Effect of anesthetic drugs and techniques on CBF and CMR

1. Effect of anesthetic drugs and techniques on CBF and CMR Dr Prashant Kumar University College of Medical Sciences & GTB Hospital, Delhi

2. Rationale Why should we know the effect of anesthetic agents on CBF & CMRO2? • CBF - Continuous delivery of energy substrates is dependent on CBF. ↓ can influence neuronal outcome (particularly during ischemia). - CBF & CMR : important etiology of cerebral ischemia • CBF ≈ICP

3. Intravenous anesthetic drugs All IV Induction Agents (except ketamine) ↓ GABAA receptor agonist ↓ Opening of Cl- channel ↓ Inhibition neuronal transmission • Ketamine acts as antagonist on excitatory NMDA receptor

4. Globally all IV Induction Agents (except ketamine) • reduction in CBF & CMR • Slowing of surface EEG ► Deep Level: Burst suppression pattern ► Extremely deep level: Isoelectric pattern

5. Ideal IV anesthetic drugsfor use in neuro anaesthesia • Rapid recovery of consciousness • Easily & rapidly titrable • Minimal effects on other organ systems • Analgesia • Non-epileptogenic (or even anti-epileptogenic)

6. Advantageous effects on cerebral hemodynamics: ►Reduction of CMR coupled with a decrease in CBF ►no increase in ICP (or even reduction in ICP) ► prevention of increase in CBV ►maintenance of cerebrovascular auto regulation ►maintenance of vasoreactivity to CO2

7. Summary IV induction agents

10. ketamine • Antagonist at NMDA receptor • Limited use • In neuroanesthesia: - ► Increase in CBF (but not when used with other sedatives or in a brain injured pts) ► Increase in ICP (but not when used with other sedatives or in a brain injured pts) ► Increase in CMR (particularly in Limbic structures) ► Cerebral protection via NMDA antagonism in animals

11. Commercially available ketamine ►(S) enantiomer → ↑ in CMR ►(R) enantiomer → ↓in CMR, particularly in temporomedial cortex & in cerebellum Anesthetic drugs (diazepam, midazolam, propofol, isoflurane) have been shown to blunt or eliminate ↑ in ICP effect of ketamine.

12. Benzodiazepines • Uses in neuroanesthesia:- ► Premedication ►Limited use as induction agent ► Sedation in ICU (Head injury patients in whom hypothermia is being used)

13. Effects in neuroanesthesia:- ► Modest decrease in CBF ► modest decrease in CMRO2 ► modest decrease in ICP ► maintains autoregulation ► Preserves vasoreactivity to CO2 ► Increases seizure threshold – used as antiepileptic ► Antidote (flumazenil) is available

14. Flumazenil • Highly specific, competitive benzodiazepine antagonist • Reverses the CBF, CMR, ICP lowering effects of BZD.

15. Narcotics • Analgesia • HYPNOTIC SPARING EFFECT” Potentiates the cardiovascular effects of hypnotics (so, with moderate dose of opioids, reduce the dose of hypnotics) ↓ Stable haemodynamics during induction • Increased parasympathetic tone (large dose: Bradycardia)

16. Attenuation of pressure response because of ET intubation, suction, skull pin application. • Improved intra-op hemodynamics with rapid emergence. • Profound synergism b/w resp depressant action of opioid & hypnotics

17. Cerebral hemodynamics ► Modest reduction in CBF & CMRO2 ► No effect on ICP (if MAP is maintained) ► Autoregulation : maintained ► Cerebral vasoreactivity to CO2 maintained ► EEG changes depends on dose (small dose: minimal change)

18. Other concerns with regard to neuro anaesthesia: - • Opioids underused in peri-op period ► fear of sedation, pupillary changes, nausea, cough suppression ↓ Inspite of studies showing that morphine does not ↑S/E • Nausea & vomiting: rare after propofol-remifentanyl anesthesia

19. Impaired gastric emptying • constipation • Ileus • Large intra-op dose: delayed emergence

20. Morphine • Modest reduction in CBF • Reduction in CMR • CBV: ↑ (histamine release) • ICP: ►No Change if MAP is maintained ►↑ 2º to autoregulatory vasodilatation after reduction in MAP

21. Fentanyl • Moderate to large global reduction in CBF & CMR Alfentanyl • No change in CBF, CMR, CBV, ICP. Sufentanyl • No change or slight reduction in CBF & CMR (depending on doses) • ICP ↑ if MAP decreases

22. Remifentanyl • In low dose: minor ↑in CBF • Higher doses or with other anesthetic adjuvant ↓ CBF unaltered or modest reduction • No change in ICP • Used in TIVA

23. Lidocaine • Dose related reduction in CMR & CBF • Membrane stabilizing effect: ↓ CMR • In bolus dose (1.5-2mg/kg): adjunct to the prevention or treatment of ↑ICP. • Lidocaine (1.5mg/kg) Vs thiopentone (3mg/kg)→ equal reduction in ICP [more ↓in MAP with thiopentone ]

24. Total intravenous anesthesia • Use of IV inducing agents with opioids for maintenance of anesthesia: popular • Propofol @3-12mg/kg/hr - suited for prolonged infusion • Blood target level of propofol 4-6μg/ml for induction 2-4μg/ml for maintenance

25. Remifentanyl: • Ideal for use in addition to propofol for maintenance of anesthesia. • Maintenance dose 0.05 to 0.5μg/kg/min TIVA:- • Administered by TCI (for both induction & maintenance) • Improved hemodynamics, especially during induction- beneficial in neurosurgery

26. Muscle relaxants Succinylcholine • Recent studies: SCh causes drug induced↑ICP (independent of other events) • Modest ↑in ICP (5mmHg) in lightly anesthetized humans • In deep anesthesia: no ↑ in ICP • Mechanism of ↑ ICP • Due to cerebral activation • Afferent activity from the muscle spindle apparatus ↓ Although poor correlation between the occurrence of visible muscle fasciculation & ↑ in ICP is seen

27. Prevention of SCh induced ↑ ICP:- • Deep plane of anesthesia • Precurarization • Vecuronium (0.01-0.014mg/kg) • metocurine (0.03mg/kg) • Effect of other defasciculating drugs has not been studies in human

28. Does that mean SCh is C/I In Neurosurgery? • Probably NOT • Change in ICP is modest & transient • ↑ in ICP: not seen in head injured pts ↓ Little reason to avoid SCh when rapid paralysis is required

29. NON DEPOLARIZING MUSCLE RELAXANT: • Extra-ordinary benign effect on CBF & ICP [except large dose of d-TC ]: • ↑ed CBF & ICP through release of histamine • Interaction with phenytoin & other anti-convulsant: • ↑ dose required • ↓ duration of action

30. In presence of neurological deficit • Resistance to NDMR. • So, overdose & difficulty with reversal of anaesthesia. • Effect of histamine on intact BBB is not clear ►direct cerebral vasodilation ►2̊ (autoregulation) response to a reduction in MAP

31. D—TC is most potent histamine releaser: ↑ ICP • Metocurine, atracurium & mivacurium: lesser histamine release. • Cis-atracurium: least histamine releasing effect. No histamine release @ dose 0.15mg/kg (3 times ED95 for twitch suppression) • Vecuronium @ 0.1-0.14mg/kg: no significant effect on cerebral physiology

32. Pipecuronium & rocuronium: No human study but should be similar. • Pancuronium • In large doses, ↑in BP • ↑in ICP in Pts with impaired intracranial compliance & defective autoregulation • Laudanosine - crosses BBB, & is epileptogenic in animals ↓ ↑ CBF, CMR, ICP. • But highly unlikely in Humans

33. Volatile anesthetics Common Effects:- • All ↓ MAP • ↓ in CPP [ dose dependent manner ] • CBF & CMRO2 • Direct vasodilation • ↓ cerebral activity ↓ ↓CMR (reduced need for substrate) ↓ associated vasoconstriction (which balances vasodilation)

34. At > 0.6 MAC, vasodilatory effects predominate:- ↑ CBF • ↑ CBF in face of ↓in CMR : UNCOUPLING • Autoregulation • >0.5 MAC: Impaired autoregulation • Blood flow passively follow BP • Making ischemia or luxury perfusion with edema or hemorrhage more likely

35. Cerebrovascular response to PaCO2: Maintained • Slowing of EEG • VASODILATORY EFFECT: Halothane > enflurane > desflurane= isoflurane > sevoflurane

36. Effect of isoflurane on CBF, CMR & MAP at different MAC

37. Summary: inhalation agents

39. Nitrous Oxide • Alone: stimulatory effect • ↑ CBF, CMR & ICP • Sympatho-adrenal stimulating effects So, CMR may ↑ or ↓ or no change • N2O with IV anesthetics or hypocapnia: • No change in CBF (vasodilatory effects of N2O is attenuated/even completely inhibited)

40. N2O with volatile anesthetics: • Synergism b/w N2O & other volatile anesthetics • ↑in CBF: ↑ ICP • Ideally should not be used in pts with ↑↑ ICP. • Autoregulation: Maintained • Should be avoided in pneumocephalus

42. Xenon • Inert gas • MAC: 63-71%, females lower MAC: 51% • At MAC 1: • CBF: cortex ↓ 15%, cerebellum ↓35%, white matter ↓22% • CMR ↓26%

43. ICP is maintained. • Cerebral autoregulation: Intact • CO2 reactivity: maintained • Diffusion of xenon into air containing spaces occur (less than N2O) • Use of xenon in NS: not evaluated, but data suggests a favorable profile for neuroanesthesia

44. OTHER DRUGS USED IN NEURO SURGICAL PATIENTS • Diuretics • Steroids • Antihypertensive

45. Diuretics Mannitol: • Mainstay of hyperosmolar therapy • Free radical scavenging property • Lack of toxicity • Very low irritant property

46. How does it reduces ICP? • Osmotic diuretics effect: ↓ in ICP • Rheological effect :↓ Blood viscosity→↑ CBF→autoregulatory vasoconstriction →↓ ICP • Dose: 0.25-1gm/kg (slow iv. over 10-15 minutes) • Neurotrauma guidelines • 20% mannitol • @ 2ml/kg • Pts with clinical signs of brain herniation & neurological deteoration

47. Combined with loop diuretics: maintains osmotic gradient Fluid from brain parenchyma ↓mannitol Blood vessel ↓diuretic Renal excretion of fluid • Side effects : • Mild hyponatremia & hypokalemia • Rapid IV→ extreme hyperosmolarity→ cerebral vasodilation→ ↑ICP

48. Steroids • Beneficial in primary & secondary brain tumor • Stabilize BBB • ↑ CSF absorption ↓ ↓ICP (onset 48-72 hours) • No role in traumatic brain injury

49. Use of antihypertensive drugs in neurosurgery - Obtundation of vasopressor response during laryngoscopy, incision or during extubation Why optimization of BP is must before neurosurgery? Sudden hypertensive episode ↓(Disturbed cerebral autoregulation) ↑ICP ↓ Intra-cranial hemorrhage

50. Direct acting vasodilators • Drugs: SNP, GTN, hydralazine • MOA - Smooth muscle relaxation • Vasodilation • ↑CBF & ↑ICP • ↓ CPP • Steal phenomenon • Clinical Implication: • Caution with the use of these drugs • Drugs withdrawn cautiously (reduce risk of rebound HTN)