement methods, and chronic liver or kidney diseases.[23] Notably, a study conducted in the Medical Emergency Department of BIRDEM General Hospital found that the frequency of hypoglycemia among attending patients was 2.80%.[25] Additionally, the study demonstrated a significant relationship between blood glucose levels upon ICU admission and mortality rates.

Relative hypoglycemia (RHG) is another type of hypoglycemia that can occur in critically ill patients with diabetes. RHG is defined as a blood glucose level more than 30% below the estimated average based on the patient's hemoglobin A1c measurement at admission.[26] RHG is associated with increased mortality and a higher incidence of delirium among critically ill patients with diabetes.[26]

• 2. Hyperglycemic crisis: Critically ill patients frequently experience hyperglycemia, which has been identified as a separate risk factor for adverse outcomes, including death, especially in those patients who have known diabetes but also in non-diabetic patients.[27] The idea that hyperglycemia is an adaptive reaction to increased medical stress and is regarded as a marker of illness severity rather than a specific medical condition that needs to be managed is under attack by recent evidence.[27] The type of emergency, the presence of an infection, and the patient's sex are some of the factors that affect the prognosis of hyperglycemic emergencies.[28] Depending on the study population, mortality rates can range from 4.8 to 23.1%.[28] [29] In neurocritical care, aggressive treatment is used to reduce blood glucose levels and avoid complications during hyperglycemic crises. Treatment options include intravenous insulin, electrolytes replacement of fluids, the reversal of acidosis, and monitoring of neurological status and vital signs.[27] Certain levels of blood glucose are related to complications with neurocritical care conditions like blood glucose over 150 mg/dL after thrombolysis for acute stroke can lead to hemorrhagic conversion.

• 3. Hypoxic-ischemic crisis: The term hypoxic-ischemic crisis refers to a medical emergency caused by hypoxia, ischemia, cytotoxicity, or a combination of these mechanisms. It can have negative consequences, such as significant personality changes and cognitive impairments in memory, cognition, and attention.[30] The hypoxic-ischemic crisis is a major concern in neurocritical care because it can cause brain damage and worsen neurological outcomes.

Hypoxic-ischemic brain injury refers to a group of pathophysiological and cellular brain injuries caused by hypoxia, ischemia, cytotoxicity, or a combination of these mechanisms.[31] Moderately severe reductions in cerebral blood flow and oxygen supply suppress brain tissue metabolism, whereas critically severe reductions can result in irreversible membrane disruption, cytotoxic edema, and cell death.[32]

• 4. Metabolic acidosis crisis: In critically ill patients, metabolic acidosis is a common acid–base disorder. It occurs when the body accumulates acid, resulting in a decrease in bicarbonate levels. In critically ill patients, severe metabolic acidosis (pH 7.20) is associated with poor outcomes.[33] Metabolic acidosis is diagnosed using arterial blood gas analysis and other relevant tests.[33] The physicochemical approach is used in critically ill patients to quantify complicated metabolic acidosis.[34] Serum pH, HCO₃, lactate levels, and strong ion gap monitoring may have prognostic and therapeutic implications.[33]

• 5. Electrolyte imbalance crisis: Electrolytes are essential in neurocritical care as they maintain fluid balance, nerve conduction, and muscle contraction.[35] Sodium and potassium levels are particularly important as changes in their levels can disrupt the delicate balance necessary for healthy cellular functions. Hyponatremia can cause cellular swelling, impairing cellular function and having serious consequences for vital organs such as the brain.[36] [37] Hypernatremia can cause dehydration and disrupt normal cellular functions.[36] Both hypokalemia and hyperkalemia can negatively impact cellular processes essential for neurological function.[35] Potassium is necessary for nerve signal transmission and muscle contractions as it maintains the electrical potential across cell membranes.[35] Electrolyte imbalances can also interfere with energy production within cells, which is dependent on several metabolic processes influenced by electrolyte concentrations. Disruptions in these concentrations can impair energy production efficiency, affecting overall cellular function and potentially having systemic consequences.[35] Recognizing and correcting electrolyte imbalances is therefore critical in neurocritical care.[38]

Subarachnoid hemorrhage is a typical example where initial neurocritical care management is about securing the ruptured aneurysms, control of intracranial pressure (ICP), and systemic impact followed by cerebral vasospasm crisis. This crisis is a true metabolic crisis where smooth muscles of cerebral blood vessels spasm down due to free blood inside the subarachnoid space. In normal conditions, the movement of potassium into smooth muscles via ATP helps with the proper tone of the muscle. This process can be hindered if there is any hypocarbia like hyperventilation for high ICP ([Figs. 2] and [3]).[39] [40] [41] Later with free blood and breakdown products, this shift is reduced, leading to less availability of intracellular potassium, hence vasoconstriction.

Fig. 2 Relationship of potassium–ATP on brain blood vessels and impact of hypocarbia.

Fig. 3 Presence of free blood after subarachnoid hemorrhage and impact on cerebral vasospasm metabolic crisis.[39] [40] [41]

Bundle of Therapeutic Interventions for Acute and Hyperacute Stages

Importance of a Bundle Approach

The bundle approach is a structured set of evidence-based interventions that are implemented as a cohesive unit to improve patient outcomes.[42] This approach is especially important in the acute and hyperacute stages of metabolic crisis when prompt and coordinated interventions are critical for preventing further neurological damage and improving patient prognosis. The bundle approach has gained widespread acceptance and importance in the management of metabolic crises in neurocritical care.[43] [44]

Bundling has been shown in studies to improve patient outcomes in a variety of clinical settings, including critical care.[45] [46] One study, for example, found that using a sepsis bundle was associated with a significant reduction in mortality among patients suffering from severe sepsis or septic shock.[47] Another study discovered that using a ventilator bundle was linked to a significant decrease in ventilator-associated pneumonia rates.[46] Bundles can improve patient outcomes, reduce variability in practice, and promote teamwork and communication among healthcare providers by providing a standardized and coordinated approach to patient care.

Components of the Bundle

The bundle of therapeutic interventions for acute and hyperacute stages of neurocritical care metabolic crisis includes both pharmacological and non-pharmacological strategies, as well as careful monitoring and assessment.

Pharmacological Interventions

Pharmacological interventions are critical in the management of metabolic crises in neurocritical care. These interventions include the administration of medications to address the underlying metabolic disturbance and mitigate its negative effects on the brain. Depending on the specific metabolic abnormality, various medications can be used.

Hyperglycemia is a common metabolic disorder in neurocritical care, and glucose-lowering agents like insulin are commonly used to keep blood sugar levels under control. Insulin therapy helps to normalize glucose metabolism and lower the risk of secondary hyperglycemia complications such as cerebral edema and impaired cerebral autoregulation.[48]

Seizures frequently accompany metabolic crises, and antiepileptic drugs (AEDs) are administered to control and prevent seizure activity. AEDs, such as phenytoin, levetiracetam, or valproate, can effectively suppress epileptic activity and minimize the risk of further neuronal injury.[49] The choice of AED depends on factors such as the type of seizure, patient characteristics, and potential drug interactions.[49]

Metabolic acidosis is another critical component of metabolic crisis, and sodium bicarbonate may be used to correct acid–base imbalances.[50] Sodium bicarbonate acts as a buffer, neutralizing excess acid and restoring the body's pH balance.[50] By reversing acidosis, sodium bicarbonate helps maintain cerebral perfusion and neuronal function.[50]

It is important to emphasize that the selection and dosage of pharmacological agents should be individualized based on the patient's specific condition. Careful clinical evaluation and continuous monitoring of biochemical markers, such as blood glucose levels, electrolyte concentrations, and arterial blood gases, are essential for assessing the effectiveness of pharmacological interventions and making necessary adjustments ([Table 1]).[51] [52] [53] [54] [55] [56] [57]

Table 1 Commonly used pharmacological interventions in the management of the metabolic crisis in neurocritical care

Intervention	Mechanism of action	Indication
Glucose	Provides energy substrate for brain metabolism	Hypoglycemia[51]
Insulin	Promotes glucose uptake and utilization in tissues	Hyperglycemia[48]
Sodium bicarbonate	Corrects metabolic acidosis and restores pH balance	Metabolic acidosis[52]
Thiamine	Essential coenzyme in glucose metabolism	Suspected or confirmed thiamine deficiency[53]
Magnesium sulfate	Regulates neuronal excitability and energy metabolism	Hypomagnesemia[54]
Lorazepam or midazolam	Controls seizures and reduces cerebral metabolic demand	Seizures[55]
Mannitol or hypertonic saline	Reduces cerebral edema and intracranial pressure	Cerebral edema or increased intracranial pressure[56]
Target temperature management	Reduces metabolic demand Reduces neuronal injury with fever	Glial and neuron stability[57]

Non-pharmacological Interventions

A comprehensive bundle of therapeutic interventions is critical for optimizing patient outcomes during the acute and hyperacute stages of metabolic crisis in neurocritical care. Non-pharmacological interventions, in addition to pharmacotherapy, play an important role in addressing metabolic disturbances and promoting overall patient well-being.

Optimizing oxygenation is another critical aspect of non-pharmacological interventions in neurocritical care during the acute and hyperacute stages of metabolic crisis,[58] ventilation,[59] and perfusion.[60] It is critical to ensure adequate cerebral oxygen delivery and maintain cerebral perfusion by using supplemental oxygen, mechanical ventilation, and vasopressor agents to support hemodynamic stability. These interventions help to prevent secondary brain injury and maintain neuronal viability.

Temperature control is another important non-pharmacological intervention in neurocritical care during the acute and hyperacute stages of metabolic crisis.[61] To reduce the risk of exacerbating brain injury, it is critical to maintain optimal body temperature within a narrow therapeutic range.[61] Healthcare professionals can reduce metabolic demands, inflammation, and the development of cerebral edema by carefully managing body temperature through active cooling or warming techniques.

Monitoring and Assessment

Monitoring and assessment are critical components of the bundle of metabolic crisis therapeutic interventions in neurocritical care. Monitoring vital signs such as heart rate, blood pressure, respiratory rate, and body temperature regularly is critical for detecting any deterioration in the patient's condition early. Frequent laboratory assessments, such as blood glucose, electrolyte levels, arterial blood gases, and lactate, provide valuable insights into the metabolic milieu and help guide treatment adjustments.

Continuous neurologic assessment, which includes monitoring of consciousness level, motor function, and pupillary responses, aids in assessing response to therapy and identifying any new neurological deficits. Despite the risks of infection and brain tissue damage associated with the surgical placement of a catheter or pressure transducer into the cerebrospinal fluid or brain tissue compartments, invasive ICP monitoring remains a cornerstone of modern neurocritical care.[62] Critical care ultrasound is a first-line tool in neurocritical care because these clinical situations—hemodynamic instability, acute respiratory failure, and many others—frequently accompany neurologic injury and are common problems for neurointensivists.[63]

Sedation is widely used in intensive care units. It has the advantage of lowering cerebral energy demands, but it also makes accurate neurologic assessment impossible. As a result, sedation is interrupted intermittently for a neurologic assessment, known as a neurologic wake-up test. This wake-up test, after neuronal stability is achieved, is regarded as the gold standard in the ongoing evaluation of brain-injured patients under sedation.[64] [65]

Implementation and Monitoring of the Bundle

A multidisciplinary team approach is required for the successful implementation and monitoring of a bundle of therapeutic interventions for metabolic crises in neurocritical care. Collaboration among neurointensivists, critical care nurses, pharmacists, consultants, and other healthcare professionals is critical to ensure that the bundle components are performed smoothly. Clear protocols, guidelines, and checklists promote standardized care and compliance with bundle interventions. To monitor the compliance and effectiveness of the bundle approach, regular auditing and quality improvement initiatives are required. Monitoring key performance indicators, tracking patient outcomes, and identifying areas for improvement can drive the refinement and optimization of the bundle over time, improving patient care and outcomes even further.[64]

Conclusion

The management of metabolic crises in neurocritical care requires prompt recognition and intervention. The bundle approach, which includes pharmacological and non-pharmacological interventions, has emerged as a valuable strategy to optimize patient outcomes. Successful implementation and monitoring of the bundle require a multidisciplinary team approach, clear protocols, guidelines, and checklists, as well as regular auditing and quality improvement initiatives. Early detection and intervention are crucial in the management of metabolic crises, and regular monitoring of vital signs, laboratory values, and neurologic assessments can facilitate the early identification of metabolic disturbances. Future research directions include developing more precise and reliable biomarkers to detect and monitor metabolic disturbances in real time, investigating the impact of individualized treatment approaches within the bundle, and evaluating the long-term neurologic and functional outcomes of patients who have experienced metabolic crises. Additionally, various monitoring modalities provide unique and pertinent information about the neurologic function, but their role in improving patient outcomes and guiding treatment plans has not been fully explored.

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