Coexisting Diabetes Mellitus in Neurosurgical Patients

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

C ₆ H ₁₂ O ₆ + 6O ₂ + 38ADP + 38Pi → 6CO ₂ + 6H ₂ + 38ATP

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.

Glucose + 2ADP + 2Pi + 2NAD ↔ 2pyruvate + 2ATP + 2NADH ↔ 2lactate + 2H + 2NAD

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

Preoperative Evaluation and Management

The preoperative management of diabetic patients presenting for elective neurosurgery requires some considerations common to all diabetic patients along with management modifications due to neurosurgical considerations. Before elective surgery, the patient’s blood glucose targets should include glycosylated hemoglobin (HbA1C) <7.0%, fasting plasma glucose ≤140 mg/dL, and postprandial plasma glucose ≤200 mg/dL. In case of poor glycemic control (HbA1C >9%) or evidence of hyperglycemic emergencies such as diabetic ketoacidosis (DKA) and nonketotic hyperglycemic coma, elective neurosurgery should be deferred. Regular glucose monitoring should be instituted and hypoglycemia avoided at all costs. Diabetic patients should be given preference while planning the operation theater list. Diabetics with peripheral and cardiac autonomic neuropathy are prone to precipitous hypotension, life-threatening arrhythmias, slowed gastric motility, and loss of glucose counter regulation.

Antidiabetic Agents

An exhaustive perusal of antidiabetic agents (ADAs) including the currently available ADAs, their mechanism of action, duration of effects, dosing, and adverse effects is beyond the scope of this chapter; however, the reader is directed to the ensuing reference for such details. The side effects of the important classes of ADAs along with the recommended withholding periods is presented in a tabular form ( Table 44.1 ).

Table 44.1

Important Classes of ADAs Along With Their Side Effects and the Recommended Withholding Periods

ADA Drugs	Significant Side Effects	When to Withhold Before Surgery? (h)
Metformin and short-acting sulfonylureas (glibenclamide, glimepiride, gliclazide)	Lactic acidosis (metformin) especially in elderly persons with compromised kidney function	24
Long-acting sulfonylureas, e.g., chlorpropamide and glyburide	Hypoglycemia	48–72
Thiazolidinediones, e.g., rosiglitazone, pioglitazone	Causes fluid retention, intravascular volume expansion, and dilutional anemia Can trigger pulmonary edema and congestive heart failure in susceptible patients	24–36

ADAs , antidiabetic agents.

ADAs do not seem to have a significant place in the perioperative management of diabetic or hyperglycemic neurosurgical patients because of unpredictable pharmacokinetics, pharmacodynamics and efficacy, drug interactions, and a propensity to cause severe hypoglycemia in critical patients.

Intraoperative Management

Glycemic Management

Insulin is the first-line agent for management of hyperglycemia in patients presenting for neurosurgical procedures. Its advantages include its significant potency, rapid onset of action, predictable effect and limited known contraindications. Insulin is the preferred medication in critically ill patients and in those with concomitant involvement of other major organ systems such as the heart, liver, and kidney. Long-acting insulin should be substituted with short- or intermediate-acting insulin. The usual course of action for insulin-dependent diabetic patients undergoing nonneurosurgical procedures is the institution of a glucose insulin intravenous (IV) solution during the perioperative period. However, in neurosurgical patients glucose is avoided in the perioperative period except when the blood glucose concentrations fall below 70 mg/dL (<3.9 mmol/L), in which case glucose-containing fluids neutralized with insulin are instituted in conjunction with frequent glucose monitoring.

Insulin therapy in neurosurgical patients is best instituted with a continuous IV insulin infusion formulated by the addition of 100 U regular insulin to 100 mL of 0.9% sodium chloride solution, thus achieving a concentration of 1 U/mL. The insulin infusion protocols for glycemic management of neurosurgical patients differs among various institutes but can be broadly divided into proactive and reactive regimens. While the proactive approach typically aims for attainment of blood glucose in a predefined target, the reactive approach is similar to the sliding scale regimens and basically delays therapy till onset of hyperglycemia. There seems to be little evidence to choose between the two regimens, and the insulin protocols for the perioperative management in neurosurgical centers classically aim for blood sugar values in the range of 6.1–16.2 mmol/L (110–180 mg/dL) with a watchful monitoring for hypoglycemia.

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

Introduction

Hypertension is one of the most common chronic medical conditions. It has been estimated that by the year 2025, approximately one-third of the global population will be suffering from this illness. Hypertension is a major risk factor for adverse cardiovascular outcome, stroke, and renal insufficiency. The 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults, a report from the panel members appointed to the 8th Joint National Committee (JNC 8), highlights that there is strong evidence to support treating hypertensive persons aged 60 years or older to a blood pressure goal of less than 150/90 mmHg, while for hypertensive persons younger than 60 years, the panel recommends a blood pressure of less than 140/90 mmHg based on expert opinion. The thresholds and goals recommended for hypertensive adults with diabetes or nondiabetic chronic kidney disease are the same as those for the general hypertensive population younger than 60 years.

Careful preparation of hypertensive patients undergoing surgery is of major clinical importance because of high prevalence of chronic hypertension in the general population. Moreover, previously normotensive individuals may develop acute hypertension in perioperative settings due to various causes. This is of great importance in neurosurgical patients as cerebral pressure autoregulation may be lost under a variety of conditions, such as cerebral tumors, infarcts, and hematomas. In these situations sudden increase in blood pressure, which may occur either during induction of anesthesia or intraoperatively as well as during recovery from anesthesia, may lead to an increase in cerebral blood flow, ICP, and cerebral edema.

Physiology of Cerebral Circulation

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

F = \frac{(P 1 - P 2)}{R}

$F = \frac{(P 1 - P 2)}{R}$

where in F is the flow, P1 is the input pressure, P2 is the outflow pressure, and R is the resistance.

In cerebral circulation P1 − P2 (i.e., inflow pressure minus outflow pressure) reflects the cerebral perfusion pressure (CPP) and is usually calculated as mean arterial pressure minus the outflow pressure. The cerebral venous system is compressible, hence it may act as a “starling resistor.” Therefore outflow pressure is higher pressure, either ICP or venous pressure. True CPP is often overestimated since a small gradient exists between systemic and cerebral vessels. In a normal individual, cerebral blood flow is constant between a CPP of approximately 50–150 mmHg.

After the cerebral vessels’ responsiveness capacity to the changes in cerebral pressure is exhausted, cerebral blood flow passively follows changes in CPP. At the extremes, vascular resistance probably does not remain fixed. Vessel collapse and passive dilation may actually potentiate the predicted decline or rise caused by CPP changes. Resistance does not correlate in a linear manner to pressure. Thus autoregulation limit is only a statistical expression of how population responds, and a value of 50 mmHg, even in a normotensive person, does not guarantee that a particular patient’s cerebral circulation remains within “autoregulatory plateau.” Ideally, at the lower limit of cerebral pressure autoregulation, a near-maximal vasodilation is supposed to take place. However, even below the lower limit of autoregulation, pharmacologic vasodilation may occur.

In short, a cerebral autoregulation curve expressing cerebral blood flow as a function of CPP is formed by three segments. Two obliquely placed segments meet a horizontal segment at points that represent the lower and upper limits of cerebral autoregulation. The horizontal segment represents the pressure-independent flow within the autoregulatory range; on the other hand, the oblique lines represent pressure-dependent flow outside the autoregulatory range.

Pathophysiology of Arterial Hypertension

Chronic hypertension is accompanied by a rightward shift of the brain pressure autoregulation curve ( Fig. 44.1 ).

Figure 44.1, Cerebral autoregulatory curves in normotensive and chronic hypertensive patients. Autoregulation curve shifts to right in patients with chronic hypertension.

Possible mechanisms are as follows:

1.
Vascular hypertrophy, accompanied by an increase in tunica media thickness and a resulting decrease in the intravascular lumen (thicker wall to lumen ratio), increases proximal conductance vessel resistance.
2.
Neurogenic factor may be contributory. Thus, when cerebrovascular dilation in the resistance vessels is maximal, total vascular resistance is more in the hypertensive individual, as it is seen in acute sympathetic stimulation.

The clinical implication of the rightward shift of the upper autoregulation threshold is that the hypertensive patient is provided with a protective mechanism. Increase in blood pressure, which in normotensive patients would increase cerebral blood flow leading to compromising the integrity of the blood–brain barrier or causing hypertensive encephalopathy, has negligible effect in hypertensive patients. Cerebral vascular hypertrophy resists the tendency toward forced vasodilation, predominately in the smaller arterioles. Anesthetic agents that diminish cerebrovascular tone (e.g., halothane) have been shown to attenuate this protective effect during extreme elevations of blood pressure. Carbon dioxide reactivity is well preserved in hypertensive patients.

The clinical implication of the rightward shift of the lower autoregulation threshold is that, with decreases in blood pressure (due to hemorrhage, shock, aggressive antihypertensive treatment, deliberate hypotension) hypertensive patients may suffer cerebral ischemia at blood pressure levels well tolerated by normotensive patients. Both the lower limit of autoregulation and the blood pressure at which cerebral hypoxia occurs seem to correlate with the extent to which the resting blood pressure is elevated.

Effect of antihypertensive medications : The vascular changes and autoregulatory shift induced by chronic hypertension are modified by chronic antihypertensive therapy. The extent of regression appears to be related to the length of treatment and correlates with the resultant fall in blood pressure. With regard to acute antihypertensive therapy, the net effect of any antihypertensive drug can be attributed to some combination of the predicted fall in cerebral blood flow that is due to autoregulatory failure and the direct pharmacologic effect of the drug on the cerebral vasculature in the chronically hypertensive subject. Barry and coworkers have proposed a system for categorizing the effects of antihypertensive agents on autoregulatory phenomena as follows:

Group 1: Systemic direct vasodilators—without an action on cerebrovascular smooth muscle
Group 2: Systemic direct vasodilators—with an action on cerebrovascular smooth muscle
Group 3: α-Adrenergic receptor and ganglion-blocking agents
Group 4: Converting enzyme inhibitors

Agents in groups 1 and 3 do not have an effect on cerebrovascular autoregulation, in that they do not independently influence cerebrovascular tone. On the other hand, vasodilators that affect either the conductance or resistance vessels in the brain, such as hydralazine, sodium nitroprusside (SNP), nitroglycerin, and calcium channel blockers, may influence autoregulation.

Captopril appears to foreshorten the autoregulatory plateau, but it shifts the autoregulatory curve to the left. This shift probably accounts for the fact that patients with captopril-treated congestive heart failure tolerate lower perfusion pressure without evidence of cerebral ischemia than untreated patients. This tolerance may be due to direct involvement of the renin–angiotensin system in maintaining some influence on resting cerebrovascular tone or alleviation of sympathetically mediated conductance vessel constriction in low cardiac output states. Treatment of congestive heart failure may also improve cerebral perfusion by lowering central venous pressure, thus reducing cerebral venous outflow resistance and improving CPP.

Hypertension in Patients With Traumatic Brain Injury

Hypertension is the most common cardiovascular complication of TBI, particularly via catecholamine release. The trigger for catecholamine release could be increased ICP or regional ischemia. The effects of hypertension on the brain may be worsened during TBI because of impairment of cerebral autoregulation and capillary endothelium. Impaired arterioles fail to constrict in response to hypertension, leading to increases in cerebral blood flow, volume, and pressure and higher risk of cerebral edema. Also, impaired arterioles may fail to dilate in response to hypotension, leading to decreased cerebral perfusion. A Cushing response, in which bradycardia accompanies the hypertension, may occur. Patients with chronic hypertension are at increased risk of hypoperfusion owing to rightward shift of the autoregulation curve. Although the optimal CPP value is not well defined, the Traumatic Brain Injury Foundation recommends keeping CPP 50–70 mmHg. In general, systemic hypertension is treated when systolic blood pressure exceeds 200 mmHg.

Management of Hypertension in Traumatic Brain Injury

1.
The most common antihypertensive agents used in TBI are β-blockers because they treat not only hypertension but also complications of excessive catecholamine release such as tachyarrhythmias, myocardial ischemia, and immune suppression.

Esmolol is an ultrashort acting β1-adrenergic blocker that is suitable for use as a continuous IV infusion (500 μg/kg over 1 min, then 50–200 μg/kg/min).

The β1-adrenergic blocker metoprolol has a longer half-life than esmolol and is commonly used in the setting of myocardial ischemia and acute myocardial infarction (5 mg IV every 5–15 min to a total of 15 mg).

Labetalol, an α1- and β-adrenergic blocker, has an α1/β blocking ratio of 1:7. It has rapid onset but long (5 h) duration of action (initial dose 10–20 mg, then 40–80 mg/10 min to a total dose of 300 mg, then 2 mg/min infusion). It is commonly used in neurosurgical patients because it does not increase ICP.

All β-blockers carry the risk of bronchospasm or exacerbation of heart failure in a decompensated patient.
2.
Vasodilators are generally avoided in neurosurgical patients because they may cause cerebrovascular dilation, resulting in increased cerebral blood flow, increased ICP, and cerebral edema. Hence they are usually preferred after dura mater is opened.

Short-acting vasodilators such as SNP (0.25–10 μg/kg/min) and, to a lesser extent, nitroglycerin (0.25–5 μg/kg/min) are excellent in achieving acute titration of blood pressure.

SNP is a rapid-onset, short-acting drug that causes vascular dilation (arteriolar more than venous) through the release of endothelial nitric oxide. It is particularly useful in cases of severe hypertension or when other drugs fail to control blood pressure adequately. It is best used in conjunction with esmolol, which enhances its antihypertensive effects while counteracting its reflex tachycardia effects. SNP dosage is titrated down slowly to avoid rebound hypertension due to the activation of the renin–angiotensin system. Duration of use should be limited to less than 24–48 h to decrease the risk of tachyphylaxis and cyanide toxicity. The latter interferes with cytochrome oxidase, resulting in cellular hypoxia, metabolic acidosis, and increased mixed venous oxygen content. Treatment consists of stopping the SNP infusion and administration of an antidote such as amyl nitrite (inhalation), sodium nitrite (3%, 10 mL), sodium thiosulfate (25%, 50 mL), or hydroxocobalamin (5 g IV). Nitroglycerin causes more venous than arteriolar dilation, leading to decreased venous return and cardiac output, and may raise ICP, particularly in patients with reduced intracranial compliance. It may cause hypoxemia by increasing ventilation–perfusion mismatch due to inhibition of hypoxic regional vasoconstriction in the lungs. It causes minimal or no reflex tachycardia.

Hydralazine is a direct, arteriolar, smooth muscle dilator that decreases systemic vascular resistance and blood pressure and may result in reflex tachycardia and increased ICP.
3.
Treatment of increased ICP by evacuation of hematoma or drainage of cerebrospinal fluid significantly facilitates treatment of hypertension and achievement of adequate CPP. Assessing the adequacy of CPP in meeting the metabolic needs of the brain is facilitated by measuring jugular venous oxygen saturation or brain tissue oxygen partial pressure. Cerebral microdialysis is a well-established laboratory tool that is increasingly used as a bedside monitor to provide online analysis of brain tissue biochemistry during neurointensive care in some centers.

Perioperative Management

Hypertensive neurosurgical patients undergo several diagnostic (computed tomography, magnetic resonance imaging, positron emission tomography) and therapeutic (interventional neuroradiology, radiosurgery, neurosurgery) procedures that may require anesthesia. Anesthetic management of these patients follows general goals of neuroanesthesia to maintain adequate CPP and to prevent increases in ICP, and it focuses on preventing and managing serious perioperative complications such as intracranial bleeding. The following discussion of perioperative anesthetic management concentrates on anesthesia for neuroradiologic and intraoperative procedures.

Preoperative Evaluation

Special attention is given to cause and severity of hypertension, current therapy, adequacy of blood pressure control and evidence of end organ damage. When hypertension is detected during preoperative evaluation, by measurement or history, screenings for secondary hypertension and end organ damage are as important as blood pressure control.

End organ damage evaluation is discussed in Table 44.2 .

Table 44.2

Pathological Changes in Target Organs and Diagnostic Investigations

Target Organ	Pathological Changes Due to Hypertension	Investigations
Heart	LVH, myocardial ischemia, hypertensive cardiomyopathy, coronary artery disease	ECG, ECHO, TMT
Kidney	Renal impairment, hypertensive nephropathy	Hypervolemia, serum urea, creatinine, and electrolytes
Brain	Transient ischemic attacks, cerebrovascular accidents	CT scan, MRI, MR angiography, neck vessel doppler

CT , computed tomography; ECG , electrocardiography; ECHO , echocardiogram; LVH , left ventricular hypertrophy; MR , magnetic resonance; MRI , magnetic resonance imaging; TMT , treadmill test.

It is advantageous to review the pharmacology and potential side effects of the drugs being used for antihypertensive therapy.

Antihypertensive Drugs ( Table 44.3 )

Premedication

Depending on the neurological status and monitored care, anxiolytics should be prescribed judiciously in neurosurgical patients. Antihypertensives like angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and diuretics are avoided on the day of surgery. Intravascular volume status evaluation is important if neurosurgical patients are on decongestants.

Table 44.3

Specific Classes of Antihypertensive Agents and Their Implications in Anesthesia

Class of Drug	Examples	Relevance to Anesthesia
Vasodilators	Hydralazine	Tachycardia
Central sympatholytics	Clonidine, methyldopa	Rebound hypertension if withdrawn
Adrenergic neuron blockers	Guanethidine	Sensitive to vasopressors, postural hypotension
α-Blockers	Phenoxybenzamine, prazosin	Tachycardia, orthostatic hypotension
Angiotensin-converting enzyme inhibitors	Captopril, enalapril	Resistant hypotension
Angiotensin receptor blockers	Telmisartan, losartan	Hypotension refractory to conventional vasoconstrictors such as ephedrine and phenylephrine, necessitating use of vasopressin
β-Blockers	Atenolol, labetalol	Contraindicated in asthma, overt CHF, peripheral vascular disease. Obtund tachycardia associated with blood loss
Calcium channel blockers	Nifedipine, verapamil	Vasodilators and cardiac depressants may cause precipitous hypotension
Diuretics	Thiazide, furosemide	Electrolyte disturbances especially hypokalemia

CHF , congestive heart failure.

Intraoperative Management

Vascular Access

The likelihood for significant intraoperative blood loss should be discussed preoperatively with the neurosurgeon. Large-bore IV accesses for rapid blood administration and availability of appropriate blood products are mandatory. Preoperative planning should include consideration of a central venous catheter for both monitoring and provision of vasoactive drugs.

Monitoring

In addition to routine monitors like electrocardiogram, pulse oximeter, end-tidal CO ₂ , and temperature; intra-arterial catheters are routinely used during neurosurgeries for continuous, direct blood pressure monitoring and arterial blood sampling. Central venous catheters should be considered when there is a high risk for significant intraoperative blood loss, evidence of left ventricular dysfunction, or significant renal dysfunction. Urine output monitoring is simple but important bedside tool for monitoring volume status and renal perfusion.

Induction of Anesthesia

Anesthetic management should be directed toward avoidance of wide fluctuations in blood pressure. If patient shows significant hypertension in induction area, analgesia and sedation (e.g., midazolam 0.5–2 mg and/or fentanyl 25–100 μg or sufentanil 5–20 μg) may be provided while placing preoperative vascular access and monitoring devices by small, titrated, and IV increments under the direct and continuing control and observation of the anesthesiologist. The use of opioids will reduce the amount of induction agent required. Etomidate provides better cardiovascular stability, but thiopentone and propofol may be used if administered in titrated doses. Smooth, gentle, and fast laryngoscopy and intubation is performed after suitable muscle relaxant is administered to prevent pressor response and tachycardia. Muscle relaxant like vecuronium is preferred in contrast to pancuronium, which causes tachycardia. The therapeutic armamentarium to counteract hypertensive responses includes a wide variety of drugs ( Table 44.4 ). The ideal anesthetic drug and method would have a rapid onset of action, preserve hemodynamic stability, would be convenient to use, and would have duration of action to fit particular situation.

Table 44.4

Drugs to Counteract Hypertensive Responses

Drugs	Dose
Lidocaine	1–1.5 mg/kg, 2 min prior to stimulus laryngoscopy
IV induction agents-Propofol	Titrated
Opioids fentanyl Sufentanil Remifentanil	1.5–3 μg/kg
Opioids fentanyl Sufentanil Remifentanil	Titrated
β-Blockers Esmolol	1–2 mg/kg
Magnesium sulfate	30–40 mg/kg, 2 min prior to stimulus

Maintenance of Anesthesia

Management of intraoperative blood pressure lability is equally important as preoperative control of hypertension in these patients. Hypertension during anesthesia may reflect inadequate depth of anesthesia, hypoxia, or hypercarbia due to inadequate ventilation. These factors should be corrected before treating with antihypertensives. The reduced left ventricular compliance and more rigid vascular tree found in hypertensives make them vulnerable to small changes in blood volume. Furthermore, β-blockers prevent the physiological heart rate changes, whereas vasodilators prevent vasoconstrictive response, hence warranting careful monitoring and correction of any hypovolemia to prevent hypotension. Surgical steps like application and removal of head pins, insertion of nasal speculum, and infiltration with vasoconstrictive adrenaline need increasing depth of anesthesia and fentanyl boluses to prevent pressor response. Many a times, the cause of accelerated hypertension is brain manipulation especially in posterior fossa surgeries. In such scenario, surgeon should be informed and modification in surgical technique can be helpful.

Recovery From Anesthesia

Every effort should be made to prevent coughing and straining on the endotracheal tube, which may cause catastrophic intracranial hemorrhage. Prevention may be facilitated through the administration of lidocaine 75–100 mg and fentanyl 25–50 μg at the end of the operation. Because placement of the head dressing is associated with movement that produces airway stimulation and “bucking” of the patient on the endotracheal tube, it is appropriate to maintain neuromuscular blockade until the dressing has been secured. These guidelines do not apply to patients who were obtunded preoperatively or who had a significantly complicated intraoperative course with bleeding, brain swelling, or ischemia. Such patients should remain intubated until their neurologic status can be evaluated. Planned airway management and accordingly judicious use of sedatives and analgesics is needed. Adequate pain management and ventilation management is required to prevent pressor response especially in hypertensive patients.

Postoperative Care

Hypertensive neurosurgical patients require meticulous monitoring in the postoperative period. Postoperative cognitive dysfunction is common following major neurosurgical procedures in elderly patients. One possible mechanism for this complication is intraoperative cerebral ischemia. Persistent postoperative hypertension in a previously normotensive patient should alert the anesthesiologist to possible brainstem compression, ischemia, or hematoma especially in posterior fossa surgeries. Adequate pain management (local anesthetic infiltration at incision site and nerve blocks can be the options) and ventilation management is required to prevent pressor response. Hypertension may also be the result of intravascular volume overload from excessive intraoperative IV fluid therapy, and it persists until the fluid has been mobilized from the extravascular space. Blood pressure can also rise due to discontinuation of antihypertensive medications. Postoperatively antihypertensive medications can be resumed via suitable route of administration under supervision.

Neurocritical Care

Hypertensive emergencies (severe blood pressure elevations, >180/110 mmHg) that are complicated by evidence of acute or ongoing target organ dysfunctions require immediate blood pressure reduction to limit end organ damages. Since hypertensive urgencies are not associated with progressive end organ dysfunctions, they demand less rapid reduction in blood pressure. In critical care areas, all precautions should be taken to prevent abrupt blood pressure fluctuations. Care of critically ill, ventilated patients should be done carefully. Brief and smooth suctioning should be done to avoid pressor response. Pharmacological means can be used accordingly.

Conclusion

The goal of controlling perioperative hypertension in hypertensive neurosurgical patients should be individualized as per JNC guidelines. In general, the aim is to prevent neurological complications and end organ hypoperfusion associated with blood pressure fluctuations. Management of the perioperative hypertension in neurosurgical patients is challenging for anesthesiologists.

References

1. Capes S.E., Hunt D., Malmberg K., Pathak P., Gerstein H.C.: Stress hyperglycemia and prognosis of stroke in nondiabetic and diabetic patients: a systematic overview. Stroke 2001; 32: pp. 2426-2432.
2. Williams L.S., Rotich J., Qi R., Fineberg N., Espay A., Bruno A., Fineberg S.E., Tierney W.R.: Effects of admission hyperglycemia on mortality and costs in acute ischemic stroke. Neurology 2002; 59: pp. 67-71.
3. Jeremitsky E., Omert L.A., Dunham C.M., Wilberger J., Rodriguez A.: The impact of hyperglycemia on patients with severe brain injury. J Trauma 2005; 58: pp. 47-50.
4. Passero S., Ciacci G., Ulivelli M.: The influence of diabetes and hyperglycemia on clinical course after intracerebral haemorrhage. Neurology 2003; 61: pp. 1351-1356.
5. Van den Berghe G., Wouters P., Weekers F., Verwaest C., Bruyninckx F., Schetz M., Vlasselaers D., Ferdinande P., Lauwers P., Bouillon R.: Intensive insulin therapy in the critically ill patients. N Engl J Med 2001; 345: pp. 1359-1367.
6. Moghissi E.S., Korytkowski M.T., DiNardo M., Einhorn D., Hellman R., Hirsch I.B., Inzucchi S.E., Ismail-Beigi F., Kirkman M.S., Umpierrez G.E.: American association of clinical endocrinologists and American diabetes association consensus statement on inpatient glycemic control. Diabetes Care 2009; 32: pp. 1119-1131.
7. Turina M., Fry D.E., Polk H.C.: Acute hyperglycemia and the innate immune system: clinical, cellular, and molecular aspects. Crit Care Med 2005; 33: pp. 1624-1633.
8. Prakash A., Matta B.F.: Hyperglycaemia and neurological injury. Curr Opin Anaesth 2008; 21: pp. 565-569.
9. Tomlinson D.R., Gardiner N.J.: Glucose neurotoxicity. Nat Rev Neurosci 2008; 9: pp. 36-45.
10. Oddo M., Schmidt J.M., Mayer S.A., Chiol´ero R.L.: Glucose control after severe brain injury. Curr Opin Clin Nutr Metab Care 2008; 11: pp. 134-139.
11. Godoy D.A., MDi N., Rabinstein A.A.: Treating hyperglycemia in neurocritical patients: benefits and perils. Neurocrit Care 2010; 13: pp. 425-438.
12. Bilotta F., Rosa G.: Glucose management in the neurosurgical patient: are we yet any closer?. Curr Opin Anaesthesiol 2010; 23: pp. 539-543.
13. Kavanagh B.P., McCowen K.C.: Glycemic control in the ICU. N Engl J Med 2010; 363: pp. 2540-2546.
14. Sieber F.E., Traystman R.J.: Special issues: glucose and the brain. Crit Care Med 1992; 20: pp. 104-114.
15. Suh S.W., Hamby A.M., Swanson R.A.: Hypoglycemia, brain energetics, and hypoglycemic neuronal death. GLIA 2007; 55: pp. 1280-1286.
16. Vijaykumar G.: Anaesthesia for diabetic patient. Medicine Update2013. Available from: http://www.apiindia.org/medicine_update_2013/chap47.pdf
17. 1999.World Health OrganizationGeneva (Switzerland) Available at: http://whqlibdoc.who.int/hq/1999/WHO_NCD_NCS_99.2.pdf
18. Cengiz E., Tamborlane W.V.: A tale of two compartments: interstitial versus blood glucose monitoring. Diabetes Technol Ther 2009; 11: pp. S11-S16.
19. Glassberg B.Y.: The arteriovenous difference in blood sugar content. Arch Intern Med 1930; 46: pp. 605-609.
20. Endocrine disorders.Hines R.L.Marschall K.E.Stoelting’s anesthesia and co-existing disease.2008.Churchill LivingstonePhiladelphia:pp. 365-406.
21. Aronson D.: hyperglycemia in the pathobiology of diabetic complications. Adv Cardiol 2008; 45: pp. 1-16.
22. Aragon D., Ring C., Coveli M.: The influence of diabetes mellitus on postoperative infections. Crit Care Nurs Clin North Am 2003; 15: pp. 125-135.
23. Homer-Vanniasinkam S.: Surgical site and vascular infections: treatment and prophylaxis. Int J Infect Dis 2007; 11: pp. S17-S22.
24. Atkins J.H., Smith D.S.: A review of perioperative glucose control in the neurosurgical population. J Diabetes Sci Technol 2009; 3: pp. 1352-1364.
25. Pellerin L., Magistretti P.J.: Food for thought: challenging the dogmas. J Cereb Blood Flow Metab 2003; 23: pp. 1282-1306.
26. Schurr A.: Lactate, glucose and energy metabolism in the ischemic brain (review). Int J Mol Med 2002; 10: pp. 131-136.
27. Schurr A.: Bench-to-bedside review: a possible resolution of the glucose paradox of cerebral ischemia. Crit Care 2002; 6: pp. 330-334.
28. Hutchinson P.J., O’Connell M.T., Al-Rawi P.G., Maskell L.B., Kett-White R., Gupta A.K., Richards H.K., Hutchinson D.B., Kirkpatrick P.J., Pickard J.D.: Clinical cerebral microdialysis: a methodological study. J Neurosurg 2000; 93: pp. 37-43.
29. Payne R.S., Tseng M.T., Schurr A.: The glucose paradox of cerebral ischemia: evidence for corticosterone involvement. Brain Res 2003; 971: pp. 9-17.
30. Pellerin L., Magistretti P.H.: Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization. PNAS 1994; 91: pp. 10625-10629.
31. Bartnik B.L., Hovda D.A., Lee P.W.: Glucose metabolism after traumatic brain injury: estimation of pyruvate carboxylase and pyruvate dehydrogenase flux by mass isotopomer analysis. J Neurotrauma 2007; 24: pp. 181-194.
32. Sutherland G.R., Tyson R.L., Auer R.N.: Truncation of the krebs cycle during hypoglycemic coma. Med Chem 2008; 4: pp. 379-385.
33. Martínez-Sánchez M., Striggow F., Schröder U.H., Kahlert S., Reymann K.G., Reiser G.: Na(+) and Ca(2+) homeostasis pathways, cell death and protection after oxygen-glucose-deprivation in organotypic hippocampal slice cultures. Neuroscience 2004; 128: pp. 729-740.
34. Van den Berghe G., Schoonheydt K., Becx P., Bruyninckx F., Wouters P.J.: Insulin therapy protects the central and peripheral nervous system of intensive care patients. Neurology 2005; 64: pp. 1348-1353.
35. Krinsley J.S.: Effect of an intensive glucose management protocol on the mortality of critically ill adult patients. Mayo Clin Proc 2004; 79: pp. 992-1000.
36. Brownlee M.: Biochemistry and molecular cell biology of diabetic complications. Nature 2001; 414: pp. 813-820.
37. Banting Lecture 2004Brownlee M.: The pathobiology of diabetic complications: a unifying mechanism. Diabetes June 2005; 54: pp. 1615-1625.
38. Black C.T., Hennessey P.J., Andrassy R.J.: Short-term hyperglycaemia depresses immunity through nonenzymatic glycosylation of circulating immunoglobins. J Trauma 1990; 30: pp. 830-832.
39. Esposito K., Nappo F., Marfella R., Giugliano G., Giugliano F., Ciotola M., Quagliaro L., Ceriello A., Giugliano D.: Inflammatory cytokine concentrations are acutely increased by hyperglycaemia in humans. Circulation 2002; 106: pp. 2067-2072.
40. Singh R., Barden A., Mori T., Beilin L.: Advanced glycation endproducts: a review. Diabetologia 2001; 44: pp. 129-146. 46
41. Toth C., Martinez J., Zochodne D.W.: RAGE, diabetes, and the nervous system. Curr Mol Med 2007; 7: pp. 766-776.
42. Falciglia M.: Causes and consequences of hyperglycemia in critical illness. Curr Opin Clin Nutr Metab Care 2007; 10: pp. 498-503.
43. Duckrow R.B., Beard D.C., Brennan R.W.: Regional cerebral blood flow decreases during hyperglycemia. Ann Neurol 1985; 17: pp. 267-272.
44. Kamada H., Yu F., Nito C., Chan P.H.: Influence of hyperglycemia on oxidative stress and matrix metalloproteinase-9 activation after focal cerebral ischemia/reperfusion in rats: relation to blood–brain barrier dysfunction. Stroke 2007; 38: pp. 1044-1049.
45. Banks W.A.: The source of cerebral insulin. Eur J Pharmacol 2004; 490: pp. 5-12.
46. Prado R., Ginsberg M.D., Dietrich W.D., Watson B.D., Busto R.: Hyperglycemia increases infarct size in collaterally perfused but not end-arterial vascular territories. J Cereb Blood Flow Metab 1988; 8: pp. 186-192. 61
47. Hamilton M.G., Tranmer B.I., Auer R.N.: Insulin reduction of cerebral infarction due to transient focal ischemia. J Neurosurg 1995; 82: pp. 262-268.
48. Young M.J., Boulton A.J.M., Macleod A.F., Williams D.R.R., Sonksen P.H.: A multicentre study of the prevalence of diabetic peripheral neuropathy in the United Kingdom hospital clinic population. Diabetologia 1993; 36: pp. 150-154.
49. Russell J.W., Feldman E.L.: Impaired glucose tolerance–does it cause neuropathy?. Muscle Nerve 2001; 24: pp. 1109-1112.
50. Orskov L., Worm M., Schmitz O., Mengel A., Sidenius P.: Nerve conduction velocity in man: influence of glucose, somatostatin and electrolytes. Diabetologia 1994; 37: pp. 1216-1220.
51. Ziegler D., Gries F.A., Spuler M., Lessmann F.: Diabetic Cardiovascular Autonomic Neuropathy Multicenter Study Group: the epidemiology of diabetic neuropathy. J Diabetes Complicat 1992; 6: pp. 49-57.
52. Vinik A.I., Maser R.E., Mitchell B.D., Freeman R.: Diabetic autonomic neuropathy. Diabetes Care 2003; 26: pp. 1553-1579.
53. Defining and Reporting Hypoglycemia in Diabetes. A report from the American Diabetes Association Workgroup on Hypoglycemia American Diabetes Association workgroup on Hypoglycemia. Diabetes Care 2005; 28: pp. 1245-1249.
54. Kosiborod M., Inzucchi S.E., Goyal A., Krumholz H.M., Masoudi F.A., Xiao L., Spertus J.A.: Relationship between spontaneous and iatrogenic hypoglycemia and mortality in patients hospitalized with acute myocardial infarction. JAMA 2009; 301: pp. 1556-1564.
55. Tews J.K., Carter S.H., Stone W.E.: Chemical changes in the brain during insulin hypoglycemia and recovery. J Neurochem 1965; 12: pp. 679-693.
56. Siesjo B.K., Ingvar M., Pelligrino D.: Regional differences in vascular autoregulation in the rat brain in severe insulin-induced hypoglycemia. J Cereb Blood Flow Metab 1983; 3: pp. 478-485.
57. Vespa P.M., McArthur D., O’Phelan K., et. al.: Persistently low extracellular glucose correlates with poor outcome 6 months after human traumatic brain injury despite a lack of increased lactate: a microdialysis study. J Cereb Blood Flow Metab 2003; 23: pp. 865-877.
58. Auer R.N., Olsson Y., Siesko B.K.: Hypoglycemic brain injury in the rat. Diabetes 1984; 33: pp. 1090-1098.
59. Marks V.: Hypoglycemia.1981.Blackwell Scientific Publications, Ltd.Oxford
60. Hartings J.A., Gugliotta M., Gilman C., Strong A.J., Tortella F.C., Bullock M.R.: Repetitive cortical spreading depolarizations in a case of severe brain trauma. Neurol Res 2008; 30: pp. 876-882.
61. Strong A.J.: The management of plasma glucose in acute cerebral ischaemia and traumatic brain injury: more research needed. Intensive Care Med 2008; 34: pp. 1169-1172.
62. Watabe T., Tanaka K., Kumagae M., Itoh S., Takeda F., Morio K., Hasegawa M., Horiuchi T., Miyabe S., Shimizu N.: Hormonal responses to insulin-induced hypoglycemia in man. J Clin Endocrinol Metab 1987; 65: pp. 1187-1191.
63. De Feo P., Perriello G., De Cosmo S., Ventura M.M., Campbell P.J., Brunetti P., Gerich J.E., Bolli G.B.: Comparison of glucose counterregulation during short-term and prolonged hypoglycemia in normal humans. Diabetes 1986; 35: pp. 563-569.
64. Silverstein J.M., Musikantow D., Puente E.C., Daphna-Iken D., Bree A.J., Fisher S.J.: Pharmacologic amelioration of severe hypoglycemia-induced neuronal damage. Neurosci Lett 2011; 492: pp. 23-28.
65. Cryer P.E., Davis S.N., Shamoon H.: Hypoglycemia in Diabetes. Diabetes Care 2003; 26: pp. 1902-1912.
66. Auer R.N., Wieloch T., Olsson Y., Siesjö B.K.: The distribution of hypoglycemic brain damage. Acta Neuropathol 1984; 64: pp. 177-191.
67. Siesjo B.K., Bengtsson F.: Calcium fluxes, calcium antagonists, and calcium-related pathology in brain ischemia, hypoglycemia, and spreading depression. A unifying hypothesis. J Cereb Blood Flow Metab 1989; 9: pp. 127-140.
68. Rostami E., Bellander B.M.: Monitoring of glucose in brain, adipose tissue, and peripheral blood in patients with traumatic brain injury: a microdialysis study. J Diabetes Sci Technol 2011; 5: pp. 596-604.
69. Rosner M.J., Newsome H.H., Becker D.P.: Mechanical brain injury: the sympathoadrenal response. J Neurosurg 1984; 61: pp. 76-86.
70. Umpierrez G.E., Isaac S.D., Bazargan N., You X., Thaler L.M., Kitabchi A.E.: Hyperglycaemia: an independent marker of in-hospital mortality in patients with undiagnosed diabetes. J Clin Endocrinol Metab 2002; 87: pp. 978-982.
71. Berghe Van den G., Wouters P.J., Kesteloot K., Hilleman D.E.: Analysis of healthcare resource utilization with intensive insulin therapy in critically ill patients. Crit Care Med 2006; 34: pp. 612-616.
72. Bilotta F., Caramia R., Cernak I., Paoloni F.P., Doronzio A., Cuzzone V., Santoro A., Rosa G.: Intensive insulin therapy after severe traumatic brain injury: a randomized clinical trial. Neurocrit Care 2008; 9: pp. 159-166.
73. Bilotta F., Caramia R., Paoloni F.P., Delfini R., Rosa G.: Safety and efficacy of intensive insulin therapy in critical neurosurgical patients. Anesthesiology 2009; 110: pp. 611-619.
74. Badjatia N., Topcuoglu M.A., Buonanno F.S., Smith E.E., Nogueira R.G., Rordorf G.A., Carter B.S., Ogilvy C.S., Singhal A.B.: Relationship between hyperglycemia and symptomatic vasospasm after subarachnoid hemorrhage. Crit Care Med 2005; 33: pp. 1603-1609.
75. Kerner A., Schlenk F., Sakowitz O., Haux D., Sarrafzadeh A.: Impact of hyperglycemia on neurological deficits and extracellular glucose levels in aneurysmal subarachnoid hemorrhage patients. Neurol Res 2007; 29: pp. 647-653.
76. Bilotta F., Spinelli A., Giovannini F., Doronzio A., Delfini R., Rosa G.: The effect of intensive insulin therapy on infection rate, vasospasm, neurologic outcome, and mortality in neurointensive care unit after intracranial aneurysm clipping in patients with acute subarachnoid hemorrhage: a randomized prospective pilot trial. J Neurosurg Anesthesiol 2007; 19: pp. 156-160.
77. Thiele R.H., Pouratian N., Zuo Z., Scalzo D.C., Dobbs H.A., Dumont A.S., Kassell N.F., Nemergut E.C.: Strict glucose control does not affect mortality after aneurysmal subarachnoid hemorrhage. Anesthesiology 2009; 110: pp. 603-610.
78. Godoy D.A., Piñero G.R., Svampa S., Papa F., Di Napoli M.: Hyperglycemia and short-term outcome in patients with spontaneous intracerebral hemorrhage. Neurocrit Care 2008; 9: pp. 217-229.
79. Myers R.E., Yamaguchi S.: Nervous system effects of cardiac arrest in monkeys. Preservation of vision. Arch Neurol 1977; 34: pp. 65-74.
80. Pulsinelli W.A., Waldman S., Rawlinson D., Plum F.: Moderate hyperglycemia augments ischemic brain damage: a neuropathologic study in the rat. Neurology 1982; 32: pp. 1239-1246.
81. Lin B., Ginsberg M.D., Busto R.: Hyperglycemic exacerbation of neuronal damage following forebrain ischemia: microglial, astrocytic and endothelial alterations. Acta Neuropathol 1998; 96: pp. 610-620.
82. Nielson C., Fleming R.M.: Blood glucose and cerebrovascular disease in nondiabetic patients. Angiology 2007; 58: pp. 625-629.
83. Stead L.G., Gilmore R.M., Bellolio M.F., Mishra S., Bhagra A., Vaidyanathan L., Decker W.W., Brown R.: Hyperglycemia as an independent predictor of worse outcome in nondiabetic patients presenting with acute ischemic stroke. Neurocrit Care 2009; 10: pp. 181-186.
84. Glucose–potassium–insulin infusions in the management of post stroke hyperglycaemia. The United Kingdom Glucose Insulin in Stroke Trial (GIST-UK): a randomised controlled trial. Lancet Neurol 2007; 6: pp. 397-406.
85. Talke P.O., Sharma D., Heyer E.J., et. al.: Society for Neuroscience in Anesthesiology and Critical Care Expert consensus statement: anesthetic management of endovascular treatment for acute ischemic stroke: endorsed by the Society of NeuroInterventional Surgery and the Neurocritical Care Society. J Neurosurg Anesthesiol 2014; 26: pp. 95-108.
86. Kirkman M.A., Citerio G., Smith M.: The intensive care management of acute ischemic stroke: an overview. Intensive Care Med 2014; 40: pp. 640-653.
87. Sieber F., Smith D.S., Kupferberg J., Crosby L., Uzzell B., Buzby G., March K., Nann L.: Effects of intraoperative glucose on protein catabolism and plasma glucose levels in patients with supratentorial tumors. Anesthesiology 1986; 64: pp. 453-459.
88. Woodworth G.F., Chaichana K.L., McGirt M.J., Sciubba D.M., Jallo G.I., Gokaslan Z., Wolinsky J.P., Witham T.F.: Predictors of ambulatory function after surgical resection of intramedullary spinal cord tumors. Neurosurgery 2007; 61: pp. 99-105. discussion 105–106
89. Dhinsa B.S., Khan W.S., Puri A.: Management of the patient with diabetes in the perioperative period. J Perioper Pract 2010; 20: pp. 364-367.
90. Girard M., Schricker T.: Perioperative glucose control: living in uncertain times-continuing professional development. Can J Anesth 2011; 58: pp. 312-329.
91. Kokil G.R., Rewatkar P.V., Verma A., Thareja S., Naik S.R.: Pharmacology and chemistry of diabetes mellitus and antidiabetic drugs: a critical review. Curr Med Chem 2010; 17: pp. 4405-4423.
92. Krentz A.J., Bailey C.J.: Oral antidiabetic agents: current role in type 2 diabetes mellitus. Drugs 2005; 65: pp. 385-411.
93. Cryer P.E.: Hypoglycemia, functional brain failure, and brain death. J Clin Invest 2007; 117: pp. 868-870.
94. McCormick M.T., Muir K.W., Gray C.S., Walters M.R.: Management of hyperglycemia in acute stroke: how, when, and for whom?. Stroke 2008; 39: pp. 2177-2185.
95. Van den Berghe G., Wilmer A., Hermans G., Meersseman W., Wouters P.J., Milants I., Van Wijngaerden E., Bobbaers H., Bouillon R.: Intensive insulin therapy in the medical intensive care unit. N Engl J Med 2006; 354: pp. 449-461.
96. Brunkhorst F.M., Engel C., Bloos F., Meier-Hellmann A., Ragaller M., Weiler N., Moerer O., Gruendling M., Oppert M., Grond S., Olthoff D., Jaschinski U., John S., Rossaint R., Welte T., Schaefer M., Kern P., Kuhnt E., Kiehntopf M., Hartog C., Natanson C., Loeffler M., Reinhart K.: Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 2008; 358: pp. 125-139.
97. Wiener R.S., Wiener D.C., Larson R.J.: Benefits and risks of tight glucose control in critically ill adults: a meta-analysis. J Am Med Assoc 2008; 300: pp. 933-944.
98. Meier R., Béchir M., Ludwig S., Sommerfeld J., Keel M., Steiger P., Stocker R., Stover J.F.: Differential temporal profile of lowered blood glucose levels (3.5 to 6.5 mmol/l versus 5 to 8 mmol/l) in patients with severe traumatic brain injury. Crit Care 2008; 12: pp. R98.
99. Kramer A.H., Roberts D.J., Zygun D.A.: Optimal glycemic control in neurocritical care patients: a systematic review and meta-analysis. Crit Care 2012; 16: pp. R203.
100. Egi M., Bellomo R.: Reducing glycemic variability in intensive care unit patients: a new therapeutic target?. J Diabetes Sci Technol 2009; 3: pp. 1302-1308.
101. Waeschle R.M., Moerer O., Hilgers R., Herrmann P., Neumann P., Quintel M.: The impact of the severity of sepsis on the risk of hypoglycaemia and glycaemic variability. Crit Care 2008; 12: pp. R129.
102. Kinoshita K., Moriya T., Utagawa A., et. al.: Change in brain glucose after enteral nutrition in subarachnoid hemorrhage. J Surg Res 2010; 162: pp. 221-224.
103. Krenitsky J.: Glucose control in the intensive care unit: a nutrition support perspective. Nutr Clin Pract 2011; 26: pp. 31-43.
104. Kearney P.M., Whelton M., Reynolds K., Muntner P., Whelton P.K., He J.: Global burden of hypertension: analysis of worldwide data. Lancet 2005; 365: pp. 217-223.
105. James P.A., Oparil S., Carter B.L., Cushman W.C., Dennison-Himmelfarb C., Handler J., Lackland D.T., LeFevre M.L., MacKenzie T.D., Ogedegbe O., Smith S.C., Svetkey L.P., Taler S.J., Townsend R.R., Wright J.T., Narva A.S., Ortiz E.: 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014; 311: pp. 507-520.
106. Fieschi C., Agnoli A., Battistini N.: Derangement of regional cerebral blood flow and its regulatory mechanisms in acute cerebrovascular disease. Neurology 1968; 18: pp. 1166-1171.
107. Hulme A., Cooper R.: Changes in intracranial pressure and other variables during the induction of general anaesthesia. Proc R Soc Med 1972; 65: pp. 883-887.
108. Leech P., Barker J., Fitch W.: Changes in intracranial pressure and systemic arterial pressure during the termination of anaesthesia. Brit J Anaesth 1974; 46: pp. 315-316.
109. Van Aken H., Puchstein C., Hidding J.: The prevention of hypertension at intubation. correspondence. Anaesthesia 1982; 37: pp. 82-83.
110. Fein J.M., Lipow K., Marmarou A.: Cortical artery pressure in normotensive and hypertensive aneurysm patients. J Neurosurg 1983; 59: pp. 51-56.
111. Strandgaard S.: The lower and upper limits for autoregulation of cerebral blood flow [abstract]. Stroke 1973; 4: pp. 323.
112. Joshi S., Young W.L., Pile-Spellman J., Duong D.H., Hacein-Bey L., Vang M.C., Marshall R.S., Ostapkovich N., Jackson T.: Manipulation of cerebrovascular resistance during internal carotid artery occlusion by intraarterial verapamil. Anesth Analg 1997; 85: pp. 753-759.
113. Joshi S., Hashimoto T., Ostapkovich N., Pile-Spellman J., Duong D.H., Hacein-Bey L., Marshall R.S., James D.J., Young W.L.: Effect of intracarotid papaverine on human cerebral blood flow and vascular resistance during acute hemispheric arterial hypotension. J Neurosurg Anesthesiol 2001; 13: pp. 146-151.
114. Nordborg C., Johansson B.B.: Morphometric study on cerebral vessels in spontaneously hypertensive rats. Stroke 1980; 11: pp. 266-270.
115. Sadoshima S., Fujii K., Yao H., Kusuda K., Ibayashi S., Fujishima M.: Regional cerebral blood flow autoregulation in normotensive and spontaneously hypertensive rats: effects of sympathetic denervation. Stroke 1986; 17: pp. 981-984.
116. Forster A., Van Horn K., Marshall L.F., Shapiro H.M.: Anesthetic effects on blood–brain barrier function during acute arterial hypertension. Anesthesiology 1978; 49: pp. 26-30.
117. Lassen N.A.: Cerebral blood flow and oxygen consumption in man. Physiol Rev 1959; 39: pp. 183-238.
118. Strandgaard S., Olesen J., Skinhoj E., Lassen N.A.: Autoregulation of brain circulation in severe arterial hypertension. Br Med J 1973; 1: pp. 507-510.
119. Hoffman W.E., Miletich D.J., Albrecht R.F.: Cerebrovascular response to hypotension in hypertensive rats: effect of antihypertensive therapy. Anesthesiology 1983; 58: pp. 326-332.
120. Vorstrup S., Barry D.I., Jarden J.O., Svendsen U.G., Braendstrup O., Graham D.I., Strandgaard S.: Chronic antihypertensive treatment in the rat reverses hypertension-induced changes in cerebral blood flow autoregulation. Stroke 1984; 15: pp. 312-318.
121. Fujishima M., Ibayashi S., Fujii K., Yao H., Sadoshima S.: Effects of long-term antihypertensive treatment on cerebral, thalamic and cerebellar blood flow in spontaneously hypertensive rats (SHR). Stroke 1986; 17: pp. 985-988.
122. Hoffman W.E., Albrecht R.F., Miletich D.J.: The influence of aging and hypertension on cerebral autoregulation. Brain Res 1981; 214: pp. 196-199.
123. Barry D.I., Paulson O.B., Jarden J.O., Juhler M., Graham D.I., Strandgaard S.: Effects of captopril on cerebral blood flow in normotensive and hypertensive rats. Am J Med 1984; 76: pp. 79-85.
124. Hoffman W.E., Albrecht R.F., Miletich D.J.: Nitroglycerin induced hypotension will maintain CBF in hypertensive rats. Stroke 1982; 13: pp. 225-228.
125. Pearson R.M., Griffith D.N., Woollard M., James I.M., Havard C.W.: Comparison of effects on cerebral blood flow of rapid reduction in systemic arterial pressure by diazoxide and labetalol in hypertensive patients: preliminary findings. Br J Clin Pharmacol 1979; 8: pp. 195S-198S.
126. Barry D.I., Jarden J.O., Paulson O.B., Graham D.I., Strandgaard S.: Cerebrovascular aspects of converting-enzyme inhibition. I: effects of intravenous captopril in spontaneously hypertensive and normotensive rats. J Hypertens 1984; 2: pp. 589-597.
127. Naritomi H., Meyer J.S., Sakai F., Yamaguchi F., Shaw T.: Effects of advancing age on regional cerebral blood flow: studies in normal subjects and subjects with risk factors for atherothrombotic stroke. Arch Neurol 1979; 36: pp. 410-416.
128. Sullivan H.G., Kingsbury T.B., Morgan M.E., Jeffcoat R.D., Allison J.D., Goode J.J., McDonnell D.E.: The rCBF response to Diamox in normal subjects and cerebrovascular disease patients. J Neurosurg 1987; 67: pp. 525-534.
129. Clifton G.L., Robertson C.S., Kyper K., Taylor A.A., Dhekne R.D., Grossman R.G.: Cardiovascular response to severe head injury. J Neurosurg 1983; 59: pp. 447-454.
130. Clifton G.L., Ziegler M.G., Grossman R.G.: Circulating catecholamines and sympathetic activity after head injury. Neurosurgery 1981; 8: pp. 10-14.
131. Enevoldsen E.M., Jensen F.T.: Autoregulation and CO2 responses of cerebral blood flow in patients with acute severe head injury. J Neurosurg 1978; 48: pp. 689-703.
132. Cushing H.: Concerning a definite regulatory mechanism of the vasomotor center which controls blood pressure during cerebral compression. Johns Hopkins Hosp Bull 1901; 12: pp. 290.
133. The Brain Trauma Foundation. The American Association of Neurological Surgeons. The Joint Section on Neurotrauma and Critical Care. Guidelines for cerebral perfusion pressure. J Neurotrauma 2000; 17: pp. 507-511.
134. Neil-Dwyer G., Cruickshank J., Stratton C.: Beta-blockers, plasma total creatine kinase and creatine kinase myocardial isoenzyme, and the prognosis of subarachnoid hemorrhage. Surg Neurol 1986; 25: pp. 163-168.
135. Neil-Dwyer G., Walter P., Cruickshank J.M., Doshi B., O’Gorman P.: Effect of propranolol and phentolamine on myocardial necrosis after subarachnoid hemorrhage. Br Med J 1978; 2: pp. 990-992.
136. Cottrell J.E., Patel K., Turndorf H., Ransohoff J.: Intracranial pressure changes induced by sodium nitroprusside in patients with intracranial mass lesions. J Neurosurg 1978; 48: pp. 329-331.
137. Marsh M.L., Shapiro H.M., Smith R.W., Marshall L.F.: Changes in neurologic status and intracranial pressure associated with sodium nitroprusside administration. Anesthesiology 1979; 51: pp. 336-338.
138. Turner J.M., Powell D., Gibson R.M., McDowall D.G.: Intracranial pressure changes in neurosurgical patients during hypotension induced with sodium nitroprusside or trimethaphan. Br J Anaesth 1977; 49: pp. 419-425.
139. Cottrell J.E., Gupta B., Rappaport H., Turndorf H., Ransohoff J., Flamm E.S.: Intracranial pressure during nitroglycerin induced hypotension. J Neurosurg 1980; 53: pp. 309-311.
140. James D.J., Bedford R.F.: Hydralazine for controlled hypotension during neurosurgical operations. Anesth Analg 1982; 61: pp. 1016-1019.
141. Barash P.G.Cullen B.F.Stoelting R.K.Clinical anesthesia.2006.Lippincott Williams & WilkinsPhiladelphia: 481-89,497,946–54
142. Fleisher L.A.: Preoperative evaluation of the patient with hypertension. JAMA 2002; 287: pp. 2043-2046.
143. Aronson S., Fontes M.L.: Hypertension: a new look at an old problem. Curr Opin Anesth 2006; 19: pp. 59-64.
144. Braunwald E.: Systemic hypertension: mechanisms and diagnosis. Heart disease6th ed.2001.WB SaundersPhiladelphiapp. 950-955.
145. Franklin S.S.: Systolic blood pressure: it’s time to take control. Am J Hypertens 2004; 17: pp. 49S-54S.
146. Barash P.G.Cullen B.F.Stoelting R.K.Clinical anesthesia.2006.Lippincott Williams & WilkinsPhiladelphia:pp. 330-331.
147. Stoelting R.K., Diedorf S.F.: Anesthesia and co-existing disease.4th ed.2002.Churchill Living stoneNew Yorkpp. 99-103.
148. Gal T.J., Cooperman L.H.: Hypertension in the immediate postoperative period. Br J Anesth 1975; 47: pp. 70. Monk TG
149. Weldon B.C., Garvan C.W., Dede D.E., van der Aa M.T., Heilman K.M., Gravenstein J.S.: Predictors of cognitive dysfunction after major noncardiac surgery. Anesthesiology 2008; 108: pp. 18-30.