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Columbia University
INFO BRIEF
Volume 1, No. 1
MAILMAN SCHOOL
OF PUBLIC HEALTH
National Center for Disaster Preparedness
Direct Services, Applied Research, Analysis and Advocacy
PEDIATRIC EXPERT ADVISORY PANEL (PEAP)
National Center for
A
Disaster Preparedness
DDRESSING TERRORISM, DISASTER AND PUBLIC HEALTH EMERGENCY
Spring 2004
ATROPINE USE IN CHILDREN
AFTER NERVE GAS EXPOSURE
F ollowing the FDA’s approval of a used as initial treatment for children
with severe, life-threatening nerve agent NCDP PROGRAMS
Charles DiMaggio, PhDHealthcare System Preparedness It was further felt that while not within the published dosage range for choliner-gic toxicity, if a Mark 1 kit was the only should be used to treat all children, even International Center for Child &Adolescent Mental Health In May 2003, the first nationallyaccepted pediatric disaster and terror- Furthermore, it was felt to be imperative autoinjector kit (which contains bothatropine and an oxime and is designed Stephen Morse, PhDCenter for Public Health the Program for Pediatric Preparednessand funded by the Agency for Administration. At that time, the onlyavailable treatment for certain types of PEDIATRICS STAFF
nerve gas exposure (predominantlythose with anticholinesterase proper- established usage of antidotes forcholinergic toxicity and were felt to be ture. It was stated that the Mark 1Autoinjector kits (although not 212.342.0408
722 West 168th Street, Suite 1040, New York, NY 10032 Page 1
PEDIATRIC EXPERT ADVISORY PANEL (PEAP): ADDRESSING TERRORISM, DISASTER AND PUBLIC HEALTH EMERGENCY
Recommendations and Guidelines: What You Need to Know
Antidotes (Atropine & Pralidoxime)
Anticonvulsants
The recommendations regarding this new device, a The following additional recommendations regard- pediatric dosage AtroPen® and the existing Mark 1 ing needed anticonvulsant treatment (based on the kit (based on the key points listed, information from key points listed above, information from the con- the consensus conference and on data that have been sensus conference, and on data that have been pub- published since that meeting) are summarized lished since that meeting) was made by the Pediatric 1. The Mark 1 kit should remain as the pre-
The complete treatment of nerve agent
ferred emergency treatment for children of
exposure would necessitate the usage of
any age exposed to a nerve agent with the
anticonvulsants. All providers, agencies and
dosage based on the previously published
stockpiles in addition to atropine and prali- tables, Autoinjector Usage and Recommended
doxime must have an anticonvulsant agent in a Treatment and Management of Chemical Agents formulation and concentration that can be Used in Terrorism (Consensus Conference administered to children in as rapid a fashion Executive Summary and on pages 3 and 6 of this as possible (as available this should include the 2. The Mark 1 kit should remain as the pre-
The anticonvulsants and the dosage guidelines ferred emergency treatment for children
which can be used to treat children exposed to younger than 3 years old after bona fide
a nerve agent who have either a severe expo- nerve agent exposure if it is the only source of
sure or who are experiencing a seizure are: atropine and pralidoxime opperationally fea-
sible or available.
3. If there are overriding regulations or legislation that explicitly prohibits agencies from using the Mark 1 kits for children, then these agencies should stock and use the pediatric dosage Midazolam 0.1-0.2 mg/kg (max 10 mg) IV or IM AtroPen® for the treatment of nerve agent expo-sure in children. It is recognized that the pedi-atric dosage AtroPen® is not equivalent to theMark 1 kit and does not treat all children. As aresult these agencies must also stock and useatropine in other forms for children weighingless than 15 pounds and pralidoxime for all chil-dren (this includes stocking pediatric appropri-ate administration equipment for these pharma-ceuticals).
PEDIATRIC EXPERT ADVISORY PANEL (PEAP): ADDRESSING TERRORISM, DISASTER AND PUBLIC HEALTH EMERGENCY
Rationale for Recommendations
The Pediatric Expert Advisory Panel felt the following key points must be considered when making a determina-tion regarding the role of the pediatric dosage AtroPen®: Several stockpiles and organizations, based on 1 kit because it does not include pralidoxime.
legislation or regulation, may only stock and An oxime should be included for appropriate use devices for their FDA approved label indi- While significant attention has been focused on an approved indication for use in children the need for atropine and an oxime following a weighing less than 15 pounds, ie, infants and nerve agent exposure, complete treatment will require the usage of anticonvulsants.
z The Mark 1 Kit should be used in children 3 z Previous and recent data has shown that even years and older. This represents acceptable when atropine is administered in doses higher dosage ranges for the first 60 minutes of treat- than traditional cholinergic toxicity doses, it ment based on mg per kg dosing (see table has not been shown to cause toxicity in small below). The possible risk of use in children younger than 3 years old after bona fide nerveagent exposure would be far outweighed by thebenefit of treatment.
Autoinjector Usage
Number of
Atropine dosage
Pralidoxime
Approximate
Approximate
autoinjectors
dosage range
(each type)
NOTE: Each Mark 1 kit contains two autoinjectors (0.8 inch needle insertion depth), one each of atropine 2 mg (0.7 ml) and pralidoxime
600 mg (2 ml); while not approved for pediatric use, they should be used as initial treatment in circumstances for children with severe, life-
threatening nerve agent toxicity for whom IV treatment is not possible or available or for whom more precise IM (mg/kg) dosing would be
logistically impossible. Suggested dosing guidelines are offered; potential excess of initial atropine and pralidoxime dosage for age/weight,
although within general guidelines for recommended total over first 60-90 min of therapy for severe exposures. This table lists usage of the
Mark 1 kit only down to age 3 based on adherence to recommended dosages for atropine and pralidoxime. However, if an adult Mark 1 kit
is the only available source of atropine and pralidoxime after a nerve agent exposure, it should not be withheld from even the youngest child.
PEDIATRIC EXPERT ADVISORY PANEL (PEAP): ADDRESSING TERRORISM, DISASTER AND PUBLIC HEALTH EMERGENCY
Physiology of Nerve Agents
Nerve agents are liquids under temperate conditions. The The CNS contains both types of receptors, but the phar- most commonly discussed agents are VX, GA (Tabun), GB macology in the CNS is more complex and less well (Sarin), GD (Soman), and GF. The more volatile ones consti- understood. We know that an acute, large exposure of a tute both a vapor and a liquid hazard when dispersed. Nerve nerve agent can cause loss of consciousness, seizures, agents are organophosphorus cholinesterase inhibitors. They apnea, and even death. Whereas an acute but small expo- inhibit butyrylcholinesterase in plasma, acetylcholinesterase sure of a nerve agent can cause minor CNS effects includ- on erythrocytes, and acetylcholinesterase at cholinergic recep- ing slowness in thinking and decision making, sleep dis- tor sites in tissue. Some commonly used pesticides (for exam- turbances, poor concentration, emotional problems and ple, the organophosphate [OP] Malathion and the carbamate Sevin) and some common therapeutic drugs (the carbamatespyridostigmine [Mestinon] and physostigmine [Antilirium]) Treatment of Nerve Agents
also inhibit acetylcholinesterase and can be considered "nerveagents." However, while the OP pesticides cause the same The treatment of nerve agents includes decontamina- biological effects as nerve agents, there are some important tion, the traditional priorities of airway, breathing and cir- differences in the duration of biological activity and response culation, supportive care for the symptoms and adminis- to therapy. Acetylcholinesterase (RBC) is most sensitive for tration of antidotes. The goals of the antidotes are to nerve agents while Butyrylcholinesterase (plasma) is more After a nerve agent inhibits the tissue enzyme, the enzyme cannot hydrolyze acetylcholine, the neurotransmitter, at cholinergic receptor sites. Acetylcholine accumulates and
continues to stimulate the affected organ. The clinical effects
Atropine is a cholinergic blocking agent. Atropine from nerve agent exposure are caused by excess acetyl-
and similar compounds block the effects of excess acetyl- choline.
choline more effectively at muscarinic sites than at nico-tinic sites. This leads to drying of secretions and reduced The normal physiology is an electrical impulse goes smooth muscle constriction. But atropine does not treat down the nerve. This impulse causes release of the neuro- the skeletal muscle effects and can not treat the miosis, transmitter, acetylcholine (Ach). Then ACh stimulates a receptor site on an organ and causes the organ to act. TheACh is destroyed by acetylcholinesterase (AChE) and once The attachment of the agent to the enzyme is permanent destroyed no more organ activity is noted. Organs with (unless removed by therapy). Erythrocyte enzyme activi- cholinergic receptor sites include the smooth muscles, skele- ty returns at the rate of erythrocyte turnover, about 1 per- tal muscles, central nervous system (CNS), and most exocrine cent per day. Tissue and plasma enzyme activities return glands. In addition, cranial efferents and ganglionic afferents with synthesis of new enzymes. The rate of return of the are cholinergic nerves. There are different forms of the recep- tissue and plasma enzymes is not the same, nor is the rate tor for Ach which are categorized by their location and whether they are stimulated by either nicotine or muscarine.
The muscarinic sites include the smooth muscles and glands.
However, the agent can be removed from the enzyme Nicotine will stimulate other cholinergic sites, known as nico- and the enzyme "reactivated" by several types of com- tinic sites, which are those in skeletal muscle and ganglia.
pounds, the most useful of which are the oximes. If the Because both the muscarinic (vagal) and nicotinic (pre-gan- agent-enzyme complex has not "aged," oximes are useful lionic) receptors can affect then heart rate but in different therapeutically. Aging is a biochemical process by which way, following nerve gent exposure a person may have a the agent-enzyme complex becomes refractory to oxime reactivation of the enzyme. For most nerve agents, theaging time is longer than the time within which acutecasualties will be seen, allowing time for treatment.
Muscarinic
Nicotinic
However, the aging time of the GD-enzyme complex is about two minutes, and the usefulness of oximes in GD o Airways - constrict
o Fasciculations, twitching,
poisoning is greatly decreased after this period. o GI tract - constrict
o Pupils - constrict
In addition the oximes via the nictonic sites can o Tachycardia, hyperten-
increase muscle strength but they have no effect on the o Eyes, nose, mouth,
muscarinic sites, thus treating effects of nerve agents PEDIATRIC EXPERT ADVISORY PANEL (PEAP): ADDRESSING TERRORISM, DISASTER AND PUBLIC HEALTH EMERGENCY
Nerve Agent Clinical Signs. Vapor Exposure
o Severe breathing difficulty or cessation
o Generalized muscular twitching,
o Convulsions
Lungs: Dyspnea (“tightness in the chest”) o Loss of consciousness
o Loss of bladder, bowel control
Nerve Agents Clinical Signs. Liquid on Skin
Mild/moderate
o Severe breathing difficulty or cessation
o Generalized muscular twitching,
o Convulsions
o Loss of consciousness
o Loss of bladder and bowel control
Time of onset: 10 minutes to 18 hours after Antidotes
Auto-Injector
Atropine is a cholinergic blocking or anticholinergic
Mark 1 kit Each Mark 1 kit contains two autoinjec-
compound. It is extremely effective in blocking the tors (0.8 inch needle insertion depth), one each of effects of excess acetylcholine at peripheral mus- atropine 2 mg (0.7 ml) and pralidoxime 600 mg (2 ml); carinic sites. When small doses (2 mg) are given tohealthy individuals without nerve agent intoxication, Pediatric Dosage AtroPen® (New Device) Earlier this
atropine causes mydriasis, a decrease in secretions year, the FDA approved pediatric dosages of the (including a decrease in sweating), mild sedation, a AtroPen® (atropine injection), an auto-injector that has decrease in GI motility, and tachycardia.
an indication for use in children weighing more than 15pounds. The two dosages approved were 0.5 mg of Pralidoxime chloride
Atropine for children weighing 15-40 pounds and PAMCl) is an oxime. Oximes attach to the nerve 1.0mg atropine for children weighing 40-90 pounds.
agent that is inhibiting the cholinesterase and break At this time a device with pediatric dosage of 2-PAM is the agent-enzyme bond to restore the normal activity not available. These new devices were presented to the of the enzyme. Clinically, this is noticeable in organs working group for discussion and recommendations for that have nicotinic receptors; abnormal activity in their use in light of the existing Mark-1 device and the skeletal muscle decreases and normal strength returns.
absence of a pediatric dosage 2-PAM device. Recommended Treatment and Management of Chemical Agents Used in Terrorism
Toxicity
Clinical Findings
Decontamination
Management
Nerve Agents
Atropine 0.05-0.1 mg/kg IVb, IMc (min
MERGENCY
E
Pralidoxime 25-50 mg/kg IV, IMd (max 1 g
IV; 2 g IM), may repeat within 30-60 min prn, TH
EAL
prn for persistent weakness, high atropine H
requirements.
Diazepam 0.3 mg/kg (max 10 mg) IV,lorazepam 0.1 mg/kg IV or IM (max 4 mg), UBLIC
P
midazolam 0.2 mg/kg (max 10mg) IM prn forseizures or severe exposure.
AND
Vesicants
ISASTER
, D
ERRORISM
T
Pulmonary Agents
DDRESSING
A
Cytochrome oxi- Tachypnea, coma, seizures, apnea Riot Control Agents
Decontamination, especially for patients with significant exposure to nerve agents or vesicants, should be performed by health care providers dressed in adequate personal protective equipment. For emergency department staff, this consists of a non-encapsulated, chemically resistant body suit, boots, and gloves with a full-face air purifier mask/hood.
Intraosseous route is likely equivalent to intravenous.
Atropine might have some benefit via endotracheal tube or inhalation, as might aerosolized ipratropium.
Pralidoxime is reconstituted to 50 mg/ml (1 g in 20 ml water) for IV administration, and the total dose is infused over 30 min, or it may be given by continuous infusion (loading dose 25 mg/kg over 30 min, then 10 mg/kg/hr). For IM use, it might be diluted to a concentration of 300 mg/ml (1 g added to 3 ml water - by analogy to the Mark 1 autoinjector concentration), to effect a reasonable volume for injection.
Key: Hgb = hemoglobin; prn = as needed PEDIATRIC EXPERT ADVISORY PANEL (PEAP): ADDRESSING TERRORISM, DISASTER AND PUBLIC HEALTH EMERGENCY
PEDIATRIC EXPERT ADVISORY PANEL PARTICIPANTS
The Pediatric Expert Advisory Panel consists of the following experts and appointed individuals and the
following, organizations and agencies:
William Shea, MA, AEMT-CC
CO-CHAIRS
New York State Office of Emergency Management William Rodriquez, MD
Brad Leissa, MD
Cathy Gotschall, RN, ScD
David Markenson, MD
Lisa Mathis, MD
National Center for Disaster Preparedness Major David Dalberg
Irwin Redlener, MD
Doris Varlese, JD
National Center for Disaster Preparedness Linda Lewandowski
Deborah Mulligan-Smith, MD, FAAP, FACEP
Institute For Child Health Policy
Jon Woods, MD
REPRESENTATIVES FROM AGENCIES
Patricia Jocius, BA, MA, CEM
US Army Medical Research Institute of Infectious AND ORGANIZATIONS
International Association of Emergency Managers Shulamit Lewin, MHS
Mark S. Johnson, MPA
International Center to Heal Our Children, PARTICIPATING ORGANIZATIONS
Alaska Department of Health and Social Services Ellen Heyneman, MD
Agency for Healthcare Research and Quality Anne Baldoni, Pys.D
International Critical Incident Stress Foundation Joe Cappiello
Joseph Hagan, MD, FAAP
Joint Commission on Accreditation of Health Lou Romig, MD, FACEP, FAAP
Ann Langley
National Association of Children's Hospitals & CDC-Office of Terrorism Preparedness and Lynn Fairobent
Ben Chalpek
Thomas Tracy, Jr, MD
Jo Jaag, RN, MSN
Maryland Institute for Emergency Medical Marnie Dodson
Lisa Bernardo, PhD, RM, MPH
Sherlita Amler, MD, FAAP
National Association of Pediatric Nurse Practitioners Centers for Disease Control and Prevention Nancy Bourgeois
Nicki Pesik, MD
National Association of State EMS Directors Centers for Disease Control and Prevention- Merritt Schreiber, PhD
National Center for Child Traumatic Stress National EMSC Data Analysis Center (NEDARC) Gerard McCarty
Carl T. Cameron, PhD
National Institute of Child Health and Human Department of Homeland Security-FEMA Region II National Center of Emergency Preparedness for Rick Smith
New York State Department of Health-Bureau of Cheryl Boyce, PhD
Nitin Natarajan
DMAT NY2/Westchester County Medical Center Theresa G. San Agustin, MD
David Heppel, MD
National Institute on Disability & Rehabilitation DSSH/HRSA, Division of Child, Adolescent and Elizabeth Davis
PARTICIPATING EXPERTS
James Pointer, MD
Emergency Medical Services/County of Alameda Thomas Loyacono, NREMT
Theodore Cieslak, MD
Amanda Bogie, MD
Emergency Medical Services for Children - Malachy Corrigan
Fred Henretig, MD
Neil Richmond, MD
Kathy Haley, RN, BSN, CEN
Arthur Cooper, MD, FACS, FAAP, FCCM
Edward Gabriel
Harlem Hospital Center, Columbia University Ken Allen
New York City Office of Emergency Management Jeffrey Meade, NREMI P, CIC
John Talarico, DO, MPH
Dan Kavanaugh, MSW
New York State Department of Health/ Bureau of Richard Aghababian, MD, FACEP
University of Massachusetts Memorial Health Care Although some of these individuals were appointed to represent their organizations and agencies, and the comments contained in this document represent these individuals' input, formal approval of this document was not obtained from the boards of all organizations.
Pediatric Expert Advisory Panel (PEAP)
The purpose of the Pediatric Expert Advisory Panel (PEAP) is healthcare providers from a multitude of fields with pediatric to discuss, review the current literature, analyze current issues and other relevant experience, bench scientists, public health and to make recommendations for policy and programmatic historians, economists, legal and bioethics professionals, action on pediatric terrorism, disaster and public health emer- anthropologists, mental health professionals and sociologists, gency preparedness. The resulting information pieces are then information technologists, communication and media special- posted to the pediatric section of the National Center for ists, representatives of national professional organizations and Disaster Preparedness website at www.ncdp.mailman.colum- representatives of federal, state and local governmental agen- bia.edu and distributed to interested parties.
The Pediatric Expert Advisory Panel is a major program of the This Expert Advisory Panel is partially funded by grant number National Center for Disaster Preparedness (at the Mailman 7 H34 MC00136-01 from the EMSC Program of the
School of Public Health), which is composed of public health Maternal and Child Health Bureau, Health Resources
experts in epidemiology and program development, clinical Services Administration, Department of Health and
scientists and physicians with expertise in relevant areas, Human Services and by The Children's Health Fund.
The National Center for Disaster Preparedness
The National Center for Disaster Preparedness (NCDP) is a Major Areas of Interest & Expertise:
major national and international resource in disaster and terror- z Preparedness issues for children, families and special ism readiness. While based in the Mailman School of Public Health, the only accredited school of public health in New York City, senior investigators, program planners and experts are Hospital and community health systems preparedness & curriculum development selected from Columbia University Medical Center (College ofPhysicians & Surgeons, School of Nursing, School of Dental & Oral Surgery, New York Presbyterian Hospital) as well as from z Mental health aspects of disaster preparedness and across the campus of Columbia University including the schools of Journalism, International Public Affairs, Law, and Teachers College. The Center also actively collaborates with: the Children's Health Fund, the New York City Department of z Individual and family preparedness planning Health and Mental Hygiene, the Office of Emergency z Technology applications to enhance preparedness Management, FEMA, The Center for Disease Control, Department of Homeland Security, Department of Education and other key federal, state and city agencies. The NCDP works z Public policy implications, costs and impact of with other academic institutions, as well as advocacy and pub- Columbia University
MAILMAN SCHOOL
OF PUBLIC HEALTH
National Center for Disaster Preparedness
www.ncdp.mailman.columbia.edu

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