Neurophysiology: Introduction to Neuroscience Critical Care

1. Neurophysiology: Introduction to Neuroscience Critical Care

2. Outline • Normal physiology of cerebral metabolism and circulation • Regulation of cerebral blood flow • Autoregulation • The pathophysiology of traumatic brain injury • Primary brain injury • Secondary brain injury • Biomechanical considerations in traumatic brain injury • Mechanism of secondary injury • Raised intracranial pressure • Neurological intensive care monitoring

3. Normal physiology of cerebral metabolism and circulation • Glucose is the sole energy substrate of the brain, unless there is ketosis. • Two terms are common in reference to metabolic turnover of glucose and oxygen: the cerebral metabolic rate of oxygen and the cerebral metabolic rate of glucose. • In awake adults the cerebral metabolic rate of oxygen is approximately 3.3 mg/100 g/min and the cerebral metabolic rate of glucose is 5.5 mg/100 g/min.

4. 50% of consumed energy is used for interneuronal communication (generation, release, and uptake of neurotransmitters); 25% is used for maintenance and restoration of ionic gradients across the cell membrane; and the remaining 25% is used for molecular transport, biosynthesis, and other as yet unidentified processes.. • Glial cells that make up almost 50% of the brain have a much lower metabolic rate than neurons and account for less than 10% of total cerebral energy expenditure. • The brain accounts for only 2-3% of total body weight and does not do any mechanical work, yet it receives 20% of all cardiac output.

5. Regulation of cerebral blood flow • Substrate availability is determined by three factors: concentration of substrate in blood, flow volume, and rate of substrate passage across the blood brain barrier. • Usually the brain is able to maintain an adequate supply of substrates by regulation of cerebral blood flow. • Control of cerebral blood flow by adjustment in vessel diameter is common referred to as autoregulation. • Several mechanisms active under different circumstances have been described: • Metabolic autoregulation • Pressure autoregulation • Viscosity autoregulation

6. Metabolic autoregulation • Cerebral blood flow is coupled to cerebral metabolism, changing proportionally with increasing or decreasing metabolic demands. • Because 95% of the energy in the normal brain is generated by oxidative metabolism, cerebral metabolic rate of oxygen is considered a sensitive measure of cerebral metabolism. • In general, the brain responds to alterations in metabolism by changes in flow and thus has a tendency to keep AVDO2 relatively constant.

7. Pressure autoregulation • Changes in cerebral perfusion pressure will be followed by changes in cerebral blood flow unless diameter regulation takes place. • Flow remains constant to defend AVDO2 • This type of autoregulation is termed pressure autoregulation and is the type of autoregulation referred to in most papers on autoregulation after head injury. • The limits of pressure autoregulation range from 40 to 150 mm of mercury of perfusion pressure. • Beyond these limits, vessel caliber follows flow passively leading to collapse of vessels at low pressure and forced dilatation or pressure breakthrough at high pressures.

9. Viscosity autoregulation • Cerebral blood flow can vary with changes in the viscosity of blood. • Increased viscosity increases cerebral vascular resistance. • By means of diameter adjustment, cerebral vascular resistance is decreased and cerebral blood flow can be kept constant.

10. Theories on autoregulation • It is likely that a similar mechanism is involved in all three types of autoregulation. • Removal of the endothelium significantly reduces the contractions generated in response to various vasoconstrictors. • The observation that rapid elevation of transmural pressure triggers vasoconstriction and that this response is prevented by removal of the endothelium led to the idea that pressure on autoregulation may be endothelium mediated. • Two major endothelium derived contracting factors have been identified: thromboxane A2 and endothelin.

11. Carbon dioxide reactivity • Vascular caliber and cerebral blood flow are also responsive to changes in arterial CO2, a mechanism commonly referred to as CO2 reactivity. • Cerebral blood flow changes 2 to 3% for each mm Hg of CO2 between 20 to 60 mmHg. • Hypercarbia results in vasodilatation and higher cerebral blood flow, and hypocarbia results in vasoconstriction and lower cerebral blood flow. • Vessels respond to pH in the perivascular space. • Over 24 hours the pH in the perivascular space and the diameter of cerebral blood vessels return to baseline.

12. With CO2 reactivity, changes in cerebral blood flow are compensated for by changes in AVDO2, so that a constant supply of substrates is maintained at the level set by metabolism. • In contrast, a constant AVDO2 is a common feature of metabolic, pressure, and viscosity autoregulation.

13. The pathophysiology of traumatic brain injury

14. Primary brain injury • Two pathological processes are uniquely characteristic of trauma: diffuse axonal injury (DAI) and contusion and hematoma formation. • Diffuse axonal injury • Current thought about the development of DAI is that axotomy not complete immediately after the trauma. • Secondary, or delayed axotomy may predominate in many circumstances. • Secondary axotomy begins with an impairment of axoplasmic transport that is initiated, depending on the severity of the injury, by either focal cytoskeletal misalignment or axolemmal permeability changes with concomitant cytoskeletal collapse

15. DAI is primarily a pathological diagnosis. • Traumatic loss of consciousness for less than six hours is considered a concussion. • Traumatic coma lasting longer than six hours is usually attributed to DAI. • Three levels of severity, based on clinical criteria, and are recognized: mild DAI --coma of six to 24 hours duration, moderate DAI -- coma lasting more than 24 hours without decerebrate posturing, and severe DAI -- coma lasting more than 24 hours with decerebrate posturing or flaccidity. • Severe DAI has a 50% mortality.

16. Hematoma and contusion • Subdural hematoma usually results from a torn bridging vein between the cortex and the draining sinuses. • It appears on CT as a high-density, homogenous, crescent shaped mass paralleling the calvaria. • The following CT findings are particularly predictive of outcome: hematoma thickness, midline shift, and presence of underlying brain swelling or contusions.

17. The survival rate is 50% for patients with subdural hematoma is approximately 18 mm thick and with the midline shift of 20 mm. Survival sharply decreases to 0% when the midline shift is more than 25 mm. • A large midline shift that cannot be accounted for by the volume of subdural blood is associated with a poor outcome. • Small subdural hematomas in patients who are not in coma can be managed non-surgically, but most require prompt surgical evacuation.

18. Epidural hematomas are less common. • Only one third of patients with epidural hematomas are unconscious from the time of injury, one third have a lucid interval, and one third are never unconscious. • An epidural hematoma is almost always associated with the skull fracture. • The blood comes from torn dural vessels, usually arterial, from the fractured skull bone, or occasionally from torn venous sinuses. • On CT, an epidural hematoma is characterized by a biconvex, uniformly hyperdense lesion. • Associated brain lesions are less common than with subdural hematomas. • The primary treatment of epidural hematomas is prompt surgical evacuation.

19. Most intracerebral hematomas are visualized as hyperdense mass lesion. • They are usually located in the frontal and temporal lobes and can be detected by CT immediately after the trauma. • However, delayed inter-cerebral hematomas may also manifests during the hospital course. • Contusions appear as heterogeneous areas of brain necrosis, hemorrhage and infarct representing a mix density lesion on CT. • Multiple focal contusions have a salt-and-pepper appearance on CT.

21. Secondary brain injury • Traumatic brain swelling and intracranial hypertension • Edema is the major component of brain swelling after trauma. • Brain edema can be vasogenic (due to opening of the blood brain barrier) or cellular. • Immediate increase in brain water content after trauma is probably vasogenic, whereas the gradual increase in water content that occurs during the first few days after injury is cellular.

22. Clinical manifestation of brain swelling is intracranial hypertension. • 77% of patients with ICP less than 15 mmHg had a favorable outcome, compared with only 43% of patients with ICP greater than 15 mm Hg. • Severe intracranial hypertension can result in secondary injury to the brain through ischemia, produced by a reduction in cerebral perfusion pressure, and it can also distort and compress the brainstem. • Although no randomized clinical trial has addressed this issue, several clinical series have suggested that reducing ICP to less than 20 mmHg reduces mortality after severe head injury.

23. Effect of trauma on cerebral vasculature • An early hypoperfusion phase occurs during the first 24 hours after injury, characterized by low cerebral blood flow and normal middle cerebral artery flow velocity. • This is followed by a hyperemic phase that occurred in about 40% of patients between postinjury days 1-3; cerebral blood flow was transiently increased, with a rapidly rising MCA flow velocity but a normal hemispheric index. • Later (postinjury days 4-15), a vasospasm phase occurs with low normal cerebral blood flow values, a high MCA flow velocity, and an elevated hemispheric index.

24. Biomechanical considerations in traumatic brain injury • The forces experienced by the head during traumatic brain injury are classified as either contact or inertial loading. • Contact forces occur during an impact to the head, and damage occurs when the strain limits of the tissue (usually the skull) is exceeded. • Inertial loading of the head occurs when the brain rotates around an axis of rotation (usually lower c-spine). t= r X F • The torque is frequently two ways with an accleration and deaccleration. • With a moderate amount of torque, the periphery of the brain experiences the highest degree of strain, which can tear bridging veins and result in subdural hematoma. • If the torque is increased, the elevated strains penetrate deeper in the brain and result in diffuse axonal injury.

25. Cerebral circulation and metabolism after severe head injury: mechanisms of secondary injury • Disturbances of cerebral metabolism • The cerebral metabolic rate of oxygen in comatose patients is typically reduced from a normal value of 3.2 mL per 100 g per minute to between 1.2 and 2.3 mL per 100 g per minute. • ATP generation from oxidative metabolism is impaired by either low supply (low cerebral blood flow or hypoxia) or dysfunctional processing (mitochondrial failure). • Acidosis shifts the oxygen dissociation curve to the right, so that oxygen can be extracted more completely from hemoglobin. • Acidosis optimizes the pH for glycolysis and causes vasodilatation of blood vessels thus maximizing the available blood flow. • Functional recovery of tissue in the presence of acid is usually poor however.

26. Disturbances of cerebral blood flow • Cerebral ischemia • Experimental data suggest that the brain becomes more vulnerable to ischemia after head injury. • Metabolic and biochemical derangements and abnormal neurotransmitter receptor interactions reach a lethal threshold when the insults are combined. • Under circumstances of declining cerebral blood flow (due to failure of pressure autoregulation or severe hypotension), the brain can initially protect itself from ischemia and maintain metabolic supply by increasing extraction of the required oxygen from the available blood flow. • Clinically this results in an increase AVDO2.

27. Impaired cerebral vascular reactivity • Metabolic autoregulation • Hyperemia is thought to be most prevalent between one and five days after injury. • It has been assumed that normal cerebral metabolism is depressed after severe head injury. • In fact, cerebral blood flow is functionally coupled to cerebral metabolic rate of glucose. • Therefore increased cerebral blood flow is not necessarily luxury but may occur in response to increase glucose turnover or hyperglycolysis.

28. Pressure autoregulation • Autoregulation is usually impaired during the first few days after head injury with no apparent effect on outcome. • Based on clinical trials, it has been suggested that brainstem lesions damaging a brain stem autoregulatory center may be responsible. • Endothelial free radical damage may also be to blame.

29. Viscosity autoregulation • Cerebral blood flow increases in response to bolus administration of mannitol. • The effect is too fast to be explained by fluid shifts and may be due to decreased viscosity.

30. Carbon dioxide reactivity • CO2 reactivity is usually preserved after severe head injury. • It may be low early after injury, but in most cases, returns to a normal by 24 hours after injury. • Patients with severely impaired CO2 reactivity usually die or are left with severe neurological defects. • The pathological mechanisms leading to disturbed CO2 regulation are poorly understood. Free radicals may play a role.

31. Cerebral blood flow, cerebral blood volume, arteriovenous difference in oxygen, and autoregulation • Cerebral blood flow is influenced by vascular diameter, blood viscosity, and cerebral perfusion pressure, whereas cerebral blood volume is determined by vascular diameter only. • A decrease in cerebral metabolism results in a coupled decrease in cerebral blood flow obtained by vasoconstriction (metabolic autoregulation). • Cerebral blood volume decreases because of reduced vascular diameter, and AVDO2 remains constant because cerebral blood flow is tuned to metabolic demand.

32. A reduction in cerebral perfusion pressure leads to compensatory vasodilatation, or pressure autoregulation, when the latter mechanism is intact. • Cerebral blood flow thus remains the same, but cerebral blood volume increases because of the larger vascular diameter. • Again, metabolism and cerebral blood flow are matched, and AVDO2 stays the same.

33. Under certain circumstances, cerebral perfusion pressure decreases with defective autoregulation. • In this scenario, cerebral blood flow and cerebral blood volume follow the decrease in perfusion pressure passively. • AVDO2 increases, because cerebral blood flow is no longer adequate to meet the metabolic demand.

34. A reduction of blood viscosity, as obtained with mannitol administration, results in vasoconstriction (intact viscosity autoregulation), reduced cerebral blood volume, unchanged or slightly increased cerebral blood flow, and normal AVDO2. • When this mechanism is defective, however, reduce blood viscosity does not induce a vascular response: cerebral blood flow increases, cerebral blood volume remains the same, and AVDO2 decreases.

35. Hypocapnia leads to a reduction in cerebral blood volume due to vasoconstriction. • Cerebral blood flow is also decreased and accompanied by increased oxygen extraction when cerebral blood flow is insufficient to meet the metabolic demand.

36. Raised intracranial pressure • Four parameters describe the static and dynamic CSF pressure: the rate of CSF production, the variable compliance given by the exponential relationship of CSF pressure to volume, the outflow resistance, and the intradural sinus pressure. • The Monro-Kellie doctrine states that the total volume of the intracranial contents (cerebral blood volume, CSF, and brain) is constant. • An increase in one of the three compartments must be accompanied by an equal decrease in one of the other compartments; otherwise ICP will increase.

37. As long as these volume compensations are sufficient, ICP remains relatively constant in the range of eight to 10 mmHg. • However, at a certain volume, this buffering capacity is exhausted, resulting in an exponential increase in pressure with any further volume addition. • There are 4 ways to increase intracranial volume: CSF, cerebral blood volume, blood brain barrier damage associated edema (vasogenic edema), and neurotoxic edema. • CSF components (CSF resistant to outflow and absorption) account for approximately one third of ICP elevation.

38. Cerebral blood flow is determined by the total diameter of the cerebral vascular bed. • Approximately 20 mL of blood (one third of the total cerebral blood volume) is located in the cerebral resistance vessels. • Because most autoregulatory and CO2 dependent diameter variations take place in these vessels, cerebral blood volume is determined mainly by their diameter.

39. Neurological intensive care monitoring • The two most important secondary injury processes they can be monitored, anticipated, and treated in the intensive care unit are intracranial hypertension and cerebral ischemia. • Intracranial hypertension • Monitoring techniques • Although several new types of monitors have been marketed, the ventriculostomy catheter remains the preferred device for monitoring ICP and is the standard against which all new monitors are compared. • The ventriculostomy catheter is positioned with its tip in the frontal horns of the lateral ventricle and is coupled by fluid filled tubing to an external pressure transducer that can be reset to zero and recalibrated against an external standard. • In addition, it allows treatment of elevated ICP by intermittent drainage of CSF.

40. Complications • The two major complications of ICP monitoring are ventriculitis and hemorrhage. • Normal values • Normally, resting ICP is less than 10 mm Hg. • Transient elevations of ICP occurred normally with straining, coughing, or Trendeleburg position. • A sustained ICP greater than 20 mm Hg is clearly abnormal. • An ICP between 20 and 40 mm Hg is considered moderate intracranial hypertension. • An ICP greater than 40 mm Hg represents severe, usually life-threatening intracranial hypertension.

41. Indications for monitoring • All patients with Glasgow Coma Scale scores of 8 or less should have ICP monitoring. • A severe coagulopathy is the only major contraindication to ICP monitoring.

42. Cerebral perfusion • Cerebral perfusion pressure • The simplest measure of cerebral perfusion is CPP, which is calculator by subtracting the ICP from the mean arterial pressure. • The normal lower limit of autoregulation for CPP is 50 mmHg.

43. Transcranial doppler flow velocity • Transcranial doppler ultrasonography uses a pulsed ultrasonic signal in the 2 MHz range that is transmitted through thin areas of the skull. • Blood flow volume and flow velocity are not synonymous. • However, flow volume is directly portion of the flow velocity and can be determined by multiplying the velocity by the cross-sectional area of the vessel. • Because transcranial doppler measures flow velocity in the arteries at the circle of Willis, and because the radius of the vessels is not generally known and the collateral blood flow is variable, transcranial doppler ultrasonography cannot provide quantitative data on regional tissue perfusion.

44. During arterial spasm, flow velocity increases through the narrow segment in proportion to the reduction in the vessels diameter. • Severe vasospasm with a greater than 50% reduction in vessel diameter is associated with flow velocity greater than 200 cm per second. • However, an increase in flow velocity may also reflect hyperemia.

45. To differentiate between these two hemodynamic phenomena, the MCA-extracranial internal carotid artery flow velocity ratio (hemispheric index) is calculated. • In the presence of hyperemia, raised flow velocity in both extracranial and intracranial vessels does not alter the ratio; however, in vasospasm, flow velocity is high in the intracranial vessels, resulting in a high hemispheric index. • The main hemispheric index in normal individuals is 1.76, and pathological values suggestive of vasospasm are generally greater than three.

46. Cerebral blood flow • The stable xenon CT method relies on the radio density of xenon, its inertness, and its rapid diffusion into tissue. • Baseline scans, usually at four levels, or followed by multiple scans at each of the four levels at one minute intervals during inhalation of 28% to 33% of xenon. • The baseline scans are subtracted from the subsequent xenon scans to provide quantitative enhancement values in Hounsfield units. • Clearance curves proportional to brain xenon concentration and arterial concentrations from an end-tidal analyzer are converted into CT enhancement units. • The blood flow is then calculated for each CT voxel.

47. Cerebral blood flow adequacy • Measures of cerebral oxygenation have been used in place of quantitative cerebral blood flow measurements because they indicate the adequacy of cerebral blood flow relative to cerebral metabolic requirements. • When cerebral blood flow is low (25 to 30 mL/100 g/min), it can be difficult to decide whether this is an appropriate response to lower metabolic requirements or whether the brain is hypoperfused

48. Jugular venous oxygen saturation • Initially, increasing oxygen extraction compensates for the reduced cerebral blood flow, and there is no effect on cerebral metabolism. • At this stage, jugular venous oxygenation is decreased, and cerebral metabolic rate for oxygen is unchanged. • As cerebral blood flow decreases further, the brain can no longer compensate fully by increasing oxygen extraction, so cerebral metabolic rate for oxygen falls and cerebral lactate production increases. • Placement of an internal jugular vein catheter, similar to the type used for central venous pressure monitoring but directed upward into the jugular bulb, has allowed repetitive sampling of jugular vein oxygen without repeated needle punctures.

49. The jugular vein oxygenation saturation ranges from 55% to 71% with a mean of 61%. • This is lower than normal mixed venous oxygen saturation, indicating that the brain normally extracts oxygen more completely from arterial blood than do many other organs. • In head injured patients the average jugular venous oxygen saturation is higher than normal, and the range is considerably wider than normal subjects.

50. Brain tissue PO2 • The major limitation of jugular venous oxygen saturation as a monitor of cerebral blood flow adequacy is that regional ischemia cannot be identified. • Normal values for brain tissue PO2 are 20 - 40 mm Hg, and critical reductions are 8 to 10 mm Hg. • Microdialysis catheter • Catheter placed in parachyema to measure metabolic byproducts such as lacate and pyruvate.