Learning Objectives: Cooling the Brain: The Role of Hypothermia Therapy in Children with Brain Injury

Transcription

1 Cooling the Brain: The Role of Therapy in Children with Brain Injury Jamie Hutchison, MD Pediatric Neurocritical Care Symposium: Alberta Children s Hospital, Calgary, January 20-21, 2010 Learning Objectives: 1. To review cooling and re-warming methods in children. 2. To review the risks and benefits of hypothermia therapy in children with traumatic brain injury (TBI). 3. To review future directions in research into the use of hypothermia therapy. Effect of hypothermia therapy in rodent models of traumatic brain injury (TBI) Reduces cerebral edema, blood brain barrier permeability, inflammation, cerebral atrophy, contusion size, necrotic and apoptotic cell death, axonal injury and mortality and improves neurobehavior scores following TBI in rodents

2 therapy Lowers cerebral blood flow and intracranial pressure Lowers cerebral metabolic rate Decreases secondary injury by several different pathways 24 hours of hypothermia is safe May improve outcome Marion, et al. N Eng J Med 1997;336: Therapy: Adverse effects in human studies Bradycardia and arrhythmias Myocardial depression Immune dysfunction Increased sepsis and ventilator-associated pneumonia Cold induced diuresis and vasoconstriction Vasodilatation and hypotension during rewarming Other: Pancreatic, endocrine and metabolic abnormalities and decreased drug metabolism and elimination Randomized trials of hypothermia therapy in pediatric patients with severe TBI Biswas, et al. Crit Care Med 2002 Adelson, et al. Neurosurgery 2005 Safety no increase in arrhythmia, pneumonia, coagulopathy ICP

3 Paediatric Head Injury Trial (HyP-HIT) Randomized controlled trial of 24 hours of hypothermia therapy in Paediatric patients with severe traumatic brain injury (TBI). 17 centres in Canada, UK and France Trial coordinated by the Chalmers Group (CHEORI, Ottawa) and the Canadian Critical Care Trials Group. Funded by the Canadian Institutes of Health Research and other granting agencies N Engl J Med 2008;358:28-37 Eligibility: - Severe TBI - Informed or deferred consent - Within 8 hours of injury HyP-HIT R Te = C Te = C N = 225 (+ 2 run-in patients per centre, Dev Neuroscience 2006) Masked follow-up 1, 3, 6 and 12 months - Functional and Neuropsychological tests HyP-HIT Power Trial was powered to detect a 20% improvement in the proportion of patients with a Pediatric Cerebral Performance Category (PCPC) score of 4-6 (unfavorable outcome) at 6 months following the injury in the group receiving hypothermia therapy compared to the group treated with normothermia. We assumed that 50% of patients in the control group (normothermia) would have a PCPC score of 4-6.

4 HyP-HIT Primary Outcome Pediatric Cerebral Performance Category (PCPC) score PCPC score Definition 1 Normal 2 Mild disability 3 Moderate disability Unfavorable outcome 4 Severe disability 5 Persistent vegetative state 6 Death Debra H. Fiser. J Pediatr Trial organization Trial coordinator Ms. Roxanne Ward Chalmers Group CCCTG Clinical Care Committee Steering Committee Data Safety and Monitoring Committee Sites Inclusion Criteria Informed consent. Age 1-17 years. Glasgow coma score (GCS) 8 Abnormal cerebral CT-scan. Mechanically ventilated.

5 Exclusion criteria Impending Brain death Severe secondary hypoxic-ischemic injury Refractory shock Cardiorespiratory arrest at scene due to: High C-spine injury Severe head or vital organ injury Severe neurodevelopmental delay Acute epidural hemorrhage Randomized > 8 hours post-injury Pregnant Objective of the maneuver - Cool early and rapidly Cooling blanket under patient (5 C) Neuromuscular blocker Esophageal temperature probe Ventilator humidifier at C Ice packs +++ Cooling blanket over ice and patient Set blanket on automatic at 32.5 C once patient reaches 33 C Prevent over-cooling. Recruitment Start - February 1999 Total no. of patients screened 1441 No. of patients not enrolled 1216 Not meeting eligibility 1114 Refused to participate 33 Not approached 69 No. of patients enrolled 225 Recruitment: 69% of eligible patients.

6 HyP-HIT allocation R N=108 N=117 HyP-HIT baseline data Characteristics Age (years); mean (SD) 9.8 (4.9) 10.2 (4.8) Weight (kg); mean (SD) 39.4 (21.2) 40.3 (21.1) GCS; median (IQR) 5 (4 to 6) 5 (3 to 6) Pediatric trauma score; median (IQR) 3 (2 to 5) 3 (2 to 5) HyP-HIT baseline data 2 Characteristics Male 70 (65) 71 (61) Motor Vehicle Collision 70 (65) 64 (55) (MVC) MVC Passenger 30 (43) 32 (51) MVC Pedestrian 40 (57) 31 (49) Bicycle 12 (11) 18 (15) Fall 17 (16) 21 (18) Other 9 (8) 14 (12)

7 HyP-HIT baseline data 3 Characteristics Initial presentation: Admission Hypotension 8 (7) 3 (3) Admission Hypoxia 3 (3) 0 (0) Transport from other institution 62 (57) 79 (68) HyP-HIT baseline data 4 Characteristics CT findings: Extradural hematoma 10 (9) 22 (19.0) Intracerebral hematoma 62 (57) 62 (56.9) Diffuse axonal injury 58 (54) 61 (52) Cerebral edema 85 (79) 83 (71) Midline shift 33 (31) 27 (23) Skull fractures 59 (55) 59 (50) Characteristics HyP-HIT baseline data 5 Other injuries: Spinal cord injury 1 (1) 1 (1) Thoracic injury 38 (35) 36 (31) Cardiovascular injury 4 (4) 1 (1) Abdominal injury 10 (9) 13 (11) G/U injury 11 (10) 10 (9) Major fracture 25 (23) 22 (19)

8 HyP-HIT Temperatures 37 Temperature with 95% CI I P Time in hours - Initial (I), Pre- (P), & Post-Randomization (0-48hrs) HyP-HIT Cooling Characteristics mean (SD) [range] Time to start cooling (in hours) 6.3 (2.3) [1.6 to 19.7] Time to cool (in hours) 3.9 (2.6) [0 to 11.8] Time to re-warm (in hours) 18.8 (14.9) [2.5 to 148] HyP-HIT Primary Outcome 6 months P PCPC = (31) 23 (22) 0.14

9 HyP-HIT: PCPC 4.0 PCPC mean score with 95% CI P= baseline 1 month 3 months 6 months 12 month Time since injury HyP-HIT Pediatric Cerebral Performance Category (PCPC) score at 6 months PCPC Score 1 27 (26) 32 (31) 2 21 (21) 30 (29) 3 22 (22) 18 (18) 4 8 (8) 8 (8) 5 1 (1) 1 (1) 6 23 (23) 14 (14) Total (9% loss to follow-up) P value = % HyP-HIT Survival 75% Proportion surviving 50% 25% P=0.07 (unadjusted) P=0.04 (adjusted) Censored observations 0% Days

10 Intracranial pressure (ICP) 30 ICP (mmhg) * * * P < 0.05 I P Initial (I), Pre (P) and hours post-randomization * * HyP-HIT Subgroup analysis Subgroups analyzed where hypothermia associated with a higher relative risk of unfavorable outcome: Age 7 yrs compared to age < 7 yrs (P=0.06) Initial ICP 20 mmhg vs > 20 mmhg (P=0.03) HyP-HIT Secondary outcomes Outcomes: Durations (days) mean (SD) mean (SD) ICP monitoring 6.4 (4.0) 6.0 (0.9) Mechanical ventilation 9.5 (6.1) 8.9 (5.7) ICU stay 11.5 (7.1) 11.3 (7.2) Hospital stay 30.2 (31.7) 28.3 (24.2) Worse long term memory scores at 12 months in the hypothermia therapy group. No difference in intelligence, speed of processing or executive function at 3 and 12 months following injury.

11 HyP-HIT-Co-interventions and Adverse Events Significantly more hypertonic saline in first 24 hr in normothermia group compared to hypothermia therapy group. Significantly lower cerebral perfusion pressure and mean blood pressure and significantly more patients with hypotension and/or received vaso-active agents in the hypothermia therapy group during re-warming compared to the normothermia group. Hypotension There was a significant association between the number of hypotensive events and unfavorable outcome in the hypothermia therapy group (P=0.04). This was mostly due to hypotensive events occurring during re-warming. Hypotension = systolic BP < 90 mmhg for age of 10 years or systolic BP < 70 + age (in years) X 2 mmhg for age < 10 years. Hypotension and hypoxia worsen outcome post- TBI Clinical Experimental Hypotension increases mortality from 16 % to 67% in pediatric patients with severe TBI (Pigula et al, J Pediatr Surg 1993) Hypotension worsens neurological outcome (Kokoska et al., J Ped Surg 1998) Apop cells Apoptosis is increased by hypoxia TBI TBI + H

12 Mouse Model Weight-drop TBI Steel rod Impounder Bregma Rostral OC Dorsal MC S Caudal Ventral Hutchison, et al. J Neurotrauma Mikrogianakis, et al., J Neurotrauma Apoptotic cells post - TBI Model Mean number of apoptotic cells / section A * Section 3 (Bregma -0.2mm) Section 4 (Bregma -1.8mm) 40 Section 5 (Bregma -3.4mm) Weight-drop method of TBI 35 or sham in mouse 30 Cerebral cortex 25 Brains removed for analysis at 6, 24 and 48 hours 20 and 7 days post-tbi TUNEL Quantify apoptosis Sub-cortical white matter Hutchison, et al., J. Neurotrauma 2001 B B * 0 Control 6h 24h 48h 7 days Time post-tbi Apoptosis Post-TBI & Varying Durations of Hypoxia (FiO 2 = 0.09) in the Mouse Six experimental groups: (n=5/group) Sham Hypoxia (30 minutes) alone TBI alone TBI with 10 minutes hypoxia TBI with 20 minutes hypoxia TBI with 30 minutes hypoxia Sacrificed at 24 h., brains sectioned and TUNEL or cresyl violet staining

13 Apoptosis 24 h. Post TBI + hypoxia 500 Bregma 2.22 Bregma 0.98 Bregma Average Number of Tunel Positive Cells Sham Hypoxia TBI TBI + H 10 min TBI + H 20 min. TBI + H 30 min. Caspase activation following TBI Olfactory cortex % Fluorescence compared to control * TBI Alone TBI with Hypoxia * p <0.05 compared to TBI alone. 6 h. 24 h. X-linked Inhibitor of Apoptosis Protein Olfactory cortex 6 hours post-tbi 120 % Sham Protein * * SHAM 6 h post TBI 6 h post TBI + Hypoxia 0 * p < 0.05 compared to sham control p < 0.05 compared to TBI alone Mikrogianakis et al. J Neurotrauma 2007

14 0 Effect of hemodilution anemia in rats post-tbi Hgb 70 g/l - no hypotension 5 Contusion size Apoptosis 4 * * Damage - mm TUNEL Positive Nuclei Hare et al. J Appl Phys TBI TBI + Anemia Area of Normal selective Hypoxia brain vulnerabilty Contusion HyP-HIT - No significant difference in other adverse events N (%) N (%) Ventricular arrhythmia 1 (1) 1 (1) ARDS 8 (8) 6 (5) Pneumonia 39 (36) 51 (44) Septic Shock 2 (2) 2 (2) Other infection 16 (15) 19 (16) Bleeding (late intracranial) 3 (3) 5 (4) Bleeding (other site) 1 (1) 1 (1)

15 Conclusions No difference in the primary outcome Increased mortality with hypothermia therapy (P=0.06) Significant increase in mortality in the adjusted (exploratory) Cox proportional hazard model (P=0.04) Increase in hypotensive episodes in hypothermia therapy group during re-warming Hypotension associated with unfavorable outcome in the hypothermia therapy group (P=0.04) No other difference in adverse events Possible explanation for lack of benefit? HyP-HIT was underpowered therapy is ineffective (or even harmful). There may be a better way to apply hypothermia therapy Shorter time to implement therapy Margraff et al Longer duration (> 48 hours) McIntyre et al. JAMA 2003 Prevent hypotension during re-warming Effect of delayed onset of hypothermia therapy on behavioral testing following cortical impact injury in rat Balance-beam performance Posture-reflex test Markgraf et al. J. Neurosurg. 2001

16 Effect of delayed hypothermia therapy on cerebral edema following cortical impact injury in rat therapy started 0 minutes following brain injury therapy started 90 minutes following brain injury Markgraf et al. J. Neurosurg Advances in cooling technology Devices with improved cooling speed and servo control of temperature Disposable mattress and blanket with improved texture and flexibility to conform to the patient s surface and improved servo control eg. Blanketrol III. Devices that adhere to the patient s skin Eg. Arctic Sun. Intravenous cooling devices. Cold (4 C) normal saline IV. Accuracy and safety of temperature monitoring Brain temperature is the gold standard Rectal can be inaccurate especially during cooling phase Use 2 temperature probes and confirm correct placement eg. esophageal and bladder

17 Conclusions therapy does lower ICP-use as a second tier therapy. If using hypothermia therapy; CAUTION during re-warming prevent rebound ICP and hypotension. Further studies are necessary to define optimal timing of cooling and re-warming strategies and fluid/bp management. Acknowledgements Roxanne Ward HyP-HIT study coordinator CCCTG Deborah Cook and John Marshall HyP-HIT Steering committee (Paul Hébert, David Moher, Jacques Lacroix, Marcia Barnes and Des Bohn) Site investigators, research assistants, and psychologists Biomarkers: Nanogen Inc., Doug Fraser, Milly Lo Laboratory: Angelo Mikrogianakis, Rachel Shaye, Phillip Griffen, Julia Lockwood and Alex MacKenzie Funding: