An Evaluation of Fluid Resuscitation to Improve Outcome in Infants and Children with Out-of-Hospital Cardiopulmonary Arr

1. An Evaluation of Fluid Resuscitation to Improve Outcome in Infants and Children with Out-of-Hospital Cardiopulmonary Arrest Paul A. Checchia, MD Division of Pediatric Critical Care Medicine Loma Linda University Children�s Hospital Loma Linda, California

2. Hypothesis To determine whether the use of albumin during the resuscitation of pediatric patients who have suffered an out-of-hospital cardiopulmonary arrest reduces the severity of acute hypoxic-ischemic injury in comparison to 0.9 normal saline

3. Outcome Measures Cardiovascular function Need and duration of inotropic support Need and duration of mechanical ventilation Length of stay in pediatric intensive care unit Length of stay in hospital

4. Background Pediatric Cardiopulmonary Arrest Epidemiology and outcomes Resuscitation Practice Current Emerging therapies Albumin Theoretical advantages and disadvantages

5. Introduction to Pediatric Cardiopulmonary Arrest Incidence and epidemiology Pathophysiologic changes Initial assessment and resuscitation Prognostic evaluation and outcomes

6. Pediatric Cardiopulmonary Arrest Etiologies In-hospital versus out-of-hospital Drowning: second only to motor vehicle accidents Other Trauma (including abuse) Underlying medical conditions

8. Incidence and EpidemiologyDrowning Second leading cause of injury related death in children less than 15 years old 6500 people drown each year in the United States 90% of all drowning deaths occur within 10 yards of safety

9. Geographic Distribution 10 Western states (including California) Leading cause of death in children <14 years of age Highest incidence Phoenix, Arizona Lowest incidence Northeast United States Proximity to large bodies of water not necessarily a risk factor Even in states that border oceans or other large bodies of salt water, most pediatric drownings occur in fresh waterEven in states that border oceans or other large bodies of salt water, most pediatric drownings occur in fresh water

10. Gender Differences Males 78% of all deaths from drowning Yearly incidence 1/300 boys and 1/900 girls will be hospitalized after a nonfatal immersion event 1/1000 boys and 1/3000 girls will die from drowning

11. Age Differences Bimodal distribution Peaks < 5 years 15-19 years Alcohol involved in approximately 50% of adolescent drowning cases

12. Swimming Pool Drownings 50-90% of all pool drownings occur in children < 4 years old In 1993, 53% of all drownings occurred in swimming pools Quan et al. Pediatrics, 1989 Adult supervision in 84% of cases Only 18% witnessed the actual immersion event

13. Sequence of Events During Submersion Contrary to popular opinion, the victim does not wave or call for help Breathing instinctively takes precedence Upright posture, arms extended laterally, thrashing and slapping the water Often mistaken for playing and splashing in the water

14. Sequence of Events During Submersion Head submerges and surfaces several times during struggling activity Children can struggle for only 10 seconds Adults may be able to struggle for up to 60 seconds

15. Sequence of Events During Submersion PCO2 rises, diaphragm begins to have episodic contractions Inspiration prevented only by voluntary closure of the glottis Eventually, involuntary gasp occurs

16. Sequence of Events During Submersion Laryngeal spasm 20% of cases No aspiration of water

17. Sequence of Events During Submersion Involuntary gasping continues for several minutes Swallowing of large volumes of water into stomach Consciousness lost within 3 minutes Water passively enters lungs

18. Sequence of Events During Submersion Cardiac arrythmias Convulsions and spasmodic efforts Death

19. Pathophysiologic Changes Cardiovascular Effects Ischemia Ventricular fibrillation does occur but it is relatively uncommon Cardiogenic shock

20. Pathophysiologic Changes Neurologic Effects Timing of injury Exact time of irreversible injury presently unknown ATP depletion in as little as 2 minutes of hypoxia

21. Pathophysiologic Changes Neurologic Effects Cerebral edema 24 - 72 hours following injury Loss of autoregulation of blood flow Reperfusion injury

22. Hypothermia Case reports of miraculous recovery Cerebral oxygen consumption 50% of normal at 28oC

23. Hypothermia Cerebral blood flow decreases 6-7% per 1oC drop Negative effects include dysrhythmias, increased blood viscosity Must be cold before hypoxic

24. Secondary Hypothermia Majority of pediatric patients become hypothermic in response to cardiac arrest Body temperature spontaneously recovers in most Active rewarming measures �overshoot� in most cases (Hickey et al. Pediatrics 2000)

25. Permissive Hypothermia Human data available and suggestive of positive neurologic affects Holzer et al. Acta Anaesthesiol 1997 Colbourne et al. Mol Neurobiol 1997 Bernard et al. Ann Emerg Med 1997

26. Initial Assessment and Resuscitation Restating the obvious

27. Initial Assessment and Resuscitation Specialized issues Heimlich maneuver: thought to clear airways of liquid obstruction Amount of fluid is usually small and non-obstructive May increase risk of aspiration of gastric contents Do not waste time, correcting hypoxia is paramount

28. Initial Assessment and Resuscitation Threshold for intubation should be very low Indications for intubation Arrest Loss of airway protective reflexes Deteriorating neurologic exam Severe respiratory distress or hypoxia despite supplemental oxygen Hypothermia (core temperature < 30oC)

29. Initial Assessment and Resuscitation Hypovolemia Marked vasoconstriction IV fluids

30. Resuscitation Fluids Current practice Normal Saline 5% Albumin 25% Albumin Lactated Ringers Solution Hypertonic Saline Choice dependent on provider, cost, habit

31. Albumin Historical perspective Developed as blood substitute for combat casualty victims during World War II Studied in treatment of traumatic brain injury, hypoxic injury following cardiac arrest in adults, and hepatic encephalopathy Small series Adults only

32. Albumin Recent experimental data Renewed interest in albumin as a potential clinically relevant treatment specifically for ischemic and traumatic brain injury

33. Review of Experimental Data Belayev et al. Brain Res 1999 Temporary forebrain ischemia in rats Albumin infusion during injury and reperfusion Improvement in composite neurological scores at 7 days following injury Improvement in histological appearance of brain at 7 days following injury Belayev et al. Stroke 2001 Therapeutic window for albumin infusion determined to be as long as 4 hours following injury

34. Albumin Infusion During InjuryProposed Mechanisms for Protection Anti-inflammatory agent Emerson TE, Crit Care Med 1989 Reduction of platelet aggregation Reduction of microvascular thrombosis Jorgensen et al. Thromb Res 1980 Improved local blood flow Reaction with nitric oxide Keaney et al J Clin Invest 1993

35. Albumin Infusion During InjuryProposed Mechanisms for Protection Regulates pyruvate dehydrogenase Improved cellular bioenergetics Tabernero et al. Glia 1999 Binds free calcium Directly decreases cellular injury Wortsman et al. Am J Physiol 1980 Oxygen radical scavenger Loban et al. Clin Sci 1997 Kooy et al. Crit Care Med 1995

36. Outcomes Initial Resuscitation Current approaches to resuscitation may increase the number of successful cardiovascular resuscitations without equal neurologic recovery

37. Outcomes Long Term Prognosis Overall, >15% survivors with significant neurologic deficits Children with spontaneous, purposeful movements and had a normal brainstem examination at 24 hours progressed to full recovery Those without these findings by 24 hours suffered severe neurologic deficits or death (Bratton SL et al. Arch Pediatr Adolesc Med 1994)

38. Experimental Design Patient Population Pediatric (birth to 15 years of age) patients in cardiac arrest. Inclusion Criteria Patients who require cardiopulmonary resuscitation (CPR) for cardiac or respiratory arrest will be considered eligible for the study. An arrest will be defined as the initiation of CPR by either bystanders or prehospital personnel Patients will be eligible for the study regardless of the etiology of arrest (i.e. drowning, arrhythmia, and respiratory arrest).

39. Experimental Design Randomized controlled interventional trial. A power analysis will be preformed when 20 patients have been enrolled (10 in each arm) to determine how long the study would need to continue if any trends were noted. Patients will be randomized to one of two groups.

40. Experimental Design Group 1/Even days � ALS prehospital personnel will follow approved ICEMA protocols. Protocol Reference #7000 Pediatric Cardiac Arrest (1Day to 8 years of Age) and Protocol Reference #7002 Pediatric Cardiac Arrest (9 to 15 years of Age)

41. Experimental Design Group 2/Odd days ALS prehospital personnel will follow the study protocols. Protocol Reference #7000TS Pediatric Cardiac Arrest (1Day to 8 years of Age) and Protocol Reference #7002TS Pediatric Cardiac Arrest (9 to 15 years of Age) Patients on odd days will receive a 20cc/kg initial bolus of 5% Albumin in place of Normal Saline. If the patient has a return of any perfusing rhythm they will receive and additional bolus of 20cc/kg of albumin. Otherwise, the protocols will remain identical.

42. Outcome Measures Death Cardiovascular function as measured by: Blood pressure, heart rate, and initial arterial blood gas measurements Echocardiogram Need and duration of inotropic support Need and duration of mechanical ventilation Modified Multi-organ Failure Score on Days 1, 2, 3, and 7 Serum Creatine Cardiac Troponin I Total Bilirubin

43. Outcome Measures Lengths of stay in pediatric intensive care unit Length of stay in hospital. Admission neurologic examination as measured by the: Glasgow Coma Scale score pupillary reactivity other brain stem reflexes presence of apnea Magnetic resonance imaging and spectroscopy abnormalities at post-arrest day 7. Pediatric Cerebral Performance Category Scale Score (PCPCS) at 6 to 12 months post injury. Glasgow Outcome Score (GOS) on discharge from PICUGOS on discharge from hospital

44. Data Collection Run Sheets Emergency Department Records Admission Records History

45. Data Collection All participating personnel will be contacted by investigator team member Data collection only Feedback on protocol design Improvements Update on current state of study

46. Results You will be the first to know.