Ketamine for RSI in Head Injury: Unraveling the Myth

1. Ketamine for RSI in Head Injury:Unraveling the Myth Yael Moussadji, PGY 3 Emergency Medicine Grand Rounds Nov 9, 2006

2. Current Standard of Practice • No mention made of ketamine in the Brain Trauma Foundation Guidelines for Management and Prognosis of Severe TBI, except to say that there is insufficient data to support standards and guidelines on initial resuscitative measures, and that decisions regarding such are the left to the practitioner based on individual circumstances • Ketamine has been largely contraindicated for use in head injury in North America because of an associated rise in ICP • However, there is good animal data to support that this elevation in ICP is accompanied by a rise in MAP, vasodilation, and improved CPP • This can potentially benefit areas at risk of reduced CBF • Ketamine has also been shown to offer protection from cellular mechanisms of neuronal death in vulnerable areas of the brain

3. Objectives • Briefly review the early data against ketamine use • Review the animal models that have demonstrated benefit • Discuss current data on human subjects • How can we incorporate this into practice?

4. Pharmacology of Ketamine • Phencyclidine-derivative first synthesized in 1962 and released for use in humans in 1965 • Produces a dissociative sedation with profound analgesia and amnesia, with retention of airway reflexes, spontaneous respirations, and cardiopulmonary stability • NMDA receptor antagonist (glutamate antagonist), free radical scavenger

5. Arguments against the use of ketamine • Derived from three studies dating back to 1972 in which ICP was measured as changes in CSF pressure at the lumbar spine or lateral ventricle, or was deduced from changes in CBF (suggesting a mechanism of cerebral vasodilation) • These studies were performed in small numbers of either healthy volunteers or people with shunts and/or obstructions; no patients were head injured • A review that performed a detailed analysis of the data found that ketamine improved cerebral perfusion, did not affect cerebral metabolism, and only raised ICP deleteriously in patients with obstructed CSF pathways

6. Arguments for the use of Ketamine • Ketamine may be protective against secondary brain injury through optimizing hemodynamic parameters, providing adequate analgesia and sedation, and avoiding hypoxia and further ischemic injury • Excitatory amino acids, release of glutamate, intracellular Ca++ accumulation via NMDA receptors all leads to neuronal death; in vivo and in vitro studies support ketamine’s actions on these pathways, delaying neuronal necrosis

7. Animal Models & Ketamine

8. Therapeutic time window and dose response of the beneficial effects of ketamine in experimental head injury. Stroke. Shapira et al, 1994. • Compared ketamine in non-head injured rats to ketamine in head injured rats, and using increasing doses of ketamine at increasing time intervals (used 60mg/kg, 120mg/kg, 180mg/kg doses given intraperitoneal at 1, 2, and 4 hours); determined neurological severity scores at 1, 24, 48 hours, then used cortical slices to measure edema and hemorrhagic necrosis • Ketamine given at 2 and 4 hours decreased the volume of hemorrhagic necrosis from 37.1mm to 10.1mm and 15.1 mm respectively • High dose ketamine given early improved the NSS at 48 hours (180 mg/kg given at 1 and 2 hours, 120 mg/kg given at 1 hour)

9. Ketamine alters calcium and magnesium in brain tissue following experimental head trauma in rats. Journal of Cerebral Blood Flow & Metabolism. Shapira et al, 1993. • Same study design; 180 mg/kg given IP at 1, 2, 4 hours, and 120 mg/kg and 60mg/kg given at 1 hour • Cortical slices obtained at 48 hours to measure Ca and Mg content by emission spectroscopy • In the contused hemispheres, Ca content increased and Mg content decreased in untreated rats • In the ketamine group, the increase in brain Ca was significantly smaller than in groups not receiving ketamine, and the decrease in brain tissue Mg was significantly smaller (dose dependent)

10. Magnesium and ketamine attenuate cognitive dysfunction following experimental brain injury. Neuroscience Letters. Smith et al, 1993 • Evaluated the therapeutic effects of both MgCl and ketamine 4mg/kg (both NMDA receptor antagonists) on post injury memory dysfunction (retrograde amnesia) • Memory function has previously been shown to be a measure of cognitive dysfunction post brain injury, and correlates with the degree of hippocampal cell loss • Rats were tested at 48 hours post injury using the Morris Water Maze • Animals treated with either Mg or ketamine showed a significant attenuation of post traumatic memory dysfunction (memory scores doubled); no added effect with combined treatment

11. Comparison of seven anesthetic agents on outcome after experimental traumatic brain injury in adult, male rats. Journal of Neurotrauma. Statler, et al. 2006 • A previous study demonstrated the rats treated with isoflurane vs fentanyl had markedly better functional outcome and less hippocampal cell death • Compared 7 anesthetic/sedative agents applied after injury in the Controlled Cortical Impact model: diazepam, fentanyl, isoflurane, ketamine, morphine, pentobarb, propofol under controlled conditions (temp 37 degrees, PaCO2 35-45 mm Hg, PaO2 >70 mm Hg) • Rats treat with isoflurane had the best cognitive recovery and hippocampal neuronal survival • Rats treated with ketamine (10mg/kg IV) had the most hippocampal neuronal death • Morphine and propofol were associated with the poorest motor function on days 1-5

12. Other Animal Data • A dog model of systemic blood loss and traumatic intracranial space occupying hemorrhage showed a marked drop in CPP; an IV dose of ketamine 0.5mg/kg prior to fluids and 1mg/kg after fluids demonstrated an overall rise in CPP and nonsignificant smaller rise in ICP • A study of ketamine 5mg/kg in spontaneously breathing vs mechanically ventilated goats with intact autoregulation demonstrated a rise in CBF resulting from a combination of a rise in MAP and hypercarbia in the spontaneously breathing group

13. Conclusions from animal models • Ketamine is time and dose dependent and early administration appears to be important to benefit from these protective effects • Ketamine has an NMDA dependent effect on cellular influx of Ca, theoretically mitigating neuronal cell death, particularly at the hippocampus which contains the highest concentration of NMDA receptors; BUT this finding may also be dose dependent and is still in question • Beneficial effects of ketamine and other protective agents may result from a reduction in the cerebral blood flow – metabolism mismatches that can occur in head injury

14. Human Models Ketamine for Sedation in Head Injury

15. Ketamine decreases intracranial pressure and electroencephalographic activity in traumatic brain injury patients during propofol sedation. Anesthesiology. Albanese et al. 1997 • Purpose was to assess the effects of ketamine boluses in doses of 1.5mg/kg, 3mg/kg, and 5mg/kg on cerebral hemodynamics and EEG in 8 patients on propofol infusion, mechanical ventilation (PaCO2 35-38 mm Hg) and neuromuscular blockade • Measured ICP, CPP, jugular vein oxygen saturation, MCA velocity, cerebral AV oxygen content difference, and EEG while three doses were administered at 6 hour intervals • At all 3 doses, ketamine was associated with a significant decrease in ICP (of 18%, 30%, and 30% mm Hg respectively) was seen at 3, 2, and 3 min; at 10 min ICP increased 27% in the 1.5 mg/kg group and at 30 min it increased 23% in the 5mg/kg group • No significant differences in CPP, central venous O2 sat, MCA velocity, or AVDO2 • Ketamine induced a low amplitude EEG with marked burst suppression

17. Ketamine for angiosedative therapy in intensive care treatment of head-injured patients. Acta Neurochirurgica. Kolenda et al, 1996 • 35 moderate to severely head injured patients prospectively allocated to receive combination of ketamine and midaz or fentanyl and midaz infusions for a period of 3-14 days • 4 patients from the ketamine group and 5 from the fentanyl group were withdrawn due to persistent ICP • 2 patients in the ketamine group suffered MOF and cardiovascular arrest • The remainder of the ketamine group required less catecholamine support (only significant on day 1), had 8 mm Hg high CPP and 2 mm Hg ICP than the control • Outcomes were comparable in both groups with or without inclusion of withdrawn patients, and there was no difference in outcomes at 6 months

18. Safety of sedation with ketamine in severe head injury patients: Comparison with sufentanil. Crit Care Med. Bourgoin et al, 2003. • Prospective randomized double blinded study comparing infusions of ketamine and sufenta in combination with midaz in 25 patients with severe head injury • No significant differences noted with respect to ICP and CPP • Heart rate was higher in the ketamine group on day 3 and 4 • The sufenta group required more fluids on day 1, and showed a trend toward greater vasopressor use • There was also a trend towards increase baseline values of ICP in the ketamine group • This study lacks power, potentially hiding a significant difference in baseline values of ICP

19. Effects of sufentanil or ketamine administered in target-controlled infusion on the cerebral hemodynamics of severely brain injured patients. Crit Care Med. Bourgoin et al, 2005 • Prospective randomized study of 30 brain injured patients assigned to receive sufenta-midaz or ketamine-midaz using target-controlled infusion • Target concentrations of sufenta or ketamine were doubled for 15 min after 24 hours sedation while cerebral hemodynamics were measured • A two fold increase in drug concentrations resulted in no significant change of ICP, CPP, or Vmca • Concluded that increased plasma concentrations of ketamine did was not associated with any adverse effects of cerebral hemodynamics

20. Conclusions based on sedation studies • Results are only indirectly relevant to the suitability of ketamine as an induction agent • Ketamine administration under controlled conditions to patients under anesthesia do not seem to be associated with any significant changes in cerebral hemodynamics, effects which are likely related to the pre-existing cerebrovascular tone induced by the background anesthetic • A lack of change of the AVDO2 and Vmca suggest no impairment in the balance between CBF and CMRO2 • Likewise, control of PaCO2 may account for some of the measured effects via mediation of CBF

21. Ketamine in the field: the use of ketamine for induction of anaesthesia before intubation in injured patients in the field. Injury. Gofrit et al, 1997. • A prospective clinical study to evaluate use of ketamine for intubation in the field in Israel • Ketamine distributed to air medical rescue teams and flight docs were instructed to administer 2mg/kg IV if a single intubation attempt failed • Intubation was indicated in 161 patients, 29 (18%) were given ketamine, 27 of which had a GCS <8 • Patients requiring ketamine were all men with a mean age 27; cause of injury were MVCs (17), falls from height (6), and penetrating injuries (6); the head was the primary site of injury in 25 • Intubations failed due to “restlessness” or trismus, or traumatic airway distortions • Following ketamine administration, intubation was successful in 65.5% (19), all in whom the indications were restlessness or trismus (82.6% success rate in this group)

22. Conclusions • In acute head injury, compensatory mechanisms of CSF, blood flow, and fluid redistribution are intact, allowing increases in CBF without large increases in ICP • Any rise in ICP from ketamine is accompanied by a rise in MAP and CPP, influencing CBF, and vasoresponsivity to CO2 is preserved further contributing to cerebral vasodilation in spontaneously breathing patients • We need a RCT of ketamine for use as an induction agent in head injury

23. In Practice… • Our goal in the head injured patient is to avoid any secondary brain insults that can arise during resuscitation and stabilization • Avoiding hypotension (poor cerebral perfusion) and hypoxia may best be achieved by using ketamine in certain situations • CPP is a major determinant of outcomes, and ketamine allows us better control of CPP through maintenance of hemodynamic stability • Adjuncts such as benzodiazepines can be considered for patients in whom you are especially concerned about any increase in ICP, further minimizing effects on ICP without mitigating effects on CPP