Dear fellows, I would like to greet you all, and I would like to say thank you very much for this opportunity that you give to me so I can be here, in Busan in ASNACC as an author from Indonesia.

Today I would like to present about perioperative glycemic control in neurosurgical patients.

The prevalence of diabetes mellitus is augmenting rapidly in the 21st century mainly due to obesity, aging and the lacking of exercise. The International Diabetes Federation (IDF) declared in 2008, that 246 million adults had diabetes mellitus (DM) worldwide and the prevalence was expected to reach 380 million by 2025. Patients with diabetes preparing for surgery are facing many difficulties. They may have vascular, renal, or neurological disease as a consequence of their underlying DM and are more prone to wound infections.

As the diabetic population is keeping growing worldwide, anesthesiologists may have more chances to encounter patients with DM in the management of perioperative period. Non-diabetic patients may become hyperglycemic state due to a combination of tissue insulin resistance and decreased insulin secretion in the perioperative period. In diabetic patients, surgery and trauma are associated with an increase in the secretion of catabolic hormones in the presence of relative insulin deficiency. Therefore, the aim of perioperative metabolic management should be targeted to avoid excessive hyperglycemia, hypoglycemia and loss of electrolyte such as potassium, magnesium and phosphate

• Hyperglycemia in diabetic and nondiabetic neurosurgical patients is associated with adverse outcomes, such as an increased prevalence of complications, prolonged hospital stay, and higher mortality rates

• Maintaining normal blood glucose concentrations has been shown to reduce perioperative morbidity and mortality, although the evidence for this derives mainly from studies in patients undergoing cardiac surgery

Significant neuroendocrine response to surgery + bypass. Inadequate insulin response to hyperglycemia. Excess glucose in the pump prime+ cardioplegia. Pancreatic hypoperfusion, hypothermia. Anesthetics may modify response. E.g., epidurals

Glucose is the preferred substrate for the brain, although the brain can take up lactate, other monocarboxylic acids and ketone bodies under certain circumstances, for example, during the perinatal period. Once it enters cells, glucose is metabolised through glycolysis to pyruvate. Glycolysis (also termed Embden-Meyerhof pathway) is the series of reactions that results in the breakdown of glucose, generating pyruvate, adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide (NADH). It is

a truly fundamental pathway, found throughout nature and proceeds without the need for oxygen. The ten key enzymatic steps, in which 2 ATP molecules are consumed early on but then paid back later with the generation of 4 ATP molecules per glucose molecule, so the net production of ATP is 2 molecules per molecule of glucose, takes place in the cytoplasm. There are three key regulatory points catalysed by the enzymes hexokinase, phosphofructokinase, and pyruvate kinase. These reactions are essentially irreversible whereas the other enzymatic steps exist in equilibrium. Pyruvate is converted to acetyl CoA, which enters the tricarboxylic acid (TCA) cycle, within mitochondria. The TCA cycle results in the transfer of electrons (fromNADH and succinate), to electron transport chains (ETC.) located in the inner mitochondrial membrane, which ultimately deposit on oxygen molecules. Thus the TCA cycle generates carbon dioxide (also generated by the pyruvate dehydrogenase step prior to TCA cycle) and the ETC generates water. The ETCs pump protons across the inner mitochondrial membrane, maintaining a gradient of protons across the membrane. Protons then flow down their concentration gradient, through ATP synthetases (ATPase), resulting in the generation of ATP, the cells’ widely used energy currency. Energy production from glucose is intrinsically related to neurotransmission. Glutamate spins off the TCA cycle from α-ketoglutarate (αKG), an intermediate of the TCA cycle. Glutamate can be converted reversibly into glutamine. Glutamate can also be converted into gamma-aminobutyric acid (GABA). There is a constant cycle of glutamate released during neurotransmission, retrieved from synaptic junctions by astrocytes and returned to neurons as glutamine

Pathophysioly of hyperglycemia. Anesthesia, metabolic stress, and critical illness lead to metabolic derangements, resulting in hyperglycemia. Hyperglycemia is associated with increased inflammation, susceptibility to infection and organ dysfunction.

Best evidence in critical care. Treatment for hyperglycemia in the icu- a bittersweet message. Multivariate regression analysis suggests that glycemic control + not the insulin dose explains most of the beneficial effects.

Endothelial activation is assoc w expression of several adhesion molecules including E and P selectin, intracellular adhesion molecule, and vascular cell adhesion molecule on the cell surface. These activated molecules recruit leucocytes; subsequent leukocyte aggregation + adhesion lead to microvascular obstruction, inc microvascular permeability + multiorgan system dysfunction. Schricker believes that improved outcome related to both the beneficial effects of glucose control and the magic of insulin. He states that insulin especially at higher doses as with clamps, has benefical efftcs such as vasodilation, antiinflammatory, antooxidative, antiaggregatory, fibrinolytic, thrombolytic, positive inotropic+ cardioprotective effects

Hospitalized Diabetic pts – recommendations by the american diabetes assoc, soc critical care medicine, american heart+ american stroke association summarized in article by Mira Loh-Trivedi + David Rothenberg from Rush University medical center 2007. These targets include glycosylated hemoglobin (Hgb A1C) <7.0%, average preprandial plasma glucose between 90 and 130 mg/dL (5.0 and 7.2 mmol/L), and average postprandial plasma glucose <180 mg/dL (10.0 mmol/L)

Use target 3 blood glucos- average glu each day- day of surgery, POD 1+ POD 2. cont insulin protocol

Hyperglycemia is a phenomenon in the perioperative period, linked to the preoperative metabolic state of the patients, neuroendocrine stress response, acute prioperative insulin resistance, and and intraoperative management.

The stress of surgery activates a neuroendocrine response that antagonizes the action of insulin and predisposes the patient to hyperG and ketoacidosis (Figure 1). Consequently, an increase of the secretion of counterregulatory hormones (example : epinephrine, cortisol) can be observed. Stress also induces the development of insulin resistance, generated by proinflammatory cytokines or caused iatrogenically by commonly used drugs (in example : dopamine, noradrenaline, corticosteroids, thiazides, and dextrose containing solutions). Stress-induced hyperglycaemia may cause endothelial cell dysfunction, defects in immune function, increased oxidative stress, prothrombotic changes, cardiovascular effects, and specific brain area (insular cortex) injury or a direct hypothalamic damage/irritation of glucose regulatory centers. hyperG has been shown to aggravate these deleterious effects, whereas optimization of glucose control has been shown to reverse them

Hypoglyceia can occur under any circumstances, although the DM population is the most susceptible. There are no specific data about its incidence in neurosurgical patients, but it is well known that hypoG events worsen prognosis. The hypoG-associated risk is greater during the perioperative period, when general anesthesia may mask the symptoms and delay its recognition. The Table shows the most common causes of hypoG in these patients.

Diabetic autonomic neuropathy (advanced cardiac, respiratory, and gastrointestinal autonomic neuropathy) can lead to hemodynamic instability, abnormal gut motility, and erroneous glucose levels. In addition, inadequate glucose control leads to increased risk of infectious complications

The benefits of improved blood glucose control after neurosurgery include a lower rate of craniotomy wound infections, reduced length of stay, and reduced hospital cost. Decreased bloodstream and nosocomial infections, acute renal failure, ventilatory support, blood transfusions, critical illness polyneuropathy, and duration of stay in the neurocritical intensive care unit have also been demonstrated

A 24-hour urine collection may be indicated when there is an elevated serum creatinine level, proteinuria, or concomitant longstanding or poorly controlled hypertension. Insulin action is prolonged in renal impairment, promoting unpredictability of blood glucose and hypoglycemia. A practical way of action is reported in Table 2. It should be remembered that type II diabetics are vulnerable to an exaggerated variability in blood glucose levels possibly because surgical stress augments insulin resistance

The recently introduced incretin-based treatments are becoming popular as add-on medications in patients who do not achieve glucose goals with traditional oral therapy. These include exenatide, administered by daily subcutaneous (SC) injection, and the oral agent sitagliptin. Patients should discontinue these drugs 24 to 36 hours prior to surgery and restart the oral antidiabetics after discharge from the hospital.

Insulin is the preferred medication in critically ill patients and in those with hepatorenal disease, cardiovascular limitations, or hemodynamic compromise

The infusion should be started well in advance of the procedure (preferably 2 to 3 hours) to allow titration to the desired glucose range. Hourly glucose readings are done intraoperatively; the insulin rate is adjusted to maintain the blood glucose within the target range. Insulin drip corrections are based on diverse monitoring schemes

Reactive regimen (according to monitorized values). The measurement unit used for indicating the concentration of blood or plasma glucose can either have a weight dimension (mg/dL) or a molarity (mmol/L).

Proactive regimen: dilute 100U of insulin in 100mL of isotonic saline solution 0.9% (1U = 1mL). Administer via infusion pump according to the following scheme. The measurement unit used for indicating the concentration of blood or plasma glucose can either have a weight dimension (mg/dL) or a molarity (mmol/L)

Tables report the reactive and proactive algorithms, respectively

Basal insulin can be given as glargine, levemir, or neutral protamine Hagedorn (NPH). Bolus/nutritional insulin can be either given as regular insulin or as one of the insulin analogs such as glulisine, aspart, or lispro. Regular insulin is the preferred drug if the patient continues to be on enteral tube feeding. However, if the patient resumes his regular diet, insulin analogs are advantageous due to their immediate effect.

1. Conflicting data have been reported about isoflurane’s effect on lactate production ranging from nonaccumulation to elevation of 300%. However, a microdialysis study reported that lactate elevation is associated with a concomitant pyruvate elevation without changes in the lactate/pyruvate (L/P) ratio and in glucose or glutamate concentrations. Furthermore, isoflurane decreases insulin secretion predisposing the patient to hyperglycemia

A consensus statement of the American Association of Clinical Endocrinologists and the American Diabetes Association has recommended revising glucose targets. In critically ill patients, start treatment at a threshold of >180 mg/dL (>10.0 mmol/L), preferably with IV insulin therapy, and maintain the glucose level between 140 and 180 mg/dL (7.8 and 10.0 mmol/L). Greater benefit may be obtained at the lower end of this range. Glucose concentrations <110 mg/dL (6.0 mmol/L) are not recommended [8]. However, these goals should be flexible and individualized to the particular patient and the clinical circumstances. Persistently elevated readings indicate that the treatment regimen must be adjusted or changed and should alert the treating physician of the need to explore the possible reasons for hyperglycemia

(i)hyperG is frequent in acute neurological diseases in the perioperative period both in diabetics and nondiabetics. hyperG [>150 mg/dL (>8.3 mmol/L)] is associated with poor outcome, but causality has not been definitively demonstrated.

(ii) Extreme hypoG and hyperG episodes must be avoided.

(iii) It is recommended to maintain blood glucose levels between 140 and 180 mg/dL (7.8–10.0 mmol/L).

(iv) Oral antidiabetic agents have no place in acute and critical situations.

(v) Regular intravenous insulin is preferred to lower blood glucose levels.

(vi) IIT has no benefits.

(vii) Frequently and routinely monitor glucose levels.

(viii) Implementation of an institutional multidisciplinary management protocol is recommended.

(ix) Therapy must be accompanied by adequate nutritional support.

In a study of 918 consecutive neurosurgical patients at the University of Michigan Hospitals, Davis et al. found that increased preoperative blood glucose was associated with higher risk for postoperative complications, longer hospital stays, and longer neurosurgical ICU stays. Moreover, increasing preoperative blood glucose predicted both complication risk and ICU and hospital stay in a dose-response fashion, such that incrementally higher blood glucose predicted incrementally higher complication risk and longer ICU and hospital stay

It can be seen from the Figure here that preoperative blood glucose above 120 mg/dl predicted risk for postoperative complications, increased length of hospital stay, and increased length of neourosurgical ICU stay in a dose-response fashion following neurosurgical intervention. Tight glycemic control peri-operatively may lead to reduced risk for postoperative complications and more rapid recovery following neurosurgery. Randomized controlled trials of the effects of tight glycemic control on post-neurosurgical outcomes among hyperglycemics are in order

Intracerebral Hemorrhage

Current guidelines from the American Heart Association recommend insulin treatment for patients with blood glucose levels >185 mg/dL (>10.3 mmol/L) and possibly even those with levels >140 mg/dL (>7.8 mmol/L: evidence Class IIa, Level of Evidence C). In contrast, ICH guidelines endorsed by the major European stroke and neurological societies suggest maintaining blood glucose below 300 mg/dL (16.7 mmol/L)

Subarachnoid Hemorrhage

Recently published guidelines from the American Heart Association emphasize the importance of avoiding hyperglycemia in patients with aneurysmal SAH, but without providing specific recommendations on target glucose levels.

However, these goals should be flexible and individualized to the particular patient and the clinical circumstances. Persistently elevated readings indicate that the treatment regimen must be adjusted or changed and should alert the treating physician of the need to explore the possible reasons for hyperglycemia

Despite scientific advances in making microdialysis probes smaller and more efficient; the invasive nature of this technique still poses some practical and ethical limitations.

Glucose is the only resource for brain energy metabolism. IIT is a double-edged swords, it should be carefully considered in diabetes neurosurgical patients. Extreme hyperglycemia and hypoglycemia episodes must be avoided (4.4~7.0/5.0~8.7 mmol are suggested)

Surgical stimulation could affect patient stress response and metabolic/endocrine system and subsequently lead to increase of blood glucose level. Some anesthetics as well as some therapeutic agents have effects on systemic and cerebral glucose/oxygen consumption, and thus may affect blood glucose level.

Anesthesiologists play a very important role during the perioperative period in diabetes neurosurgical patients. Systemic and cerebral metabolism of glucose in diabetes neurosurgical patients should be measured during the operation, and a better follow-up is very necessary. Good blood glucose control protocols should be developed according to the patient’s prognosis.