Introduction

Diabetes mellitus as well as stress-related hyperglycemia in neurologically injured populations has shown association of hyperglycemia with various adverse outcomes such as a higher prevalence of perioperative complications including poor wound healing, extended hospital stay, and high mortality rates. These effects are more profound in patients with undiagnosed diabetes mellitus than in patients with established diabetes mellitus. Studies have inarguably established the negative consequences of hyperglycemia on the human body in general and the brain in particular. A clear association of hyperglycemia with the overall prognosis in neurologically injured patients has also been demonstrated. The use of intensive glycemic control regimens while initially showing favorable results, later exhibited possible harmful effects on the brain and hence should be used in perioperative and critical care management of neurologically injured patients with care and caution. Blood glucose measurements are not consistently mirrored by brain glucose levels, and hence derivation of glycemic thresholds for neurological injury is a cumbersome process. Similarly hypoglycemia has been shown to impede brain metabolism.

Incidence of Diabetes Mellitus

A 2013 estimate indicates that there were 171 million people in the world with diabetes in the year 2000 and this is projected to increase to 366 million by 2030. In India alone, the prevalence of diabetes varies from 15% to 20% of the adult population. The age of onset of diabetes is also coming down.

Glycemic Indices

Diabetes mellitus is a condition primarily defined by the level of blood glucose. Blood glucose is generally measured as venous plasma glucose level. The current World Health Organization diagnostic criteria for diabetes mellitus and impaired glucose tolerance takes into account both fasting plasma glucose and a 2-h plasma glucose after ingestion of an oral glucose load. A fasting plasma glucose of ≥7 mmol/L (126 mg/dL) or a 2-h plasma glucose ≥11.1 mmol/L (200 mg/dL) is diagnostic of diabetes mellitus. Impaired glucose tolerance differs from overt diabetes by a fasting plasma glucose of less than 7.0 mmol/L (126 mg/dL) along with a 2-h plasma glucose value between 7.8 and 11.1 mmol/L (140–200 mg/dL). The American Diabetes Association has defined blood glucose values exceeding 7.8 mmol/L (140 mg/dL) in two or more plasma samples as hyperglycemia and hypoglycemia as blood glucose value less than 3.9 mmol/L (70 mg/dL). These values serve as treatment thresholds for institution of therapy of hyper- and hypoglycemia.

Modes of Glucose Measurement

Depending on the site of collection venous and capillary samples exhibit same values in the fasting state and higher capillary glucose values in the nonfasting state. A difference of 3–5 mg/dL has been reported between arterial and venous sugar levels with higher levels in arterial samples. However, this difference in glucose values has been shown to be inconsistent especially in postprandial periods, and hence interpretation of arterial glucose values should be done with caution. Furthermore, blood glucose monitoring using arterial or venous samples has been shown to be misleading in conditions of low hematocrit, severe hypoglycemia, and poor peripheral perfusion. Hence it is advisable to rely on a trend of continuous glucose monitoring values as an indicator of glycemic status.

Pathophysiology of Diabetes Mellitus

Diabetes mellitus results from inadequate supply of insulin and/or inadequate tissue response to insulin (insulin resistance) leading to increased circulating glucose levels resulting in microvascular and macrovascular complications. Hyperglycemia causes an impairment in protein and lipid functioning by nonenzymatic glycosylation, increases oxidative stress by overproduction of superoxide anion, and induces cytokine release, which promotes inflammation. All these mechanisms are associated with vascular damage and disturbance of the immune system making hyperglycemic patients particularly susceptible to postoperative complications.

Cerebral Glucose Metabolism

Glucose is the main metabolic fuel for the central nervous system. Brain cannot synthesize or store glucose for more than a few minutes and thus needs a continuous supply of glucose from circulation. Glucose is essential for synaptic transmission, maintenance of ionic gradient, and cellular integrity. The major portion of energy is generated by glycolysis (breakdown of glucose), the citric acid cycle, and oxidative phosphorylation. Mitochondria and oxygen are critical for the efficient production of ATP from glucose. Under aerobic conditions metabolism of a single glucose molecule yields a maximum of 38 ATP molecules

In the absence of oxygen, each molecule of glucose yields only 2 molecules of ATP. This is insufficient to meet the energy demands of the brain.

Lactate production is increased in anaerobic conditions and has been the subject of much debate vis-à-vis its effect on the injured brain conditions. There is compelling evidence to suggest that lactate has a beneficial role as an energy substrate in cerebral ischemia and neuronal activation especially in the subsets of patients with traumatic brain injury (TBI) and subarachnoid hemorrhage (SAH).

The current evidence of glucose metabolism of the brain as evidenced by cerebral microdialysis levels can be summed by an apparent paradoxical role of glucose in cerebral ischemia. On the one hand, glucose is an essential ingredient for the subsistence of cellular function during cerebral injury and ischemia, whereas on the other hand, due caution should be exercised to avoid the deleterious effects of anaerobic glycolysis due to dysfunctional mitochondrial oxidation. This culminates in the generation of lactate and development of intracellular acidosis. Glutamate, an excitatory neurotransmitter typically secreted in excess after a cerebral insult has been shown to have a stimulatory effect on glycolysis. Animal studies have also established the role of accessory pathways of metabolism, e.g., pyruvate carboxylase pathway, generation of metabolic intermediaries such as oxaloacetate, and the synthesis of excitatory amino acids like aspartate in the pathogenesis of evolving cerebral injury.

Hyperglycemia and the Brain

Hyperglycemia with a plasma glucose of >8.3 mmol/L (>150 mg/dL) exacerbates ischemic neuronal injury and has been shown to be a contributor to poor outcome in patients with stroke, TBI, poor-grade SAH, and spinal cord injury. Although the exact mechanism of hyperglycemia’s deleterious effects on the nervous system remains elusive, oxidative stress at the cellular level seems to be the final common pathway. In the presence of oxidative stress, there is increased production of toxic derivatives such as polysols, hexosans, and advanced glycosylation end products (AGEs) resulting in the production of harmful reactive oxygen species implicated in the suppression of immune function and elevating circulating inflammatory cytokine concentrations. Indeed, the receptors for AGEs are found to be increased in patients with diabetes mellitus, and there is evidence of association of such receptors with cognitive dysfunction and incidence of stroke.

Adrenergic excess following neurological injury results in increased energy expenditure and requires consequent utilization of glucose reserves for the generation of energy. The aforementioned phenomenon seems to be protective for the recovery of the injured brain especially in TBI and SAH. However, clinical evidence seems to suggest otherwise with hyperglycemia associated with worse outcomes in patients with TBI and SAH.

Hyperglycemia has been found to decrease regional cerebral blood flow, which would logically suggest a resultant decrease in worsening of ongoing cerebral ischemia in patients with brain injury. In addition, hyperglycemia has been shown to have a disruptive effect on the blood–brain barrier in animals. Experimental studies have demonstrated that the peripheral insulin crosses the blood–brain barrier and acts in the maintenance of glucose homeostasis in the brain. Hyperglycemia has been shown to demonstrate a causative role in increasing infarct size in focal ischemic models. This phenomenon could be an important consideration in neurosurgical subsets such as those with SAH, TBI, stroke, and intra-cranial space occupying lesions where focal ischemia is the predominant mode of injury.

Hyperglycemic Neuropathy

Neuropathies are common in both type 1 and type 2 diabetes, and there are no major structural differences in the pathology of the nerves in the two subtypes of diabetes. This peripheral neuropathic pain presents more commonly in the feet and lower part of the leg and is readily reversed by euglycemia. Nerve conduction velocity has been shown to be affected adversely in hyperglycemic patients.

Diabetic Dysautonomia

Dysautonomia has an incidence rate of approximately 20% in the diabetic population and has an association with significant morbidity and mortality, although studies with different end points have pegged the incidence to be as varied as 1–90%. The cardiac manifestations of dysautonomia include exercise intolerance, orthostatic hypotension, and other systemic involvement in the form of gastroparesis and impaired neurovascular function. These autonomic afflictions are especially relevant in patients with neurological injury with associated cardiac involvement and an inherent risk of aspiration.

Hypoglycemia and the Brain

Hypoglycemia is defined as blood glucose concentration less than 3.9 mmol/L (70 mg/dL) in adults, with features of severe hypoglycemia at blood sugar values less than 2.8 mmol/L (50 mg/dL). The incidence of both iatrogenic and spontaneous hypoglycemia is a grave occurrence in critical care patients and has been related to adverse overall outcomes. The major effects of hypoglycemia on the brain include dysfunctional cerebral metabolism, cerebral hyperemia with consequent increase in intracranial pressure (ICP), as well as electrophysiologic disruption leading to coma. Hypoglycemia has been implicated in the causation of neuronal damage in cortex and hippocampus leading to long-term cognitive dysfunction as well as seizure generation. Cerebral hypoglycemia has also been shown to cause periinfarct depolarization leading to expansion of infarct in TBI and ischemic stroke models. It also leads to cerebral metabolic crisis in brain. In addition, hypoglycemia induces a systemic stress response leading to an increase in blood noradrenaline, adrenaline, glucagon, growth hormone, and cortisol concentrations and could be a concern in patients with coexisting heart disease. Profound hypoglycemia ultimately leads to coma, which if uncorrected for >30 min results in irreversible brain damage.

The glycemic threshold at which features of hypoglycemia begin is 3.6–3.9 mmol/L (65–70 mg/dL) at which the neuroendocrine response to hypoglycemia leads to a surge in glucagon and epinephrine. At values around 2.8–3 mmol/L (50–55 mg/dL), neurologic symptoms such as cognitive impairment begin to manifest. At values below 2.2 mmol/L (40 mg/dL) seizures, coma and brain damage occur. However, these signs and symptoms might be masked in patients with neurological injury, and hence measurement of blood glucose should be a part of routine workup of neurologically obtunded patients. Besides these observations, another interesting fact is that the neuronal susceptibility to hypoglycemia is tissue specific. While the hippocampus and cerebral cortex are highly sensitive to hypoglycemia, the cerebellum is relatively resilient to such changes.

The clinical implications of the effect of hypoglycemia is to routinely measure blood glucose in patients with neurological injury. While it is difficult to exactly predict a glycemic threshold, there is burgeoning evidence to suggest deleterious effects of moderate hypoglycemia. On the basis of recent evidence it seems reasonable to assume inception of neurological injury at values less than 3.9 mmol/L (70 mg/dL) and hence glucose replacement should start at these levels in the neurocritical care patient population.

Evidence of Glycemic Control in Important Neurosurgical Subsets

An interesting phenomenon is the lack of correlation between peripheral and brain glucose levels especially in the injured brain scenarios. As of now the search is still on for numerical values for normal levels of brain glucose as well as the optimal peripheral blood glucose targets for patients with neurosurgical pathologies. In this context it seems reasonable to consider evidence for different subsets of neurological injury separately and draw conclusions for glycemic management in individual subsets.

Traumatic Brain Injury

TBI stimulates a sympathomedullary response, the magnitude of which is directly proportional to the severity of head injury resulting in an elevated plasma glucose level. It has been proven that the degree of hyperglycemia observed can be a predictor of outcome after TBI. Hyperglycemia is being increasingly recognized as a marker of severity of TBI and as a potentially preventable cause of secondary brain injury.

Stress-related hyperglycemia previously considered as a protective physiological response has been challenged later in critically ill medical and surgical patients. It has been shown by Van Den Berghe et al. that intensive insulin therapy (IIT) to maintain blood glucose at 4.4–6.1 mmol/L (80–110 mg/dL) has been shown to be a cost-effective intervention in terms of health resource utilization in critically ill patients. Subsequent studies by Bilotta et al. showed that IIT to maintain blood glucose at 4.4–6.7 mmol/L (80–120 mg/dL), although produced shorter hospital stay, showed no difference in infection rates and overall outcome when compared with routine management of blood glucose. The incidence of hypoglycemia was significantly higher in the IIT group. As discussed before, hypoglycemia can worsen neurologic injury, and this is a concern in the perioperative management of neurosurgical patients. These results indicating deleterious effects of IIT have been validated by microdialysis studies in patients with severe TBI. These studies indicate that tight glucose control causes an increased prevalence of cerebral energy crisis with a correlation to increased mortality. To conclude it is safe to remember that while IIT may be instituted in patients with TBI, it should be done with caution with an emphasis on avoidance of hypoglycemia and a target blood sugar of around 7.8–10.0 mmol/L (140–180 mg/dL) seems reasonable and safe.

Subarachnoid Hemorrhage

Hyperglycemia has been identified as an independent predictor of poor outcome (death/disability) in patients with SAH. The various studies of the effect of IIT with target blood sugar of 4.4–6.1 mmol/dL (80–110 mg/dL) in SAH have shown a reduction in infection rates, at the expense of an increased incidence of hypoglycemic episodes with no significant improvement in outcome.

Hence, although no specific recommendations can be made in patients with SAH, it seems reasonable to institute insulin therapy at blood glucose values greater than 7.8 mmol/dL (140 mg/dL). Furthermore, the evidence available so far suggests that the group of patients might benefit from intensive glucose control (80–120 mg/dL) during periods of anticipated ischemia such as clipping of aneurysm and aneurysm rupture. The continuation of such tight control into the postoperative intensive care setup is not supported by the available evidence as of now in patients with SAH.

Cerebrovascular Accidents

The overwhelming majority of basic science research supports the theory that elevated blood glucose at the time of cerebral infarction leads to a poorer outcome. The Glucose Insulin Stroke Trial, however, failed to show a mortality benefit, but then a reduction in mortality in an acute stroke intervention study is perhaps difficult to achieve.

The available clinical evidence for management of blood glucose is definite for patients with acute stroke with suggested blood sugar targets during endovascular therapy being 70–140 mg/dL and a more liberal range of 140–180 mg/dL in the intensive care unit (ICU).

Tumor Surgery

Infusion of glucose-containing solutions as maintenance fluids in supratentorial craniotomies was associated with elevations of blood glucose to levels associated with ischemic injury. In association with the ongoing regional ischemia in brain tumor pathology as well as dysregulation of glucose homeostasis because of ongoing corticosteroid therapy, glycemic control should be achieved in this neurosurgical subset by institution of insulin for target blood sugar levels of 140–180 mg/dL and avoidance of hypoglycemic episodes.

Spine Surgery

Studies have suggested hyperglycemia as a negative influence in the recovery of spinal cord function following injury and ischemia. Available evidence suggests judicious use of insulin for the maintenance of blood sugar in the range of 140–180 mg/dL with cautious avoidance of hypoglycemia.

Blood Sugar Management in Perioperative Period and Neurocritical Care

Intraoperative Management

Anesthetic Management

The aim of intraoperative management is to provide adequate depth of anesthesia, proper positioning, and to avoid hypoglycemia, hyperglycemia, ketoacidosis, and electrolyte disturbances. Positioning of the patient is important to avoid pressure sores, and it should be done gradually to avoid sudden drop in blood pressure. Careful titration of anesthetic agents should be done to avoid hypotension due to autonomic neuropathy. Rapid sequence intubation (RSI) with cricoid pressure is followed if gastroparesis is suspected. Dehydration should be avoided; normal saline should be used as maintenance fluid. Dextrose-containing fluids and Ringer lactate are best avoided. Blood sugar should be monitored every hour along with ECG, blood pressure, SpO ₂ , end tidal carbon dioxide, urine output, and temperature. Continuous arterial blood pressure should be monitored if hemodynamic instability or large fluid shifts are anticipated.

Postoperative Glycemic Management

Blood sugar should be monitored every 2 h, and normal insulin regimen or oral hypoglycemic agents reinstituted with the first meal. It is also important to monitor the sodium and potassium levels. In the presence of stable blood glucose, insulin infusion is converted to a subcutaneous (SC) insulin regimen. When transitioning from IV to SC insulin, the drip should continue and overlap with the first SC dose of long-acting (basal) insulin. Failure to overlap IV and SC insulin can result in extreme hyperglycemia and DKA. In the postoperative period basal insulin requirements can be taken care by long-acting insulin preparations such as glargine, levemir, or neutral protamine hagedorn. Nutritional insulin requirements can be either given as regular insulin or as one of the insulin analogs such as glulisine, aspart, or lispro.

Postoperative hyponatremia and hypokalemia are common electrolyte abnormalities, and if uncorrected may lead to cardiac arrhythmias. Nausea and vomiting should be prevented, and if present, should be treated vigorously. Good analgesia decreases catabolic hormone secretion. Judicious use of antibiotics and better wound care and postoperative glycemic control can prevent postoperative infection. Assessment of comorbidities and complications will help to prevent complications in the perioperative period.

Blood Sugar Control in Emergency Neurosurgical Patient

Glycemic control in diabetic patients presenting with neurosurgical emergencies such as severe TBI, SAH, intracranial tumor bleed, etc., present a challenge to the neuroanesthesiologist on account of the adrenal crisis compounding glucose homeostasis. However, the glycemic management in this subset follows the same tenets of use of insulin infusions, rigorous glucose monitoring, and meticulous avoidance of hypoglycemia.

Blood Sugar Control in Intensive Care Setup

Two single-center studies in neurocritical care units with reported mortality benefits of tight glycemic control in postsurgical critically ill adult patients were published in the year 2001 and 2006. IIT, where the blood glucose levels are maintained at 80–110 mg/dL, was associated with a reduction in mortality by 34% as shown by Berghe et al. in 2001. This study was carried out in post–cardiac surgery patients. Berghe et al. in 2006 used the same approach in patients in the medical ICU, where a beneficial effect on in-hospital mortality was only seen in a subgroup of patients who stayed in the ICU for more than 3 days. Subsequent studies conducted by others have not shown a mortality benefit, and some even had safety issues associated with IIT.

A retrospective analysis by Meier et al. in 228 patients demonstrated that strict glycemic control (63–117 mg/dL) is associated with increased incidence of hypoglycemia and raised ICP in the first week after head injury. In addition, a worsened survival at 21 days after head injury was observed. It went on to recommend that moderate glycemic control (blood sugar 90–144 mg/dL) was more beneficial. Kramer et al. performed a systematic review and meta-analysis exploring the issue of glycemic control in neurocritical patients. The results were largely what had been discussed till now. Tight glycemic control defined as target blood glucose values from 70 to 140 mg/dL (3.9–7.8 mmol/L) had a nonsignificant improvement in mortality and resulted in better neurological outcomes. Glycemic control regimens advocating insulin initiation for glucose concentrations >200 mg/dL (11.1 mmol/L) was seen to be associated with poor neurological outcomes. Hypoglycemia was far more common with intensive therapy (3 times) than with conventional therapy. The authors concluded that IIT in neurocritical care significantly increases the risk of hypoglycemia and does not influence mortality among patients in neurocritical care unit. Presently the evidence suggests that intermediate glycemic goals of 140–180 mg/dL (7.8–10.0 mmol/L) may be most appropriate in the neurocritical care subset. Blood sugar variability is considered as one of the reason for nonimprovement of mortality and morbidity even after use of insulin in patients with hyperglycemia. Egi et al. observed that mean glucose variability was less in survivors (1.7 mmol/L) as compared to nonsurvivors (2.3 mmol/L) ( p < .001). Waeschle et al. recommended that controlling blood glucose variability is more beneficial than strict control of blood sugar. Therefore, a more sophisticated insulin protocol should be planned with continuous blood sugar measurement and closed loop insulin infusion to minimize blood sugar variability.

Nutrition

Nutrition in diabetic neurosurgical and neurocritical patients is of paramount importance in the overall outcome of patients. Inadequate calories and nutrition in diabetic neurocritical patients makes these patients susceptible to the deleterious effects of hypoglycemia. Nutritional protocols should preferentially use the enteral route and should be used in conjunction with regular nutritional assessments. There should be an onus on avoidance of excess calories especially from carbohydrates and fats with institution of nontight insulin regimens as and when needed.

Conclusions

In light of this discussion there is little to dispute the morbid effects of hyperglycemia and iatrogenic hypoglycemia on the injured brain in neurosurgical patients. All aspects of management of diabetic neurosurgical patients such as optimum glycemic targets, the modes of their measurement, and the use of pharmacologic agents in the perioperative and critical care settings for optimum management of hyperglycemic states present contentious issues. Significant research is ongoing for determination of rapid, point-of-care glucose measurement methods and the best way to deal with hyper- and hypoglycemia.

Available evidence seems to indicate that there is no definite advantage of IIT and that hypoglycemia has to be avoided at all costs. However, all centers involved in the management of neurosurgical patients should be involved in formulation of evidence-backed protocols for the management of glycemic perturbations in their patients. In addition, these centers should be well equipped and well versed in the perioperative and critical care management of diabetic neurosurgical patients to prevent fluctuations in blood sugar level.

Coexisting Hypertension in Neurosurgical Patients

Physiology of Cerebral Circulation

With respect to pressure regulation : Considering cerebral vasculature as parallel rigid cylinders, so with the application of Ohm’s law

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