errata
Apologies for the earlier typographical errors caused in the translation of material across 3 different mediums.
This is being addressed. 

Book Review

Introduction

Chemical and Bioweapons Review (Part II)

Part I:

Chemical Agents

Several years ago (2014) I wrote a blog about chemical and bioweapons. It was moderately well received.

For the most part it was an elementary guide to various aspects of past, present and future chemical and bioweapons.

In addition, it looked at interesting areas of substances classified as neither virus nor bacteria.

The article was a myriad of data, which, if coalesced with the accompanying references (and the back references – upon which the references themselves were based) formed a coherent picture useful to the amateur and the non-professional.

I stated that I am not a medical professional nor have I any specific training other than in the area of academic scientific research.

I have written technical (scientific) books based on research.
I also was engaged on a short-term contract by an independent authority (CSM) which advised UKLA on the efficacy of medicines based on AR (adverse reaction) Reports from Doctors Surgeries, Hospitals and FPCs (Family Practitioner Clinics.)

CSM was set up in the UK after the Thalidomide tragedy.

This Review will examine the work of scientific professionals whose material forms the basis of countering the effects of some widely suspected chemical agents of future terrorist attacks.

Part II (to follow) will look at Bioweapons, Synthetic Bioweapons, and how they are perceived from potential usage and countermeasures perspectives.

CIA analysis (read the Paper below) suggests that terrorists will more likely than not concentrate on easy to produce substances (mustard gas, chlorine gas) and VX nerve agents than the more exotic bioweapons I earlier discussed.

The report also suggests it highly unlikely that the terrorist emphasis will be on bioweapons and that scarce resources of governments should focus in countering the more likely probable threats than exotic bioweapons which are very challenging to produce under the required technical and environmental conditions.

This analysis is based on 'patterns of behavior' of ISIS terrorist attacks in Syria and Iraq and the pattern of 'lone wolf' attacks worldwide.

To put it bluntly, most 'terror' attacks by ISIS supporters in Europe and elsewhere are crude, unsophisticated and carried out by mentally ill individuals.

Governments and their media hacks worldwide have their own motives for the 'frenzied' hysteria (more funding for security, for systems and technologies of population control etc) which have little to do with terrorism but more to do with control of populations, using terrorism as 'bait' for the acquisition of scarce departmental resources.  
This is a personal opinion – but fairly obvious to all who think 'outside the box.'

I do not want to give too many examples of bioweapons or chemical substances which might be available for experimenting, but I will draw on another strand.

Example 1:

If North Korea really was as crazy as it is made out, it would have launched it's nuclear weapons not against a nuclear state but, against the Moon (!) – or use such a threat to 'blackmail' the world.  I do not joke nor exaggerate.  It's not difficult for a Ninth Grader, given the parameters, to calculate how many devices and of what kilotonnes would be required to 'fracture' the Moon or 'knock' it out of orbit (!)

North Korea's height above sea level would ensure that in the ensuing catastrophic rises in sea levels worldwide – which would destroy most of continental *United States, Britain, Europe and the Middle East; and the vast array of existing network caves at such high altitude as existing in North Korea, would ensure the survival of it's own population.

It is popular fiction to believe that the world would end if the Moon was displaced or fragmented or non-existent.

[Watch the film, 'The Time Machine' to get some idea of this concept. Remember also, the World Trade Center had already been the subject of attacks – and even a  film made about such a speculative terrorist air attack – before 9/11.]

*to 'Mes Amis' in 'The Rockies': I've done the altitude and elevation calculations based on a Google 'App' for measuring height above sea level for countries worldwide and you would appear to be OK for survival – should your nightly Moon 'disappear' (!)

Example 2

This is my own original 'pet' example and you will find it in my Chemical and  Bioweapons Review Blog (2014) – just use your imagination and extrapolate beyond the effects on individuals.

Immediate Gratification

Never forget, most terrorists or insurgents in conflict zones are seeking 'immediate' gratification and are not planning for long-term widespread 'stealth' population infections stretching into years or decades.

Not only are they (insurgents) not mentally configured, they have neither the knowledge, the resources nor the time - since events on the 'battlefield 'demand 'instant' successes.

All of the above limit the threat to very narrow sectors: false flags and known use of chemical weapons on historical battlefields by countries and urban terrorists.

It is for these reasons, I assume, that the CIA made the assessment which they did.

Syria and Iraq are of immense interest in the study of the pattern of terror attacks, how the technology was acquired [either stolen from Syrian army stockpiles, 'donated' by a 'false flag' entity (country) or manufactured locally (by the insurgents themselves) and their effects on urban population centers.]

All of the above suggest that chemical rather than biological weapons are the  likely 'Menu' of choice for future urban terror attacks worldwide.

[My disagreement with this professional analysis is partly based on the fact that that 9/11 was not foreseen by 'the experts' and that they are always preparing for 'the last war' which took place - one which they are confident  discussing because it is within their particular 'comfort' zone.]

I have chosen sections from this Paper which are of relevance so that you can build on what you already know from my earlier (original) Review and it's references.

(I am already assuming that if you have taken the time to read the Chemical and Bioweapons Review blog you are already familiar with the topics which need no introduction.)

After reading the selected references for this Paper please do read the books by these specialists and give them appropriate credits when using any of their materials for your own research.

Why do governments deliberately restrict access to this information, rather than proactively make it available to you and me?  You will have to ask your political representative since I do not know the answer to that question.

[Hopefully he or she will give you an honest reply.]

[I presume it is because we (you and I) will be the assumed (passive) 'victims' of the chemical or bioweapon attack and will therefore either be dead, in horrific pain, or just be guinea pigs for the medical fraternity whilst in triage or a morbidity-mortality statistic.]

Please note:

This Review will not examine the stoichiometry of reactants but if you are really interested, read the accompanying references for guidance.

Some of the references at the end are taken from Professor Gupta's book but many others are ones I personally recommend for the layperson attempting to appreciate all the parameters.

Can I again suggest that you purchase and  read this book and the contributing Papers in their entirety then follow up on the given references?

I cannot overemphasize the importance of this book if you care about protecting your loved ones from future chemical emergencies at home or otherwise.
In addition to this, please visit the CDC and other disaster preparedness websites which you will find at this website.
(Simply insert ''CDC'' or ''Emergency Preparedness'' into the 'find' section [''Search This Site For Over 500 Blogs''] and you will be taken to these websites.)
My suggestion is that you 'stock up' with the recommended emergency kit (or that which you deem appropriate for your particular circumstances) as per the contents of this book.
This will also make you less of a burden on non-existent - or overwhelmed - emergency services - at a time of crises, confusion, panic and (likely) chaos (being overwhelmed) at hospitals and clinics.
You should also be familiar with the basic symptoms for the likely chemicals and retain a supply(ies) of bottled water for consumption and sterile use in preparation for such circumstances.

The final (unofficial) narrative given to health professionals by their trainers for such situations is that not everyone will survive the chemical attack and that priority be given and scarce resources applied to those with the best possibility of survival whilst 'humanely' (but using minimal scarce resources) attending those likely to succumb.
If you have your own store of knowledge and have prepared for an incident, you can be the arbiter of such decisions - for better or for worse.

You should also, of course, at the earliest opportunity available, find or seek professional medical assistance and advice for your particular situation.

(All of the above assumes panic and chaos in the immediate aftermath of such an incident where speed in dealing with the emergency can mean the difference between permanent paralysis, disfigurement or permanent brain damage and is not  in any way meant to detract from the work of the emergency services coping as best they can in such a situation.) 

Thank you.

Patrick Emek

January 2019

ISBN: 978-0-12-800159-2

For information on all Academic Press publications

visit our website at http://store.elsevier.com/

Typeset by MPS Limited, Chennai, India

www.adi-mps.com

PE:

This is a very concise compilation by Professor Ramesh Gupta.

It is easily written and should form one of your core reading books on chemical warfare agents.

It is important that you know exactly who the contributing papers to this book were written by.

This is the list of contributors to Professor Gupta's book:

Xin-an Liu, MD, PhD Neuroscience, The Scripps Research

Institute, Jupiter, FL, USA

Oksana Lockridge, PhD Eppley Institute, University of

Nebraska Medical Center, Omaha, NE, USA

Bommanna G. Loganathan, PhD Department of Chemistry

and Watershed Studies Institute, Murray State University,

Murray, KY, USA

Andres M. Lugo, MD, MPH, FACMT 5855 Evergreen Ln,

Shoreview, MN, USA

Mark Maguire, MS Department of Neuroscience and

Pharmacology, Center for Molecular and Behavioral

Neuroscience, Meharry Medical College, Nashville, TN,

USA

Galina F. Makhaeva, PhD Institute of Physiologically

Active Compounds, Russian Academy of Sciences,

Chernogolovka, Russia

Jitendra K. Malik, DVM, MVSc, PhD Division of

Pharmacology and Toxicology, Indian Veterinary Research

Institute, Izatnagar, Bareilly, India

Tomaz Mars, MD, PhD Institute of Pathophysiology,

Medical Faculty, University of Ljubljana, Ljubljana,

Slovenia

Maria Rosa Martínez-Larrañaga, PhD Departamento

de Toxicología y Farmacología, Facultad de Veterinaria,

Universidad Complutense de Madrid, Spain

Patrick Masson, Pharm Sci D Institute of Structural

Biologie, DYNAMOP, Grenoble, France and Eppley

Institute, University of Nebraska Medical Center, Omaha,

Nebraska, USA

Shigeki Masunaga, PhD Faculty of Environment &

Information Sciences, Yokohama National University,

Yokohama, Japan

Monique McCallister, PhD Department of Neuroscience

and Pharmacology, Center for Molecular and Behavioral

Neuroscience, Meharry Medical College, Nashville, TN, USA

Linda A. McCauley, PhD Nell Hodgson Woodruff School

of Nursing, Emory University, Atlanta, GA, USA

Patrick M. McNutt, PhD Cell and Molecular Biology, US

Army Medical Research Institute of Chemical Defense,

Aberdeen Proving Ground, MD, USA

Edward Meek, MS Center for Environmental Health

Sciences, Mississippi State University, Mississippi, USA

Elaine Merrill Biological Modeling Group, The Henry

M. Jackson Foundation, Wright-Patterson AFB, OH, USA

Sylvia Milanez, PhD, DABT Environmental Sciences

Division, Oak Ridge National Laboratory, Oak Ridge, TN,

USA

Igor Mindukshev, PhD, DSc (Physiology) Sechenov

Institute of Evolutionary Physiology and Biochemistry,

Russian Academy of Sciences, Saint-Petersburg, Russia

Katarina Mis, PhD Institute of Pathophysiology, Medical

Faculty, University of Ljubljana, Ljubljana, Slovenia

Shree Mulay, PhD Community Health and Humanities

Division, Memorial University, St. John’s, NL, Canada

Michael J. Murphy, DVM, JD, PhD University of

Minnesota, Stillwater, MN, USA

Kamil Musilek, PhD University of Defence, Faculty of

Military Health Sciences, Department of Toxicology and

Military Pharmacy, Hradec Kralove, Czech Republic

University Hospital, Biomedical Research Center, Hradec

Kralove, Czech Republic University of Hradec Kralove,

Faculty of Science, Department of Chemistry, Hradec

Kralove, Czech Republic

Trond Myhrer, PhD Protection and Societal Security

Division, Norwegian Defence Research Establishment

(FFI), Kjeller, Norway

Tetsu Okumura, MD, PhD Department of Crisis

Management Medicine on CRANE Threats, Saga

University, Saga, Japan

Dennis Opresko Toxicology and Hazard Assessment,

Environmental Sciences Division, Oak Ridge National

Laboratory, Oak Ridge, TN, USA

Tatiana Orlova Research Institute of Hygiene, Occupational

Pathology and Human Ecology, Saint-Petersburg, Russia

Aas Pål, PhD Protection and Societal Security Division,

Norwegian Defence Research Establishment (FFI), Kjeller,

Norway

Xiaoping Pan, PhD Department of Biology, East Carolina

University, Greenville, NC, USA

Jiri Patocka, DSc Department of Radiology and Toxicology,

University of South Bohemia, Ceske Budejovice, Czech

Republic

Sergej Pirkmajer, MD, PhD Institute of Pathophysiology,

Medical Faculty, University of Ljubljana, Ljubljana,

Slovenia

Rene Pita, PhD Major Chemical Defense Department,

CBRN Defense School, Spain

Jason Pitt, PhD Department of Physiology, Northwestern

University, Chicago, IL, USA

Carey Pope, BS, MS, PhD Department of Physiological

Sciences, CVHS, Oklahoma State University, Stillwater,

OK, USA

Daria Prokoieva, PhD Research Institute of Hygiene,

Occupational Pathology and Human Ecology,

Saint-Petersburg, Russia

Andrey Radilov, PhD, DSc (Medicine) Research Institute

of Hygiene, Occupational Pathology and Human Ecology,

Saint-Petersburg, Russia

Shashi K. Ramaiah, DVM, MVSc, PhD, DACVP,

DABT Translational Pharmacology and Clinical

Pathology, Pizer Inc., Cambridge, MA, USA

Aramandla Ramesh, PhD Department of Biochemistry and

Cancer Biology Meharry Medical College, Nashville, TN,

USA

Arunabha Ray, MD, PhD Department of Pharmacology,

V.P. Chest Institute and Faculty of Medicine, University of

Delhi, Delhi, India

Kausik Ray, PhD NIDCD National Institutes of Health,

Bethesda, MD, USA

Vladimir Rembovskiy, PhD, DSc (Medicine) Research

Institute of Hygiene, Occupational Pathology and Human

Ecology, Saint-Petersburg, Russia

CONTRIBUTORS LIST xiv

Raina Rhoades, MS Department of Neuroscience and

Pharmacology, Center for Molecular and Behavioral

Neuroscience, Meharry Medical College, Nashville, TN, USA

Rudy J. Richardson, ScD, DABT Computational

Toxicology Laboratory, Toxicology Program, Department

of Environmental Health Sciences and Department of

Neurology, University of Michigan, Ann Arbor, MI, USA

Valerio Rizzo, PhD Neuroscience, The Scripps Research

Institute, Jupiter, FL, USA

Peter J. Robinson Biological Modeling Group, The Henry

M. Jackson Foundation, Wright-Patterson AFB, OH, USA

Chris Ruark Biological Modeling Group, The Henry M.

Jackson Foundation, Wright-Patterson AFB, OH, USA

Harry Salem, PhD, ATS Research and Technology,

Department of the Army, Aberdeen Proving Ground, MD,

USA

Tetsuo Satoh, PhD Department of Pharmacology and

Toxicology, Chiba University, Chiba, Japan

Russell E. Savage, MTSC, PhD Division of Environmental

Health Sciences, College of Public Health, The Ohio State

University, Columbus, OH, USA

Elena Savelieva, PhD, DSc (Chemistry) Research Institute

of Hygiene, Occupational Pathology and Human Ecology,

Saint-Petersburg, Russia

Lawrence M. Schopfer, PhD Eppley Institute, University of

Nebraska Medical Center, Omaha, Nebraska, USA

Alfred M. Sciuto, PhD Medical Toxicology Branch,

Analytical Toxicology Division, US Army Medical

Research Institute of Chemical Defense, Aberdeen Proving

Ground, MD, USA

Yasuo Seto, PhD Third Department of Forensic Science,

National Research Institute of Police Science, Kashiwa,

Chiba, Japan

Michael P. Shakarjian, PhD Environmental Health Science,

New York Medical College, School of Health, Sciences and

Practice, Valhalla, NY, USA

Miguel Sogorb, PhD Institute of Bioengineering,

University Miguel Hernández de Elche, Elche, Spain

Hermona Soreq, PhD Edmond and Lily Safra Center

for Brain Science, The Hebrew University of Jerusalem,

Jerusalem, Israel

Sigrun Hanne Sterri, MSc Department of Protection,

Norwegian Defence Research Establishment (FFI), Kjeller ,

Norway

Melissa Stick, PhD, MPH, NIDCD National Institutes of

Health, Bethesda, MD

Kouichiro Suzuki Department of Emergency Medicine,

Saga University, Japan

Kenji Taki Department of Emergency Medicine, Saga

University, Japan

Horst Thiermann, MD Bundeswehr Institute of

Pharmacology and Toxicology, Munich, Germany

Larry J. Thompson, DVM, PhD, DABVT Global Quality

and Applied Sciences, Nestlé Purina PetCare, St. Louis,

MO, USA

Chibuzor Uchea, PhD Oklahoma State University,

Stillwater, OK, USA

Anton Ukolov, PhD Research Institute of Hygiene,

Occupational Pathology and Human Ecology, Saint-

Petersburg, Russia

Luis G. Valerio Jr., PhD Editorial Ofice, Baltimore, MD, USA

Deon Van der Merwe, BVSc, MSc, PhD Department of

Diagnostic Medicine/Pathobiology, College of Veterinary

Medicine, Kansas State University, Manhattan, KS, USA

Marcel J. van der Schans CBRN Protection TNO, Rijswijk,

The Netherlands

Daya R. Varma, MD, PhD Department of Pharmacology

and Therapeutics, McGill University, Montreal, Quebec,

Canada

Eugenio Vilanova, PhD Institute of Bioengineering,

University Miguel Hernández de Elche, Elche, Spain

Maxim Vinokurov, PhD, DSc (Biophysics) Institute of

Cell Biophysics, Russian Academy of Sciences, Pushchino,

Russia

Natalia Voitenko, PhD Research Institute of Hygiene,

Occupational Pathology and Human Ecology, Saint-

Petersburg, Russia

Nir Waiskopf, MSc The Alexander Silberman Institute of

Life Sciences and The Institute of Chemistry, The Hebrew

University of Jerusalem, Jerusalem, Israel

Annetta Watson, BS, PhD Environmental Sciences Division,

Oak Ridge National Laboratory, Oak Ridge, TN, USA

Sanjeeva J. Wijeyesakere, MPH, PhD Department of

Microbiology and Immunology, University of Michigan,

Ann Arbor, MI, USA

Tina Wismer, DVM, DABVT, DABT ASPCA Animal

Poison Control Center, Urbana, IL, USA

Randall L. Woltjer, MD, PhD Section of Neuropathology,

Oregon Health and Science University, Portland, OR, USA

R. Mark Worden, PhD Chemical Engineering and Materials

Science, Michigan State University, East Lansing, MI, USA

Franz Worek, MD Bundeswehr Institute of Pharmacology

and Toxicology, Munich, Germany

Linnzi Wright, PhD US Army Medical Research Institute of

Chemical Defense, Aberdeen Proving Ground, MD, USA

David T. Yeung, PhD National Institutes of Health,

Bethesda, MD, USA

Takemi Yoshida, PhD Department of Biochemical

Toxicology, School of Pharmacy, Showa University,

Shinagwa, Tokyo, Japan

Robert A. Young, DABT, PhD Environmental Sciences,

Oak Ridge National Laboratory, Oak Ridge, TN, USA

Snjezana Zaja-Milatovic, B.Eng, MS Department of

Hematology and Oncology, University of Virginia School

of Medicine, Charlottesville, VA,USA

Valeriy Zinchenko, PhD, DSc (Biophysics) Institute of

Cell Biophysics, Russian Academy of Sciences, Pushchino,

Russia

Csaba K. Zoltani, PhD US Army Research Laboratory,

Aberdeen Proving Ground, MD, USA

Please could you note that I have only focused on one contributing Paper in this book of 1184 pages.

This does not in any way detract from the excellence of the other 75 Papers, all of which are fascinating, concise and easy to read.

I chose this particular Paper to focus on because it interested me the most as it dovetailed with sections of my earlier Review.[PE]

Medical Management of Chemical Toxicity In Pediatrics

Elora Hilmas and Corey J. Hilmas

INTRODUCTION

There are millions of chemical compounds knownto humanity, but only a limited number are weaponized by conventional militaries. The Organization for the Prohibition of Chemical Weapons (OPCW), the 184-member watchdog agency enforcing the guidelines of the Chemical Weapons Convention (CWC), has identified 55 chemical agents and their precursors that can be

used as weapons (OPCW, 2005). Although some of the chemicals are well known [e.g., sarin, soman, O-ethyl S-[2-(diisopropylamino)ethyl] methylphosphonothioate (VX),mustard], other less obvious choices for chemical terrorism include industrial chemicals such as chlorine and toxic pre-

cursors, which are considered “weapons of opportunity.”In the hands of terrorists, chemical warfare agents (CWAs) and toxic industrial chemicals (TICs) pose sig-

niicant threats to civilian populations. A 2002 report to the US Congress by the Central Intelligence Agency (CIA) reported that terrorist groups “have expressed interest in many toxic industrial chemicals—most ofwhich are relatively easy to acquire and handle—and

traditional chemical agents, including chlorine and phosgene” (DCI, 2002). While traditional chemical warfare nerve agents are attractive to terrorist groups, they require a significant degree of financial resources and capital knowledge to manufacture. Furthermore, the United States and remaining signatory members of the CWC have pledged nonproliferation of CWAs (OPCW, 2005). Unfortunately, millions of tons of TICs continue to be manufactured annually in the United States alone. While they support the wide variety of products generated on a daily basis, including dyes, textiles, medicines, solvents, plastics, paints, and insecticides, they are lethal

compounds in the hands of terrorists. Chemical terrorism is the intentional use of toxic

chemicals to inlict mass casualties on an unsuspecting military or civilian population, including children. Such an incident could quickly overwhelm local and regional public health resources and emergency medical services. In addition to the use of CWAs and TICs, an act of chemical terrorism may involve the targeting of industrial factories, tanker cars, or vehicles containing toxic substances with conventional explosives near residential communities or schools. Regardless of the methods used,the release of toxic chemicals by terrorists embodies a real and serious threat to US national security and public health. They can quickly incapacitate those who are exposed and can lead to mortality if not recognized and treated promptly. Moreover, the toxicity of these agents can be enhanced in children due to pediatric vulnerabilities. It is imperative to recognize the different ways that children may react to toxicity compared to adults.

BACKGROUND

Even though many efforts have been made to protect the United States from terror threats, it remains paramount for the scientiic community to continue building the knowledge base regarding CWAs and better understand the toxicities that can occur when children are exposed. Unfortunately, pediatric treatment recommendations are often extrapolated from adult data, Even though it is well recognized that pediatric patients should not be regarded as miniature adults. Children

present unique vulnerabilities to these chemicals, and special considerations should be taken.

Due to the possibility of pediatric casualties from chemical agent attacks, several pediatric advocacy

groups, such as the American Academy of Pediatrics (AAP), have commented on the urgent need for pediatric chemical casualty research (Blaschke and Lynch, 2003). The Committees on Environmental Health and Infectious Diseases have provided the following consensus statement regarding children and chemical–biological threats (CEH/CID, 2000). Because children would be disproportionately affected by a chemical or biological weapons release, pediatricians must assist in planning for a domestic chemical–biological incident. Government agencies should seek input from pediatricians and pediatric subspecialists to ensure that the situations created by multiple pediatric casualties after a chemical–biological incident are considered.After the terrorist attacks of September 11, 2001, the

AAP initiated a number of initiatives to address the need to prepare for terrorism against children. For example, the AAP created a Task Force on Terrorism, a comprehensive web resource to disseminate information on terrorism and its impact on children. In addition, the AAP has published several reports and policy statements to provide guidance for healthcare practitioners preparing

for a mass chemical casualty event. These efforts were augmented by the passage of several key federal legislative acts aimed at improving public health emergencies and their response to chemical terrorism. Finally, the Centers for Disease Control and Prevention (CDC) created the Strategic National Stockpile (SNS) site as a national repository of antibiotics, chemical antidotes,and antitoxins. The SNS contains a pediatric formulary, along with compounding materials that would assist clinicians in creating dosage forms appropriate for pediatric administration of chemical antidotes (CEH/CID, 2006) in the event of chemical terrorism. Indeed, chemical terrorism on US soil is a very sobering possibility in the future. A significant subset of casualties from a mass chemical exposure will be comprised of vulnerable populations such as children and the elderly. In the hopes of better understanding the impact of such an event, it is necessary to learn from historical incidents and case studies where children were exposed to toxic chemicals and treated. In this chapter, the CWAs and “weapons of opportunity” most likely to be used by terrorists to inlict casualties will be examined, along with a brief historical account and discussion of the unique challenges of managing

pediatric chemical casualties. The sections focusing on each chemical agent will highlight the pediatric-relevant vulnerabilities and guidelines for medical management. The final two sections will discuss decontamination of children and recommendations to help prepare health care managers and providers in the event of a chemical event. It is hoped that this compilation will provide the necessary guidance and treatment recommendations on how best to treat children involved in a chemical attack.

HISTORY OF PEDIATRIC CHEMICAL
CASUALTIES

Historically, chemical attacks were limited to the battlefield, and casualties were predominantly military personnel. In turn, the majority of our knowledge concerning management of chemical casualties has come from the experiences of treating members of the military.

Today, the threat of chemical use is extended to civilian populations as state and non-state sponsored terrorists target innocent civilians. The risk of chemical and biological terrorism is more tangible since the events of September 11, 2001 and the intentional spread of anthrax through the US Postal Service. Terrorists expanded their scope and threat to inflict mass civilian casualties on a scale never before seen. The threat from attack has moved from the traditional battlefield to the home front. Innocent civilians, including children, are now prime targets for groups to foment terror and destabilize governments. Even before the attack on the World Trade Center towers, the twentieth century witnessed numerous instances where civilian populations were exposed to toxic chemicals or targeted on a grand scale. During the flurry of chemical barrages across trench lines in World War I, children from bombed towns in France and Belgium were treated at British, French, and American “gas” hospitals as a result of CWA exposure. Numerous reports of civilian casualties from mustard,chlorine, and phosgene are well documented in British archives (Thomas, 1985). After the initial tally of civilian casualties from gas warfare was complete, participants saw how ill prepared their civilians were against such weapons. School-age children learned the importance of protective measures against chemicals through donning gas masks and evacuating contaminated areas (Figure 68.1). Civilians have been unintended and, in some cases, intended targets of CWAs since World War I. While cyanide was used on Jewish prisoners in World War II, chemical weapons would not be used again during combat on civilian populations until the Iran–IraqWar. In the spring of 1987, Saddam Hussein bombed the Iranian city of Sardasht with mustard munitions,resulting in thousands of civilian casualties (Foroutan,1996a,b, 1998a–c). Following the attack on Sardasht, Iraq attacked Kurd settlements in early 1988, leading to the infamous attack on Kurdish residents of Halabja in March. Thousands of innocent civilian ethnic Kurds perished during the chemical attack, and 75% of them were women and children. Mustard and nerve agents were dropped on civilians from helicopters and planes, and eyewitnesses reported large smoke clouds causing great morbidity and mortality among children (Hay and Roberts, 1990). While the list of nations who have not signed the international treaty to ban chemical weapons is short, it is not surprising that one of those countries has recently been in the international spotlight for stockpiling and deploying chemical weapons in its ongoing civil war. In July 2012, Syria admitted to possessing stocks of chemical weapons. Rebels in northern Syria employed chemical weapons in the town of Khan al-Assal, and opposition forces reported use of chemical weapons (phosphorus bombs) in the Damascus suburb of al-Otaybeh in March 2013. Similar attacks were reported on March 24 in the town of Adra, and on April 29 in the city of Saraqeb. Escalating tensions led to the worst use of chemical weapons since Saddam Hussein’s ethnic cleansing of Kurds from northern Iraq in 1988. Another attack happened in the early morning hours on August 21, 2013, in multiple civilian locations on the outskirts of the Syrian

capital of Damascus. Concluding a monthlong investigation by the United Nations, Secretary-General Ban Ki-Moon confirmed that Sarin nerve gas was indeed the culprit in this rocket assault (Figure 68.2). Sarin gas was deployed in either opposition-held or contested regions

containing significant numbers of civilians. Many of the reported casualties were women and children, arriving with constricted pupils, profuse salivation, and hypotonia. News agencies posted numerous photographs involving pediatric casualties in the aftermath of the

sarin rocket attack. While in all numbers of the actual civilian death toll from Sarin are unknown, Damascus field hospitals and clinics reported up to 1,300 dead, with pediatric numbers climbing into the hundreds. The full extent of morbidity among Sarin survivors of the attack is also unknown, but it is clear that hospitals were unprepared to handle the mass influx of casualties with suffi-

cient stockpiles of nerve agent antidotes. Damascus is a reminder of the horror and threat posed by nerve agents. These events confirm the devastating reality that chemical threats pose to our unprotected population today. A military and civilian response to the use of chemical weapons on American soil may not be a matter of if, but rather when. These events underscore the need

for all pediatric-related healthcare workers to prepare for a mass casualty incident involving CWAs or TICs.

CHALLENGES TO MANAGING
PEDIATRIC CHEMICAL CASUALTIES
Overview

Managing the pediatric victims of chemical terrorism is an especially difficult challenge. In addition

to the obvious physiologic and anatomic differences in children compared to adults (Table 68.1),there are important psychological and behavioral differences that put children at risk (Rotenberg and Newmark, 2003). Anecdotal reports have claimed that children are likely to be the first to manifest symptoms, to develop more severe manifestations, and to be hospitalized for other related illnesses. In fact, it is anticipated that children will be overrepresented among the initial index cases in a mass civilian exposure to toxic chemicals. Children have many characteristics that make them vulnerable to toxic exposures. The smaller mass of a child automatically reduces the dose of toxic agents needed to cause observable or lethal effects. Studies involving organophosphates (OPs), compounds related to nerve agents,have shown that immature animals have greater vulnerability. Some OPs produce the same degree of lethality in juveniles at a fraction of the dose producing lethal-

ity in adults (Rotenberg and Newmark, 2003). Children exhibit an exceptional vulnerability to both the acute and chronic effects of chemicals and are disproportionately more susceptible than adults. The increased toxicity seen in children compared to adults from various routes of exposure can be attributed to a wide variety of factors (shown in Exhibit A). These unique anatomical and physiological considerations described next cause the rates of absorption, distribution, metabolism, and excretion of toxic chemicals and drugs to differ in children with respect to adults.

TABLE 68.1 Summary chart of pediatric vulnerabilities and implications for clinical Management.

Unique Vulnerability in Children
Implications and Impact from Chemical Toxicity
BODY COMPOSITION
● Larger BSA/body mass
● Lower total lipid/fat content
● Greater dermal absorption
● Less partitioning of lipid
soluble components
VOLUME STATUS
● More prone to dehydration
● Chemical agents lead to
diarrhea and vomiting
● Children can be more
symptomatic and show signs of
severe dehydration
RESPIRATORY
● Increased basal metabolic
rate/greater minute volume
● Enhanced toxicity via
inhalational route
BLOOD
● Limited serum protein-
binding capacity
● Greater cutaneous blood low
● Potential for greater amount
of free toxicant and greater
distribution
● Greater percutaneous absorption
SKIN
● Thinner epidermis in preterm
infants
● Greater cutaneous blood low
● Increased toxicity from
percutaneous absorption of
chemical agents
ORGAN SIZE/ENZYMATIC FUNCTION
● Larger brain/body mass
● Immature renal function/
lower renal function
● Immature hepatic enzymes
● Greater CNS exposure
● Slower elimination of renally
cleared toxins, chemicals and
metabolites
● Decreased metabolic clearance
by hepatic phase I and II
reactions
ANATOMICAL CONSIDERATIONS
● Short stature: breathe closer
to ground where aerosolized
chemical agents settle
● Smaller airway
● Greater deposition of ine
particles in the upper airway
● Higher proportion of rapidly
growing tissues
● Mustard signiicantly affects
rapidly growing tissues
● Exposure to chemicals can have
signiicant impact on bone
marrow, developing CNS
● Increased airway narrowing
from chemical agent-induced
secretions
CNS
● Higher BBB permeability
● Rapidly growing CNS
● Increased risk of CNS damage
MISCELLANEOUS
● Immature cognitive function
● Unable to lee emergency
● Immature coping
mechanisms
● Inability to discern threat,
follow directions, and protect
themselves

● High risk for developing PTSD

(It is not always appreciated that many first responders will also suffer long-term PTSD - from seeing horribly disfigured individuals, seeing those whose lives they were unable to save dying in agony, having to negotiate the trauma of dealing with swollen lesions and dermatological post consequences which training has not adequately prepared them for - in its extreme. PE) 

PREPARATION FOR A CHEMICAL EVENT

Understanding chemical agents used for terrorism and knowing how to manage toxicity is just the first step in preparing for a chemical event. Appropriate training on how to manage pediatric patients in these scenarios

is critical. Pediatricians are uniquely trained to participate in the management of pediatric casualties and to advocate for children so that their needs are addressed in emergency planning (Bradley et al., 2003). Many hospitals have held emergency exercises to see how prepared they are for these situations. Beyond this, the assessments should identify deficits and should be used to forge partnerships and relationships and share assets in the community to manage every possible scenario (Blaschke et al., 2003). Healthcare facilities responsible for treating pediatric victims in a chemical–biological event could be easily strained and overwhelmed. Often large-scale

chemical–biological incidents necessitate the use of alternative areas to triage patients such as auditoriums and arenas. These alternative triage areas need to know how to manage pediatric victims (CEH/CID, 2000). Planning for an attack begins with the development of local health resources. Unfortunately, with chemical releases, clinical effects can occur extremely quickly, limiting the amount of time available to borrow resources from nearby communities. First-responders must be educated to recognize pediatric signs and symptoms from each chemical agent, how to wear protective gear in the face of persistent agents, handle pediatric patients, and be able to manage field decontamination. It is critical that adequate supplies of protective gear are available. When planning for decon-tamination procedures, pediatric vulnerabilities and challenges need to be considered, such as the temperature of the water and the ability of children to follow directions. Since children spend the majority of the day at school,community preparation for a threat must include the local educational system. Development of a rapid evacuation plan and the establishment of in-school shelters are critical. Schools can play a valuable role for the management of pediatric casualties. Another key element to appropriate preparedness is the development of a pharmaceutical cache of antidotes, antibiotics, and vaccines. This cache will play a key rolein the initial management of a chemical attack. Even though the SNS is now in place throughout the United States, it may be several hours before it reaches a hospital and the supply is divided among several sites. The SNS has made efforts to include pediatric-ready medications, such as suspensions and solutions. Efforts must be made for local pharmaceutical caches to address pediatric needs. An example of a pediatric pharmaceutical cache is displayed in Table 68.9.

EFFECTS OF SPECIFIC AGENTS

Nerve Agents

Introduction

Nerve agents pose a real threat to our unprotected civilian population. They can quickly incapacitate those  who are exposed and can lead to mortality if not recognized and treated promptly. The toxicity of these agents can be enhanced in children due to pediatric vulnerabilities. Also, it is important to recognize the different ways that children may react to toxicity compared to adults. The major nerve agents are the G-series (tabun, sarin, cyclosarin, and soman) and V-series (VX) compounds, which are clear, colorless, tasteless, and in most cases, odorless. They have been demonstrated to penetrate normal clothing and skin. Also, these agents are highly toxic, as evidenced by the fact that as little as 10 mg of VX on the skin is considered to be an LD 50 in adults

(Rotenberg and Newmark, 2003). In addition, these agents produce toxicity rapidly compared to biological agents. Most G-series nerve agents are highly volatile, and can be dispersed into aerosols that are inhaled by victims. One of the G-series agents, Sarin, is volatile and may sink close to the ground (in undisturbed air) where children breathe. Nerve agents may also be dissemi-

nated in liquid form. Treatment for dermal exposure begins with rapid topical decontamination. Although our military experience managing toxicity from nerve agent exposure is limited, exposures to related chemicals such as the OP class occur commonly each year in the United States. In 2006, there were a total of approximately 5,400 OP exposures across the United States (Bronstein et al., 2007). OPs, such as malathion, are commonly used as pesticides. OP toxicity manifests in a similar fashion as toxicity from nerve agents; however,

this chemical class is considerably less toxic. One case series of 16 children who experienced poisoning with OPs conirmed that pediatric patients present with toxicity differently than adults (Lifshitz et al., 1999). These children often did not manifest the classic muscarinic effects (such as salivary secretions and diarrhea) seen in adults.

Mechanism of Toxicity

Nerve agents cause toxicity by inhibiting esterase enzymes, especially  acetylcholinesterase (AChE;Rotenberg and Newmark, 2003). When nerve agents bind to AChE, they prevent hydrolysis of acetylcholine (ACh). When ACh accumulates in the synaptic space of neurons, this leads to overstimulation of muscarinic and nicotinic receptors that is often termed cholinergic crisis. Also, it is important to note that the nerve agent–AChE bond undergoes a reaction called aging (Dunn and Sidell, 1989). Once this process is complete, the enzyme becomes irreversibly inactivated. This aging process dictates the need for prompt therapy to prevent irreversible toxicity.

Clinical Presentation

The signs and symptoms of a cholinergic crisis can be remembered using the mnemonic BAG the PUDDLES (Figure 68.4); these range in severity from lacrimation and urination to seizure activity (Rotenberg and Newmark, 2003). The manifestations of cholinergic crisis seen in a particular individual depend on the dose and route of exposure, as well as the duration of exposure. If

death occurs from nerve agents, it is primarily attributed to respiratory failure. Nerve agents affect the respiratory system by causing central apnea, laccid neuromuscular paralysis, bronchoconstriction, and profound glandular

secretions (Hilmas et al., 2006). Children present a clinical picture that can be very different to that observed in adults. Children in cholinergic crisis may not necessarily manifest with miosis (constriction of pupils) (Rotenberg and Newmark, 2003). In fact, one case series demonstrated absence of miosis

in 43% of pediatric victims. Many of the pediatric case reports involving nerve agent exposure in children in Halabja and Damascus involved mydriasis (pupil dilation), so children may not always follow a classic picture of cholinesterase inhibition with regard to pupillary indings. Studies involving pediatric exposure to OPs have suggested the appearance of isolated CNS effects

(such as stupor and coma) in the absence of peripheral muscarinic effects. Pediatric victims of OP intoxication display significant muscular weakness and hypotonia in the absence of glandular secretions in 70–100% of cases involving moderate to severe levels of exposure (Rotenberg and Newmark, 2003). For adults, a presentation of central intoxication (weakness and hypoto-

nia) from OPs without peripheral muscarinic signs and symptoms would be extremely atypical. Unfortunately, there are no data on the long-term effects of nerve agent poisoning in children, and the effects must be extrapolated from  hat has been discovered in the adult population (Rotenberg and Newmark,2003). Surveillance studies performed on victims of the Sarin attacks in Japan revealed a wide range of sequelae, such as continued respiratory problems, vision disturbances, headache, and fatigue. Neuropsychiatric prob-

lems were also reported as a delayed effect.

Laboratory Findings

Use of cholinesterase levels is limited, especially for confirmation of exposure (Rotenberg and Newmark,2003). Treatment should not be delayed for these levels to return. Levels should be used after exposure only to confirm diagnosis (after treatment has begun), to monitor recovery, or for forensic investigation.

Pediatric Vulnerability

Children have several vulnerabilities, putting them at risk of increased toxicity from this class of chemical agents. A child’s smaller mass alone reduces the dose needed to cause symptoms or lethality. For volatile nerve agents, children are especially at risk for respiratory toxicities due to their anatomic differences compared to adults. Their smaller airways can become compromised by the large amount of secretions and the bronchospasm caused by the agents. Also, a greater dose of nerve agent will be inhaled in children due to their higher respiratory rate and minute volumes.

Treatment

The overall treatment approach to nerve agent exposure focuses on airway and ventilatory support, aggressive use of antidotes (atropine and pralidoxime), prompt control of seizures, and decontamination as necessary (Henretig et al., 2002a). Atropine is used for its antimus-carinic effects, and oxime is used to reactivate AChE. The combination of atropine and pralidoxime chloride (2-PAM Cl) is recommended for the prompt treatment of all serious cases. The timing of atropine and 2-PAM Cladministration is critical. In short, the sooner these antidotes are given, the better the outcome. Oxime therapy is rendered ineffective if given after the enzyme aging

process has been completed (Dunn and Sidell, 1989). This fact has led to the use of autoinjectors because of their ability to rapidly administer intramuscular doses of these medications. However, there are no current Food and Drug Administration (FDA)–approved pediatric autoinjectors for 2-PAM Cl. Other administration routes and methods include intravenous (IV) or intraosseous (IO) for atropine and slow IV or continuous infusion for 2-PAM Cl. Data show that peak plasma concentra-

tions of medications administered from autoinjectors are achieved in less than 5 min versus 25 min for intramus-

cular (IM) administration using a needle and syringe (Rotenberg and Newmark, 2003). The mainstay of adult therapy includes the use of autoinjector technology con-

taining atropine and 2-PAM. Recently, a dual-chambered

autoinjector called the Antidote Treatment Nerve Agent

Autoinjector (ATNAA) has received FDA approval for the military and Duodote for civilian emergency medical technicians and irst-responders (see Figure 68.5). Meridian also produces the older Mark I kit (Figure 68.6), which is composed of separate autoinjectors for atropine and 2-PAM. These products are provided by Meridian Medical Technologies, which has partnered with the US Department of Defense to be the only FDA-approved supplier of nerve agent antidotes. The Mark I kit and the single autoinjector devices deliver 600 mg of 2-PAM Cl and 2 mg of atropine (AtroPen) in seconds. This kit

was developed originally for administration to soldiers, not for children, and with the approval of the Duodote system, the Mark I kit will most likely become antiquated. The autoinjector technology incorporates a spring-loaded needle to disperse medication in an all-or-nothing fashion. It is impossible to give partial doses of an autoinjector to children. Drug dosing of atropine and 2-PAM Cl in pediatrics is primarily weight based, so astandard dose cannot be used. Pediatric versions of the Mark 1 kit are available overseas but are not currently

available in the United States (PEAP, 2004). In June 2003,

the FDA approved pediatric doses of the AtroPen (atropine autoinjector) to respond to the lack of pediatric-speciic therapy (Meadows, 2004). Meridian’s AtroPen is now available in four dosages, 0.25, 0.5, 1, and 2 mg (Figure 68.7). The 0.25-mg dose should be used for infants weighing less than 7 kg, the 0.5 mg treats patients weighing 7–18 kg, the 1 mg treats patients weighing 18–41 kg,and the 2 mg dose should be used for children and adolescents who weigh more than 41 kg. The needle length for these autoinjectors is 0.8 inches, with a needle gauge of 22. The administration technique of autoinjectors in children is shown in Figure 68.8. Since the AtroPen delivers only atropine and not 2-PAM Cl, there continues to be a limitation to the prompt treatment of children. This fact has caused groups such as the pediatric expert advisory panel from the National Center for Disaster Preparedness to recommend the use of the Mark 1 kit before using the AtroPen (PEAP, 2004). Information on how to use the Mark 1 kit for children is given in Table 68.2. The use of adult dose-based autoinjectors in children has been addressed. Amitai et al. (1999) reviewed 240 instances of accidental pediatric atropine injections using adult dose-based autoinjectors. A low incidence of toxicity was found, with no seizures, arrhythmias, or death. Subsequently, several pediatric guidelines have suggested adult-dose atropine and 2-PAM Cl autoinjectors can be safely used in children larger than 13 kg and inserted 0.8 in. Administration of atropine and 2-PAM Cl must be done cautiously (Rotenberg and Newmark, 2003). Atropine can cause increased heart rate, dry mouth and

skin, and near vision can be affected for up to 1 day. Because sweating is prevented, elevated temperatures and heat stress may be observed. Exposure to 2-PAM Cl can cause double or blurred vision and dizziness (Anon, 2002). Doses must be reduced with renal insuficiency. If a medication is given too quickly as an IV injection, laryngospasm and rigidity can occur. Higher doses can cause hypertension while lower doses can cause mild electrocardiogram (ECG) changes (Rotenberg

and Newmark, 2003). Although benzodiazepines are not considered to be an antidote, their use in the treatment of nerve agent exposure is critical (Rotenberg and Newmark, 2003). Status epilepticus can often occur as the nerve agent crosses

the BBB and causes irritation. Benzodiazepines are the only effective agents that have been proven to treat nerve agent-induced seizures. This group of medications should be used for both prevention and treatment. It is recommended that if more than one organ is impaired, there is impaired consciousness or muscle twitching, and benzodiazepines should be quickly administered. In choosing a specific medication, various agents can be used. Our military department uses the medication diazepam that is administered as an autoinjector (Figure 68.9). In Israel, there is a move toward using midazolam for their

population. Some physicians are recommending the use of lorazepam in the pediatric population. Regardless of which medication is used, repeat doses may be needed. For the pediatric population, benzodiazepines should be considered if there is any suspicion of seizure. Nonconvulsive status and subtle seizures are common in infants and children, making it difficult for healthcare providers to recognize nerve agent toxicity.

FIGURE 68.4 Helpful mnemonic for cholinergic crisis (BAG the PUDDLES). 

Source: Illustrations are copyright-protected and printed with permission by Alexandre M. Katos (Rotenberg and Newmark, 2003).

VIII. PROPHYLACTIC, THERAPEUTIC AND COUNTERMEASURES

FIGURE 68.5 ATNAA and Duodote. Source: Photo reproduced with permission from Meridian Medical Technologies.

FIGURE 68.7

Atropen pediatric autoinjectors.

Dose sizes:

0.25 mg—infant,

0.5 mg—child (7–18 kg), 1 mg—child (18–41 kg),

2 mg—adolescents and adults.

Source: Photograph reproduced with permission from Meridian Medical Technologies.

Effects Of Specific Agents

VIII. PROPHYLACTIC, THERAPEUTIC AND COUNTERMEASURES

For each of the medications used to treat nerve agent toxicity, there are weight-based dosing recommendations for pediatric patients. The exact dose to utilize for a specific patient will depend on two critical factors: the severity of the exposure and the weight or age of the patient. Pediatric-dosing recommendations for medications used to treat mild to moderate nerve agent exposure are displayed in Table 68.3. Dosing recommendations to treat severe nerve agent exposure are displayed in Table 68.4.

Perioperative Care of Children with Nerve Agent

Intoxication

As mentioned earlier, it is not uncommon for chemical exposures and trauma to occur at the same time, requiring surgery. It is important to realize that many drugs

used for perioperative management can exacerbate the side effects encountered with nerve agent exposure. Nerve agents can cause drug interactions with medications typically used for resuscitative efforts (Abraham et al., 2001). Anesthetics, such as sodium pentothal and propofol, cause cardiac depression, an effect exacerbated by the excessive muscarinic activity induced by nerve agents. Doses of these drugs may need to be reduced.

Use of volatile anesthetics may be preferable because they bronchodilate and reduce the need for nondepolarizing drugs. When nondepolarizing drugs are used, they are often reversed by the use of neostigmine, which affects AChE activity. Halothane should be avoided in infants because the cardiac side effects can be accentuated in the presence of nerve agents. Depression of the cardiovascular system by halothane may cause further bradycardia, hypotension, and reduction in cardiac output. In general, the use of muscle relaxants is not recommended in the setting of nerve agent toxicity. Nerve agents provide a depolarizing block, and in the presence

of inhibited AChE activity, drugs such as succinylcho-line can have longer effects than expected (Rotenberg,2003b). Careful use of analgesia is important when caring for victims of nerve agent exposure (Abraham et al., 2001). In general, opioids are considered safe to use because they do not act on the cholinergic system directly. However, some side effects of the drugs, such as histamine release and rare muscle rigidity, can cause difficulty in patient management. Careful dose titration and monitoring for side effects is critical. However, there is one opioid that can have an interaction with nerve agents. Remifentanil, a potent opioid, contains an ester linkage susceptible to hydrolysis because it is partially metabolized by plasma cholinesterase. This is the same enzyme that is inacti-

vated by nerve agents, resulting in a prolonged duration of action for remifentanil. Therefore, use of remifentanil in the postoperative care of nerve agent-exposed victims is not recommended, as other analgesics are available (Rotenberg, 2003b). Compared to other CWAs, patients exposed to nerve agents pose unique challenges for medical and surgical management.

Summary

Nerve agent exposures must be handled quickly and efficiently. When children are exposed, it is important to remember that antidote dosing will be determined by the patient’s weight and the severity of exposure. Progress has been made to provide pediatric-specific autoinjectors; however, since 2-PAM Cl is not yet available in a pediatric autoinjector form, adult autoinjectors can be used (but carefully) to manage pediatric patients.

Carbamates/Organophosphates

Introduction

Carbamates and OPs are chemicals that are often used as fungicides, insecticides, or pesticides and possess actions similar to nerve agents. These compounds are considered weapons of opportunity since their primary use is not by conventional militaries. In the United States, toxicity from these compounds is fairly rare. In 2006, there were approximately 1,200 cases of carbamate exposures and 1,500 OP exposures documented for children 19 years old and younger (Bronstein et al., 2007).

Although there were a few fatalities reported in 2006 from these substances, these fatalities occurred only in older individuals.

In general, the toxicity of these compounds resembles that of nerve agents, but it is less severe. Pediatric cases of toxicity reported in the literature are often due to accidental poisoning, when a young child ingests chemicals placed in unsecured or unlabeled containers. Exposure also can come by consuming foods that havebeen sprayed with pesticides. Most of the  writings on pediatric toxicity from these agents includes retrospective reviews coming out of Israel, where use of these

substances as a pesticide for the home and agriculture is common. A retrospective review of 37 cases from the United States has also been published (Zwiener and Ginsburg, 1988).

Mechanism of Toxicity

These compounds inhibit the hydrolysis of the neurotransmitter ACh by the enzyme AChE within the mammalian nervous system (Zwiener and Ginsburg,

1988). This inhibition causes ACh levels to rise, thus causing cholinergic hyperstimulation at muscarinic and nicotinic receptors. There are important differences in the way carbamates and OPs bind to AChE, as well as their ability to affect the CNS. Carbamates are reversible inhibitors of cholinesterase enzymes. Carbamates create a reversible bond to the cholinesterase enzyme through carbamylation, which can spontaneously hydrolyze and reverse the toxicity. Carbamate poisoning produces toxicity similar to that of OPs; however, the toxicity is usually of a shorter duration and less severe in nature (Lifshitz et al., 1994). In contrast, OPs inhibit cholinesterase via an irreversible bond of phosphate radicals to the active esteratic site of the enzyme (Lifshitz et al., 1999).

Thus, the toxicity is more severe.

Clinical Presentation

OPs and carbamates have different receptor activities in the mammalian nervous system. OPs have effects on muscarinic and nicotinic receptors and can cause neurological effects in the CNS (Levy-Khademi et al., 2007). Carbamates are thought to cause only parasympathetic muscarinic effects, with limited nicotinic and CNS effects (Sofer et al., 1989). However, there are case reports in children that have revealed the presence of CNS effects with carbamate exposures (de Tollenaer et al., 2006). One pediatric case series stated that the signs and symptoms from carbamate poisoning were indistinguishable from OP exposures, with severe CNS depression, and stupor and coma occurring in eight cases (Sofer et al., 1989).

Muscarinic hyperstimulation leads to a clinical presentation of miosis, lacrimation, salivation, bradyarrhythmia, urinary incontinence, and intestinal hypermotility (Levy-Khademi et al., 2007). Nicotinic hyperstimulation leads to fasciculations, weakness, and paralysis of skeletal muscles. CNS effects include depression and agitation with coma and seizures occurring in the most severe cases for adults. Generalized tonic–clonic seizures have been seen in several pediatric exposure cases reported in the literature (Zwiener and Ginsburg, 1988).

Additional toxicities that have been reported in children include diarrhea, pulmonary edema [which was associated with OP exposure but not carbamate exposure (Lifshitz et al., 1999)], acute pancreatitis, hyperglycemia (Weizman and Sofer, 1992), dyspnea, sweaty cold skin (Sofer et al., 1989), respiratory distress or failure, lethargy, and tachycardia (Zwiener and Ginsburg, 1988).

Laboratory Findings

Key findings that have been reported include significant hypoxia, acidosis, and carbon dioxide retention (Soferet al., 1989). Also, hyperglycemia, hypokalemia, and leukocytosis were observed in a case series of OP exposures (Levy-Khademi et al., 2007). A study done on 17 children with typical OP or carbamate poisoning looked at laboratory abnormalities that are associated with acute pancreatitis. Five of the patients (30%) had laboratory values consistent with pancreatitis with elevated immunoreactive trypsin, amylase, and serum glucose. None of the patients had hypocalcemia, renal dysfunction, or acidosis, and all experienced complete recovery of pancreatic

function. The authors concluded that acute pancreatitis, due to anticholinesterase (anti-AChE) intoxication, is not uncommon in the pediatric population (Weizman and Sofer, 1992). Pancreatitis has been described in adult exposures, and the association has been investigated in animal studies (Weizman and Sofer, 1992). Another laboratory value that is often obtained in these exposures is serum pseudocholinesterase. Serum pseudocholinesterase activities are often assessed as normal in children because the reference standards may not be reliable when assessing them. To add to the complexity, the normal range of serum cholinesterase activity is wide (Sofer et al.,1989). Researchers have described the limitations of this

measurement in determining therapy for children. In fact,

it is recommended that a therapeutic and diagnostic trial

of atropine should be given whenever there is any possibil-

ity of intoxication with these chemicals (Sofer et al., 1989).

Additional laboratory abnormalities that have been reported in children are cardiac disturbances. Prolonged QTc intervals were reported in a few children exposed to OPs. However, there was spontaneous resolution, with no evidence of ventricular dysrhythmia on ECG (Levy-Khademi et al., 2007.)

Pediatric Vulnerabilities

The clinical picture of anti-AChE intoxication in children is very different than that of adults. Often, clinicians have difficulty in diagnosing the exposure in pediatric patients. In fact, in a retrospective review of OP/carbamate toxicity cases that were admitted to a children’s medical center in the United States, the transfer diagnosis was incorrect in 80% of the patients (Zwiener and Ginsburg, 1988). Patients were misdiagnosed with a wide variety of disease states that ranged from head trauma to cranial aneurysm to diabetic ketoacidosis. It was noted that the difficulty in identifying nicotinic and

muscarinic signs in children may have contributed to the high misdiagnosis rate. For example, it may be difficult to distinguish normal infant crying from excessive lacrimation (Zwiener and Ginsburg, 1988.)

The lack of classic muscarinic effects does not exclude the possibility of cholinesterase inhibitor poisoning in young children with CNS depression. In one case series, tearing and diaphoresis were not observed in pediatric patients (Lifshitz et al., 1999). Miosis was absent in a number of pediatric patient cases reported in the literature with 27% of children in one case series lacking miosis on admission (Zwiener and Ginsburg, 1988). The percentage was 20% in another case series of pediatric patients (Sofer et al., 1989).

Adult literature states that the most important signs of OP toxicity are fasciculations and miosis.

VIII. PROPHYLACTIC, THERAPEUTIC AND COUNTERMEASURES

Effects Of Specific Agents

In one published pediatric case series, fasciculations were quite infrequent, occurring in only 16% of cases (Sofer et al.1989.) Another pediatric case series veriied this result, with the frequency of fasciculations being 22% (Zwiener

and Ginsburg, 1988.) Another difference is the cardiac manifestations that are seen in adults compared to children. In one pediatric case series, cardiopulmonary manifestations were the least common, with tachyarrhythmias being more common than the bradyarrhythmias that are typically seen in adults (11 patients versus 1 patient) (Levy-Khademi et al., 2007.)

Compared to adults, neurological manifestations of toxicity were the most common in children. In one case series, signiicant hypotonia and muscle weakness were observed in all children (Lifshitz et al., 1999). In addition, severe CNS depression with stupor and coma occurred in all the cases (Lifshitz et al., 1999). In another case series, coma occurred in 54.8% and seizures in 38.7% of children who were accidentally exposed to OPs (Levy-

Khademi et al., 2007). It can be theorized that the more

permeable BBB in young children permits penetration of the toxic agents into the brain, thus causing CNS depression. Another theory is that in young children, cholinesterase inhibitors have a stronger affinity to AChE in the CNS and less affinity to cholinergic synapses in the autonomic ganglia (Lifshitz et al., 1999). Accumulation of toxic compounds or their metabolites in the brain could also result in severe CNS dysfunction. Another thought is that the hypoxemia that has been observed in several pediatric cases could contribute to CNS depression (Sofer et al., 1989).

Treatment

In all pediatric cases, supportive care was used to balance electrolyte disturbances and oxygen was administered for hypoxic episodes. Often, patients were intubated and given mechanical ventilation due to the excessive salivation and bronchial hypersecretion. Gastric lavage was utilized in one case of OP ingestion (Rolfsjord et al.1998). The treatment of OP intoxication mimics that of nerve agent exposures. Atropine and an oxime (such as pralidoxime) are the agents of choice for OP exposures. Atropine therapy alone is recommended for carbamate exposure because carbamates reversibly inhibit AChE, so there is little need for an agent such as an oxime, which reactivates the enzyme. In cholinesterase inhibitor poisoning, atropine will alleviate most of the muscarinic signs, few of the CNS symptoms, and almost none of the nicotinic symptoms (Lifshitz et al., 1999.) Although atropine use is standard, clinicians are some times faced with the dilemma of administering atropine to a pediatric patient with an elevated heart rate. Due to the fact that children may manifest tachycardia with toxic exposures and the fact that the chronotropic effects of atropine may be minimal in infants and small children compared with healthy young adults, one group of authors suggests that atropine should not be withheld or administered in subtherapeutic doses in tachycardic infants and children with OP or carbamate exposure. Their experience with pediatric patients showed that for patients with tachycardia at the time that atropine was administered, their heart rate decreased and none of the patients developed cardiac arrhythmias (Zwiener and Ginsburg, 1988.)  Use of oximes is well accepted for OP exposures, but their role in carbamate poisoning is controversial.

Animal studies have shown oxime use can increase toxicity when treating carbaryl exposure (Lifshitz et al. 1994.) Therefore, there is a general guideline that oximes should be avoided if a carbamate exposure is suspected.  One case series reported the routine use of oxime therapy for carbamate exposures in children (Lifshitz et al.1994). Marked clinical improvement was observed in all patients, regardless of whether they were exposed to an OP or a carbamate. In addition to the retrospective review of cases, the authors completed an in vitro study of oxime use with carbamate toxicity and discovered that oximes play a minor role in direct reactivation of human carbamylated AChE. Due to this inding, the authors concluded that the current guideline to avoid

oxime use in a carbamate exposure is valid. Fortunately, in most cases of OP or carbamate toxicity, pediatric patients recovered fully if they were diagnosed rapidly and appropriate treatments were administered in a timely fashion.

Summary

There is a limited amount of literature available describing the toxicities of OP and carbamate exposure in pediatrics. What literature is available describes major differences between the manner that children manifest toxicity compared to adults. It is critical to understand these differences so that patients are not misdiagnosed and appropriate therapy is not delayed. In general, the CNS toxicities are greater in children than in adults with coma, stupor, and seizures being common. It is important to recognize that if therapy is given in a timely man-

ner, complete recovery is often the outcome for children  exposed to these toxic agents.

Vesicants

Introduction

Blister agents or vesicants are chemicals that cause blister or vesicle formation upon dermal contact. Agents such as mustards or Lewisite have been used as CWAs in the past (Yu et al. 2003.) Although these agents have less toxicity than nerve agents, they cause prolonged morbidity. There are two types of mustard: sulfur mustard (HD) and nitrogen mustards (HNs.) HD caused-

more casualties in World War I than  any other chemical weapon.   It caused a significant number of casualties,

both civilian and military, during the Iran–Iraq War of the 1980s. HD vapor is the route most likely to be used by terror groups (Yu et al., 2003). It affects multiple organ systems including skin, eyes, respiratory and gastrointestinal tracts, and bone marrow (Yu et al., 2003.)

Nitrogen mustards, on the other hand, have never been used on the battlefield and will not be discussed further.  Lewisite, a vesicant with HD-like properties, causes a similar constellation of signs and symptoms involving the skin, eyes, and airways, as well as systemic effects (e.g., increased capillary permeability) after absorption. However, it does not produce immunological suppression like mustard. Another difference is that the management of lewisite toxicity includes an antidote, British anti-lewisite (BAL) (Yu et al., 2003.)

Mechanism of Toxicity

HD rapidly penetrates cells and generates a highly toxic reaction that disrupts cell function and eventually causes cell death (Sidell et al., 1997). It is classified as an alkylating agent, targeting poorly differentiated and rapidly reproducing cells (Yu et al., 2003.) Death is a result of massive pulmonary damage complicated by infection.

Clinical Presentation

Mustard can cause local effects on skin, airways, and eyes; however, large doses can cause fatal systemic effects (Yu et al., 2003). In a study of clinical findings among children exposed to vesicants, ocular, cutaneous,and respiratory signs were the most prevalent (Azizi and Amid, 1990). 

Ocular findings consisted of the following:

conjunctivitis (94%), palpebral edema (81%), eye closure (63%), keratitis (38%), blepharospasm (25%), corneal

ulceration (19%), and chemosis (6%). Cutaneous signs included erythema (94%), hyperpigmentation (75%), ulceration (69%), erosion (63%), blister (56%), edema (50%), vesicles (31%), and hypopigmentation (13%.)

Respiratory signs included dyspnea (63%), crepitation

(50%), and wheezing (25%.)

Other pediatric signs of mustard exposure were photophobia, lacrimation, ophthalmalgia, and eye burning (94%). Dry cough (81%), dermal pain, and burning (94%) were also frequent complaints. Less frequent complaints were diplopia, itchy eyes, sore throat, sneezing, nasal secretions, dyspnea, burning sensation of the upper respiratory tract, suffocation, and dysphonia (Azizi and Amid, 1990.)

Initial dermal signs of toxicity consist of erythema, occurring 4–8 h after exposure. Pruritus can occur with or prior to erythema (Azizi and Amid, 1990; Yu et al.2003). Over the next 24 h, large yellowish blisters form in areas of thin skin, such as the groin and underarms.

Eye damage can occur, ranging from pain and irritation

to blindness. Mustard also causes clinical effects that

can be delayed for hours (Azizi and Amid, 1990; Sidell

et al., 1997; Yu et al., 2003). This causes victims not to recognize toxicity until well after exposure. During this time lag, sulfur mustard works to subclinically damage the skin. This latent period is significant because the shorter the latent period, the more severe the exposure and the worse the outcome.

The CNS and bone marrow can also be affected, as displayed by symptoms of fatigue, headache, and depression (Sidell et al., 1997). HD can also lead to pneumonia, the cause of death for many HD casualties in World War I due to lack of antibiotics. A leukopenic pneumonia usually occurs between 6 and 10 days after HD exposure. The manifestation of leukopenia (specifi-

cally lymphopenia) results from the myelosuppressive

effects of mustard agents.

Laboratory Findings

While there is no diagnostic confirmatory test for mustard exposure, some laboratory tests can prove useful. As described previously, inlammation and infection will show up as fever and leukocytosis. Erythrocyte sedimentation rate (ESR) has been shown to be elevated in patients after mustard exposure (Motakallem, 1988.)

Some of these patients were in the pediatric age range of 0–18 years. Complete blood count (CBC) determinations may show abnormalities depending on the severity of the vapor inhalation or exposure (Azizi and Amid, 1990; Yu et al., 2003). The CBC may show a low hematocrit and leukopenia if the exposure was severe. There may be only a transient decrease in white blood cells (WBCs), with subsequent recovery. In pediatric cases of HD vapor exposure, decreases in hematocrit and/or WBC were likely to occur in the first 2 weeks, with the lowest levels of Hb, Hct, WBC, and neutrophil count observed in the 6th- to 10th-day samples after exposure (Azizi and Amid, 1990.) These pediatric patients also suffered from clear signs of hypoxemia and renal failure (Azizi and Amid, 1990.) Unfortunately, serum creatinine and renal function tests (RFTs) were not found in the charts. ABGs may provide useful information, but they may show a varied picture. In one pediatric study of mustard casualties, most cases (43%) showed simple metabolic acidosis. The other groups showed the following:

● Mixed metabolic acidosis and respiratory alkalosis (29%)
● Simple respiratory alkalosis (14%)
● Mixed metabolic and respiratory acidosis (7%)
● Mixed metabolic alkalosis and respiratory acidosis (7%).

Blood urea nitrogen can be elevated with mustard exposure, but it does not necessarily predict outcome or mortality. Blood urea nitrogen was significantly elevated in severe mustard exposure cases in the Azizi study; three of the four pediatric mustard victims that died showed very high blood urea nitrogen (Azizi and Amid, 1990). While elevations in blood urea nitrogen were found in many of the pediatric casualties from mustard exposure, blood urea nitrogen returned to normal levels soon afterward in survivors.

Pediatric Vulnerability

The effects of sulfur mustard on children are more severe than on adults (Yu et al., 2003). Premature infants have thinner skin, and the dermal–epidermal junction is not fully developed in children (Rutter and Hull, 1979; Harpin and Rutter, 1983; Nopper et al., 1996; Seidenari et al., 2000; Mancini, 2004); therefore, the time between exposure and onset of blisters is shortened, and the number and severity of blisters will be more severe (Yu et al., 2003). In fact,lesions in children exposed to mustard have been shown to be more severe. Initial index cases of mass casualties are typically children. Eye findings tend to be greater in children because of their inability to protect themselves and tendency to rub their eyes (Azizi and Amid, 1990; Yu et al., 2003). Children are also shown to be more sus-

ceptible to pulmonary injury for reasons previously discussed. One case report looked at the long-term effects of mustard exposure in a child (Dompeling et al., 2004). This child suffered an acute, severe chemical pneumonia; the long-term consequence was chronic bronchiolitis. Finally, signs of gastrointestinal toxicity may be greater in children secondary to fluid losses in combination with lower intravascular volume reserves (Yu et al., 2003.) While the decision to evacuate and hospitalize HD casualties is based on the extent [total body surface area (TBSA) >5%], severity of the skin lesions, and the recognition of multiple organ involvement (Graham et al. 2005), the threshold to hospitalize children with HD injuries should be lower. One reason is that vapor mustard used by terrorists may cause extensive pulmonary involvement while producing mild skin blisters.

Treatment

While decontamination and supportive therapy are the mainstays of treatment, antidotes to counteract HD vapor, aerosol, or liquid exposures do not exist (Yu et al. 2003.) Adult decontamination may include bleach solutions; however, this method can cause greater toxicity in children. Soap and water are the preferred agents to use for decontamination in children. Supportive care consists of the management of pulmonary and skin manifestations, such as the use of cough suppressants and

topical silver sulfadiazine for burns (Azizi and Amid,1990; Sidell et al., 1997; Yu et al., 2003.) Pediatric dosage and treatment recommendations for vesicant exposure are displayed in Table 68.5.

There are currently no standardized guidelines of casualty management or drugs available to prevent HD effects on skin and mucous membranes (Sidell et al. 1997; Graham et al., 2005.) The mainstay of treatment is prompt decontamination, blister aspiration or deroofing (epidermal removal), physical debridement, irrigation, topical antibiotics, and sterile dressing application for cutaneous HD injuries. Current treatment strategies rely on symptomatic management to relieve symptoms, prevent infections, and promote healing. The general recommendations are described in the Medical Management of Chemical Casualties Handbook (USAMRICD, 2000a),the Field Management of Chemical Casualties Handbook (USAMRICD, 2000b), and other references (Graham et al., 2005.) We will discuss the aspects of treatment

that relate to the pediatric population. Most pediatric casualties will involve multiple organ systems (e.g., skin, ocular, gastrointestinal, bone marrow, and respiratory), as documented by Iranian physicians treating pediatric casualties of HD vapor during the Iran–Iraq War (Azizi and Amid, 1990.)

Dermatological Management

Managing mustard skin lesions is especially challenging in the pediatric population. The goal of blister management is to keep the patient comfortable, keep the lesions clean, and prevent infection. Children especially will be extremely anxious at the sight of bullae and erythema, in addition to the burning, pruritis, and allodynia associated with HD blisters (Sidell et al., 1997.) Anxiolytics may be appropriate to calm them down and

prevent them from picking at bullae. Burning and itching   associated with erythema can be relieved by calamine or soothing lotions and creams such as 0.25% camphor, menthol corticosteroids, antipruritics (i.e., diphenhydramine),and silver sulfadiazine cream (Azizi and Amid, 1990;Sidell et al., 1997). Pain and discomfort can be relieved with systemic analgesics. Systemic analgesics such as

morphine should be given liberally before manipulation of the burned area.

Vapor mustard typically causes a first- or second-degree burn, while liquid mustard produces damage similar to a third-degree burn. In either case, tense bullae are the hallmark of HD injuries. Bullae are typically dome-shaped, thin-walled, 0.5–5.0 cm in diameter,supericial, translucent, yellowish, multiloculated,  honeycombed (Moradi et al., 1986), and surrounded by erythema (Sidell et al., 1997). Preventing children from breaking the blisters can be a challenge, especially when constant friction from clothing and blankets is irritating to the skin. These areas should be wrapped in protective dressings. Graham et al. (2005) have made an important point about the existence of a reservoir of unbound HD in human skin following a vapor (Logan et al., 2000) or liquid exposure, leading to an off-gassing period. They suggested that this off-gassing period can last for 24–36 h, whereby application of an occlusive dressing is not beneicial to prevent vapor buildup (Graham et al., 2005).

It is recommended that small blisters (<1 cm) should be left alone on the child, but the immediate area should be cleaned, irrigated daily, and covered with topical antibiotic (Sidell et al., 1997). Petroleum gauze bandage dressings should be wrapped around these unbroken blisters and changed every few days. Larger blisters (>1 cm) should be unroofed and irrigated several times a day with saline, sterile water, clean soapy water, or

Dakin’s solution and covered with topical antibiotic cream or ointment. It should be noted that blister fluid does not contain mustard (Buscher and Conway, 1944) and therefore does not represent a hazard to the healthcare worker. Options for topical antibiotic creams in children include silver sulfadiazine, and triple-combination antibiotic (bacitracin, neomycin sulfate, and polymyxin B sulfate; Sidell et al., 1997) but not mafenide acetate, which can cause toxicities in children (Ohlgisser et al.,

1978; Geffner et al., 1981). These topical antibiotics should be applied to the area of bullae and surrounding areas of erythema. There is no information comparing the use of this combination (triple-antibiotic topical ointment) in children with use in other age groups. While skin healing can take months to complete, pigment changes (hyperpigmentation or hypopigmentation) can persist (Sidell et al., 1997; Graham et al., 2005.) It is also important to note that not all burn injuries require treatment at a burn center. Patients will require aggressive pain management and close observation for the systemic effects of HD exposure. Skin grafting, although rare, has been successfully used for deep burns (Ruhl et al.994.)

Ophthalmology

The objective for any ophthalmology consultation on pediatric HD injuries involving the eye is the prevention of scarring and infection (Sidell et al., 1997). Eyes exposed to HD should be irrigated to remove traces of vesicant. Severe ocular involvement requires topical antibiotics (such as tobramycin OD) applied several times a day. Topical steroids may be useful in the first 48 h after exposure. Temporary loss of vision may also occur after mustard exposure (Motakallem, 1988; Azizi and Amid, 1990; Sidell et al., 1997). The patient should be reassured that vision loss is not permanent and is due to palpebral edema, not corneal damage.

Respiratory System

The conducting and ventilation portions of the respiratory tract are affected with HD vapor, necessitating a pulmonary examination (Azizi and Amid, 1990; Sidell et al., 1997; Dompeling et al., 2004). Bronchodilators are useful to diminish hyperreactive airways and should be used if a prior history of asthma or hyperreactive airways is documented. Further support with humidified oxygen may be required. Ventilatory support may be required for severe cases of HD vapor exposure before laryngeal spasm makes intubation dificult. Bronchoscopy is critical for diagnosis, therapeutic dilation against HD-induced tracheobronchial stenosis, and removal of

pseudomembranes that cause airway obstruction. Since the toxic bronchitis produced by HD is nonbacterial, antibiotic therapy should not be given during the first 3–4 days (Sidell et al., 1997). Continuous monitoring of sputum for Gram’s stain and culture growth is necessary to identify the speciic organism responsible for the late-developing superinfection. The presence of leukopenia in children, a grave sign of HD exposure, will require aggressive support with combination antibiotic treatment.

Gastrointestinal Tract
Atropine or common antiemetics can be given to provide relief from nausea and vomiting, early signs ofHD intoxication (Yu et al., 2003). Excellent choices for
pediatric-speciic antiemetics include medications such
as promethazine, metoclopramide, and ondansetron
(Sidell et al., 1997). Persistent vomiting and diarrhea are
later signs of systemic toxicity requiring prompt fluid
replacement.
Bone Marrow Suppression
As a radiomimetic, HD affects rapidly dividing tis-
sues like bone marrow in addition to the gastrointestinal
tract (Sidell et al., 1997; Graham et al., 2005). HD destroys
hematopoietic precursor cells; WBCs have the shortest
life span and decrease in number first, followed by red blood cells (RBCs) and thrombocytes. The bone mar-
row suppression that is sometimes seen can be treated
with ilgrastim injections. This medication stimulates the
bone marrow to create and release WBCs.
Other Treatment Considerations
Fluid status, electrolytes, and urine output should be
monitored in the HD-intoxicated patient. Tetanus pro-
phylaxis should also be administered because fatal teta-
nus may occur even after a small, partial-thickness burn
(Marshall et al., 1972).

Summary

Pediatric exposures to vesicants can be quite toxic; however, in contrast to nerve agent exposures, HD causes signiicantly greater morbidity than mortality. While mustard did not cause many deaths in World War I, death from HD exposure is usually due to massive pulmonary damage, complicated by infection (bronchopneumonia) and sepsis. Children often show a quicker onset and greater severity of toxicity. Skin and eye toxicity occurs in the form of blisters or irritation that can

result in blindness for the most severe cases. Except for Lewisite, vesicant exposures must be managed with supportive care and rapid decontamination.

VIII. PROPHYLACTIC, THERAPEUTIC AND COUNTERMEASURES

Medical Management Of Chemical Toxicity In Pediatrics

Morbidity.

There are two types of mustard: sulfur mus-

tard (HD) and nitrogen mustards (HNs). HD caused-

more casualties in World War I than any other chemical

weapon. It caused a significant number of casualties,

both civilian and military, during the Iran–Iraq War

of the 1980s. HD vapor is the route most likely to be

used by terror groups (Yu et al., 2003). It affects mul-

tiple organ systems including skin, eyes, respiratory and

gastrointestinal tracts, and bone marrow (Yu et al., 2003).

Nitrogen mustards, on the other hand, have never been

used on the battlefield and will not be discussed further.

Lewisite, a vesicant with HD-like properties, causes

a similar constellation of signs and symptoms involving

the skin, eyes, and airways, as well as systemic effects

(e.g., increased capillary permeability) after absorp-

tion. However, it does not produce immunological sup-

pression like mustard. Another difference is that the

management of lewisite toxicity includes an antidote,

British anti-lewisite (BAL) (Yu et al., 2003).

Mechanism of Toxicity

HD rapidly penetrates cells and generates a highly

toxic reaction that disrupts cell function and eventually

causes cell death (Sidell et al., 1997). It is classified as an

alkylating agent, targeting poorly differentiated and rap-

idly reproducing cells (Yu et al., 2003). Death is a result

of massive pulmonary damage complicated by infection.

Clinical Presentation

Mustard can cause local effects on skin, airways,

and eyes; however, large doses can cause fatal systemic

effects (Yu et al., 2003). In a study of clinical findings

among children exposed to vesicants, ocular, cutaneous,

and respiratory signs were the most prevalent (Azizi and

EXHIBIT D

P E D I AT R I C C A S E H I S T O R I E S — V E S I C A N T S

Mustard Gas Exposure in 14 Children and

Teenagers from Halabja, Iraq

Mustard gas was used on the civilian population dur-

ing the Iraq–Iran War (1980–1988). A case series of 14 chil-

dren and teenagers affected by mustard gas was reported

by Momeni and Aminjavaheri (1994). They found that

facial involvement was the most frequent disorder (78%),

followed by genital (42%) and trunk and axillar lesions

(both 14%). The most prominent laboratory abnormality

was eosinophilia (in 12% of patients). As far as the time

course of toxicity, skin lesions appeared 4–18 h after expo-

sure, and then erythema developed within 20–30 h. After

the erythema, blisters appeared. The authors concluded

that the time of onset of toxicity was shorter and more

severe in children and teenagers compared with adults

(Momeni and Aminjavaheri, 1994).

Clinical Cases from Moid Medical Center

(Mustard Exposure Following the Halabja

Attack on March 17, 1988)

A 3-year-old male presented to Moid Medical Center 8

days after the Halabja chemical attack with fever (39.5°C),

tachycardia (140 bpm), and tachypnea (respiratory rate (RR)

60). Cutaneous skin lesions were mild, but erythema and

edema covered 45% of his skin surface area. Ocular and respi-

ratory indings were as previously described. Laboratory

indings were unremarkable except for a mild anemia. Chest

roentograms revealed hilar congestion and consolidation

bilaterally. The fever continued despite antibiotic therapy.

On day 10 of admission (18 days after exposure), the patient

developed leukocytosis with 82% polymorphonuclear neu-

trophils (PMNs) and worsening respiratory distress. The

patient inally died 21 days after exposure. An 8-year-old Iranian male presented at 5:30 p.m. with fever (40°C), severe agitation, delirium, and somnolence 24 h after exposure to chemical agents the previous day in Halabja. BP was 110/70 mm Hg, and the patient was notably tachycardic (120 bpm), and tachypneic (RR 42). The patient was noted to have serious dermatologic, ocular, and respiratory impairment. Erythema, vesicles, erosions, bullae, ulcerations, and edema were present on 35% of the body. Ocular manifestations included conjunctivitis and palpebral edema. At this point, the patient was working hard to breathe, as evidenced from accessory muscles of respiration (sternocleidomastoid). On physical examination of the lungs, wheezing and crepitation were noted

throughout the lung ield. Laboratory findings were the

following: Na + 139, K + 4.1 mEq/L, BUN 25 mg/dL, cal-

cium 7.3 mg/dL, and WBC 9,900/mm 3 , with 90% neutro-

phils. Arterial blood gases (ABGs) were as follows: pH

7.30, pCO 2 31, pO 2 65, and HCO 3 15.1. Chest roentograms

showed bilateral iniltrates. The patient died 24 h after

admission and 48 h after exposure, despite receiving sup-

portive care (Azizi and Amid, 1990).

VIII. PROPHYLACTIC, THERAPEUTIC AND COUNTERMEASURES

1021 Effects Of Specific Agents

Amid, 1990). Ocular findings consisted of the following:

conjunctivitis (94%), palpebral edema (81%), eye closure

(63%), keratitis (38%), blepharospasm (25%), corneal ulceration (19%), and chemosis (6%). Cutaneous signs

included erythema (94%), hyperpigmentation (75%), ulceration (69%), erosion (63%), blister (56%), edema

(50%), vesicles (31%), and hypopigmentation (13%).

Respiratory signs included dyspnea (63%), crepitation (50%), and wheezing (25%).

Other pediatric signs of mustard exposure were photophobia, lacrimation, ophthalmalgia, and eye burning (94%). Dry cough (81%), dermal pain, and burning (94%) were also frequent complaints. Less frequent complaints were diplopia, itchy eyes, sore throat, sneezing, nasal secretions, dyspnea, burning sensation of the upper respiratory tract, suffocation, and dysphonia (Azizi and Amid, 1990).

Initial dermal signs of toxicity consist of erythema, occurring 4–8 h after exposure. Pruritus can occur with or prior to erythema (Azizi and Amid, 1990; Yu et al. 2003). Over the next 24 h, large yellowish blisters form in areas of thin skin, such as the groin and underarms. Eye damage can occur, ranging from pain and irritation to blindness. Mustard also causes clinical effects that can be delayed for hours (Azizi and Amid, 1990; Sidell et al., 1997; Yu et al., 2003). This causes victims not to

recognize toxicity until well after exposure. During this time lag, sulfur mustard works to subclinically damage the skin. This latent period is significant because the shorter the latent period, the more severe the exposure and the worse the outcome. The CNS and bone marrow can also be affected, as displayed by symptoms of fatigue, headache, and depression (Sidell et al., 1997). HD can also lead to pneumonia, the cause of death for many HD casualties in World War I due to lack of antibiotics. A leukopenic pneumonia usually occurs between 6 and 10 days after HD exposure. The manifestation of leukopenia (specifically lymphopenia) results from the myelosuppressive effects of mustard agents.

Laboratory Findings

While there is no diagnostic confirmatory test for mustard exposure, some laboratory tests can prove useful. As described previously, inflammation and infection will show up as fever and leukocytosis. Erythrocyte sedimentation rate (ESR) has been shown to be elevated in patients after mustard exposure (Motakallem, 1988). Some of these patients were in the pediatric age range of 0–18 years. Complete blood count (CBC) determinations may show abnormalities depending on the severity of the vapor inhalation or exposure (Azizi and Amid,

1990; Yu et al., 2003). The CBC may show a low hematocrit and leukopenia if the exposure was severe. There may be only a transient decrease in white blood cells (WBCs), with subsequent recovery. In pediatric cases of HD vapor exposure, decreases in hematocrit and/or WBC were likely to occur in the irst 2 weeks, with the lowest levels of Hb, Hct, WBC, and neutrophil count observed in the 6th- to 10th-day samples after exposure (Azizi and Amid, 1990). These pediatric patients also suffered from clear signs of hypoxemia and renal failure (Azizi and Amid, 1990). Unfortunately, serum creatinine and renal function tests (RFTs) were not found in the charts. ABGs may provide useful information, but they may show a varied picture. In one pediatric study of mustard casualties, most

cases (43%) showed simple metabolic acidosis. The other

groups showed the following:

● Mixed metabolic acidosis and respiratory alkalosis

(29%)

● Simple respiratory alkalosis (14%)

● Mixed metabolic and respiratory acidosis (7%)

● Mixed metabolic alkalosis and respiratory acidosis

(7%).

Blood urea nitrogen can be elevated with mustard exposure, but it does not necessarily predict outcome or mortality. Blood urea nitrogen was significantly elevated in severe mustard exposure cases in the Azizi study; three of the four pediatric mustard victims that died showed very high blood urea nitrogen (Azizi and Amid, 1990). While elevations in blood urea nitrogen were found in many of the pediatric casualties from mustard exposure, blood urea nitrogen returned to normal levels soon afterward in survivors.

Pediatric Vulnerability

The effects of sulfur mustard on children are more severe than on adults (Yu et al., 2003). Premature infants have thinner skin, and the dermal–epidermal junction is not fully developed in children (Rutter and Hull, 1979; Harpin and Rutter, 1983; Nopper et al., 1996; Seidenari et al., 2000; Mancini, 2004); therefore, the time between exposure and onset of blisters is shortened, and the number and severity of blisters will be more severe (Yu et al., 2003). In fact, lesions in children exposed to mustard have been shown to be more severe. Initial index cases of mass casualties are typically children. Eye findings tend to be greater in children because of their inability to protect themselves and tendency to rub their eyes (Azizi and Amid, 1990; Yu et al., 2003). Children are also shown to be more sus-

ceptible to pulmonary injury for reasons previously discussed. One case report looked at the long-term effects of mustard exposure in a child (Dompeling et al., 2004). This child suffered an acute, severe chemical pneumonia; the long-term consequence was chronic bronchiolitis. Finally, signs of gastrointestinal toxicity may be greater in children secondary to fluid losses in combination with lower intravascular volume reserves (Yu et al., 2003).

VIII. PROPHYLACTIC, THERAPEUTIC AND COUNTERMEASURES 68.

Medical Management of Chemical Toxicity in Pediatrics

1022

While the decision to evacuate and hospitalize HD casualties is based on the extent [total body surface area (TBSA) >5%], severity of the skin lesions, and the recognition of multiple organ involvement (Graham et al.2005), the threshold to hospitalize children with HD injuries should be lower. One reason is that vapor mustard used by terrorists may cause extensive pulmonary involvement while producing mild skin blisters.

Treatment

While decontamination and supportive therapy are the mainstays of treatment, antidotes to counteract HD vapor, aerosol, or liquid exposures do not exist (Yu et al.2003). Adult decontamination may include bleach solutions; however, this method can cause greater toxicity in children. Soap and water are the preferred agents to use for decontamination in children. Supportive care consists of the management of pulmonary and skin manifestations, such as the use of cough suppressants and

topical silver sulfadiazine for burns (Azizi and Amid,1990; Sidell et al., 1997; Yu et al., 2003). Pediatric dosageand treatment recommendations for vesicant exposureare displayed in Table 68.5.

There are currently no standardized guidelines of casualty management or drugs available to prevent HD effects on skin and mucous membranes (Sidell et al.1997; Graham et al., 2005). The mainstay of treatment is prompt decontamination, blister aspiration or deroofing (epidermal removal), physical debridement, irrigation, topical antibiotics, and sterile dressing application for cutaneous HD injuries. Current treatment strategies rely on symptomatic management to relieve symptoms, prevent infections, and promote healing. The general recommendations are described in the Medical Management of Chemical Casualties Handbook (USAMRICD, 2000a),the Field Management of Chemical Casualties Handbook (USAMRICD, 2000b), and other references (Graham et al., 2005). We will discuss the aspects of treatment

that relate to the pediatric population. Most pediatric casualties will involve multiple organ systems (e.g., skin, ocular, gastrointestinal, bone marrow, and respiratory), as documented by Iranian physicians treating pediatric casualties of HD vapor during the Iran–Iraq War (Azizi and Amid, 1990).

Dermatological Management

Managing mustard skin lesions is especially challenging in the pediatric population. The goal of blister management is to keep the patient comfortable, keep the lesions clean, and prevent infection. Children especially will be extremely anxious at the sight of bullae and erythema, in addition to the burning, pruritis, and allodynia associated with HD blisters (Sidell et al., 1997.)

Anxiolytics may be appropriate to calm them down and prevent them from picking at bullae. Burning and itching

associated with erythema can be relieved by calamine or soothing lotions and creams such as 0.25% camphor, menthol corticosteroids, antipruritics (i.e., diphenhydramine),and silver sulfadiazine cream (Azizi and Amid, 1990;Sidell et al., 1997). Pain and discomfort can be relieved with systemic analgesics. Systemic analgesics such as morphine should be given liberally before manipulation of the burned area.

Vapor mustard typically causes a first- or second-degree burn, while Liquid mustard produces damage similar to a third-degree burn. In either case, tense bullae are the hallmark of HD injuries. Bullae are typically dome-shaped, thin-walled, 0.5–5.0 cm in diameter,supericial, translucent, yellowish, multiloculated, honeycombed (Moradi et al., 1986), and surrounded by erythema (Sidell et al., 1997). Preventing children from breaking the blisters can be a challenge, especially when constant friction from clothing and blankets is irritating to the skin. These areas should be wrapped in protective dressings. Graham et al. (2005) have made an important point about the existence of a reservoir of unbound HD in human skin following a vapor (Logan et al., 2000) or liquid exposure, leading to an off-gassing period. They suggested that this off-gassing period can last for 24–36 hours, whereby application of an occlusive dressing is not beneficial to prevent vapor buildup (Graham et al.2005.)

It is recommended that small blisters (<1 cm) should be left alone on the child, but the immediate area should be cleaned, irrigated daily, and covered with topical antibiotic (Sidell et al., 1997). Petroleum gauze bandage dressings should be wrapped around these unbroken blisters and changed every few days. Larger blisters (>1 cm) should be unroofed and irrigated several times a day with saline, sterile water, clean soapy water, or Dakin’s solution and covered with topical antibiotic cream or ointment. It should be noted that blister fluid does not contain mustard (Buscher and Conway, 1944) and therefore does not represent a hazard to the healthcare worker. Options for topical antibiotic creams in children include silver sulfadiazine, and triple-combination antibiotic (bacitracin, neomycin sulfate, and polymyxin B sulfate; Sidell et al., 1997) but not mafenide acetate, which can cause toxicities in children (Ohlgisser et al.,

1978; Geffner et al., 1981). These topical antibiotics should be applied to the area of bullae and surrounding areas of erythema. There is no information comparing the use of this combination (triple-antibiotic topical ointment) in children with use in other age groups. While skin healing can take months to complete, pigment changes (hyperpigmentation or hypopigmentation) can persist (Sidell et al., 1997; Graham et al., 2005.) It is also important to note that not all burn injuries

require treatment at a burn center. Patients will require aggressive pain management and close observation for the systemic effects of HD exposure. Skin grafting, although rare, has been successfully used for deep burns (Ruhl et al., 1994.)

Ophthalmology

The objective for any ophthalmology consultation on pediatric HD injuries involving the eye is the prevention of scarring and infection (Sidell et al., 1997). Eyes exposed to HD should be irrigated to remove traces of vesicant. Severe ocular involvement requires topical antibiotics (such as tobramycin OD) applied several times a day. Topical steroids may be useful in the first 48 h after exposure. Temporary loss of vision may also occur after mustard exposure (Motakallem, 1988; Azizi

and Amid, 1990; Sidell et al., 1997). The patient should be reassured that vision loss is not permanent and is due to palpebral edema, not corneal damage.

Respiratory System

The conducting and ventilation portions of the respiratory tract are affected with HD vapor, necessitating a pulmonary examination (Azizi and Amid, 1990; Sidell et al., 1997; Dompeling et al., 2004). Bronchodilators are useful to diminish hyperreactive airways and should be used if a prior history of asthma or hyperreactive airways is documented. Further support with humidiied oxygen may be required. Ventilatory support may be required for severe cases of HD vapor exposure before laryngeal spasm makes intubation difficult. Bronchoscopy is critical for diagnosis, therapeutic dilation against HD-induced tracheobronchial stenosis, and removal of

pseudomembranes that cause airway obstruction. Since the toxic bronchitis produced by HD is nonbacterial, antibiotic therapy should not be given during the irst 3–4 days (Sidell et al., 1997). Continuous monitoring of sputum for Gram’s stain and culture growth is necessary to identify the speciic organism responsible for the late-developing superinfection. The presence of leukopenia in children, a grave sign of HD exposure, will require aggressive support with combination antibiotic treatment.

Gastrointestinal Tract
Atropine or common antiemetics can be given to provide relief from nausea and vomiting, early signs of HD intoxication (Yu et al., 2003). Excellent choices for pediatric-speciic antiemetics include medications such as promethazine, metoclopramide, and ondansetron (Sidell et al., 1997). Persistent vomiting and diarrhea are later signs of systemic toxicity requiring prompt fluid replacement.
Bone Marrow Suppression
As a radiomimetic, HD affects rapidly dividing tissues like bone marrow in addition to the gastrointestinal tract (Sidell et al., 1997; Graham et al., 2005). HD destroys hematopoietic precursor cells; WBCs have the shortest life span and decrease in number irst, followed by red blood cells (RBCs) and thrombocytes. The bone marrow suppression that is sometimes seen can be treated with filgrastim injections. This medication stimulates the bone marrow to create and release WBCs.
Other Treatment Considerations
Fluid status, electrolytes, and urine output should be monitored in the HD-intoxicated patient. Tetanus prophylaxis should also be administered because fatal tetanus may occur even after a small, partial-thickness burn (Marshall et al., 1972).
Summary

Pediatric exposures to vesicants can be quite toxic; however, in contrast to nerve agent exposures, HD causes significantly greater morbidity than mortality.

While mustard did not cause many deaths in World War I, death from HD exposure is usually due to massive pulmonary damage, complicated by infection (bronchopneumonia) and sepsis. Children often show a quicker onset and greater severity of toxicity. Skin and eye toxicity occurs in the form of blisters or irritation that can result in blindness for the most severe cases. Except for Lewisite, vesicant exposures must be managed with supportive care and rapid decontamination.

TABLE 68.5 Management of Vesicant Exposures

Vesicant

Agents Symptoms Antidotes/Treatment

Mustard

● Skin erythema and pruritis

● Development of large yellow

blisters leading to ulcers

● Eye damage

● Inhalational damage: hoarseness

and cough, mucosal necrosis,

toneless voice, nausea, vomiting

Decontamination: soap, water, no bleach

Copious water irrigation for eyes

Pulmonary management: cough suppressants, throat lozenges

Skin management: topical agents used for burns (1% silver

sulfadiazine), antibiotics for secondary infections (Neosporin®),

antihistamines for itching (diphenhydramine 1 mg/kg/dose

orally q6–8 h max 300 mg/day, hydroxyzine 0.5 mg/kg/dose

orally q6–8 h)

Immune system management: G-CSF (ilgrastim) 5–10

micrograms/kg/day subcutaneous for neutropenia

Lewisite

● Shock

● Pulmonary injury

● Blisters

Decontamination: soap, water, no bleach

Antidote: BAL-dimercaprol may decrease systemic effects of

lewisite

Pulmonary management: BAL 3–5 mg/kg deep IM q4 h × 4

doses (dose depends on severity of exposure and symptoms)

Skin management: BAL ointment

Eye management: BAL ophthalmic ointment

Source: Momeni and Aminjavaheri (1994) and Yu et al. (2003).

1023 Effects Of Specific Agents

Dermatological Management

Managing mustard skin lesions is especially challenging in the pediatric population. The goal of blister management is to keep the patient comfortable, keep the lesions clean, and prevent infection. Children especially will be extremely anxious at the sight of bullae and erythema, in addition to the burning, pruritis, and allodynia associated with HD blisters (Sidell et al., 1997). Anxiolytics may be appropriate to calm them down and

prevent them from picking at bullae. Burning and itching

associated with erythema can be relieved by calamine or

soothing lotions and creams such as 0.25% camphor, menthol corticosteroids, antipruritics (i.e., diphenhydramine), and silver sulfadiazine cream (Azizi and Amid, 1990; Sidell et al., 1997). Pain and discomfort can be relieved with systemic analgesics. Systemic analgesics such as morphine should be given liberally before manipulation of the burned area. Vapor mustard typically causes a first- or second-degree burn, while liquid mustard produces damage similar to a third-degree burn. In either case, tense bullae are the hallmark of HD injuries. Bullae are typically dome-shaped, thin-walled, 0.5–5.0 cm in diameter, supericial, translucent, yellowish, multiloculated, honeycombed (Moradi et al., 1986), and surrounded by erythema (Sidell et al., 1997). Preventing children from breaking the blisters can be a challenge, especially when constant friction from clothing and blankets is irritating to the skin. These areas should be wrapped in protective dressings. Graham et al. (2005) have made an important point about the existence of a reservoir of unbound HD in human skin following a vapor (Logan et al., 2000) or liquid exposure, leading to an off-gassing period. They suggested that this off-gassing period can last for 24–36 h, whereby application of an occlusive dressing is not beneficial to prevent vapor buildup (Graham et al.,2005). It is recommended that small blisters (<1 cm) should be left alone on the child, but the immediate area should be cleaned, irrigated daily, and covered with topical antibiotic (Sidell et al., 1997). Petroleum gauze bandage dressings should be wrapped around these unbroken blisters and changed every few days. Larger blisters (>1 cm) should be unroofed and irrigated several times a day with saline, sterile water, clean soapy water, or Dakin’s solution and covered with topical antibiotic cream or ointment. It should be noted that blister fluid does not contain mustard (Buscher and Conway, 1944) and therefore does not represent a hazard to the healthcare worker. Options for topical antibiotic creams in children include silver sulfadiazine, and triple-combination antibiotic (bacitracin, neomycin sulfate, and polymyxin B sulfate; Sidell et al., 1997) but not mafenide acetate, which can cause toxicities in children (Ohlgisser et al.,

1978; Geffner et al., 1981). These topical antibiotics should be applied to the area of bullae and surrounding areas of erythema. There is no information comparing the use of this combination (triple-antibiotic topical ointment) in children with use in other age groups. While skin healing can take months to complete, pigment changes (hyperpigmentation or hypopigmentation) can persist (Sidell et al., 1997; Graham et al., 2005). It is also important to note that not all burn injuries require treatment at a burn center. Patients will require aggressive pain management and close observation for the systemic effects of HD exposure. Skin grafting, although rare, has been successfully used for deep burns (Ruhl et al., 1994).

Ophthalmology

The objective for any ophthalmology consultation on pediatric HD injuries involving the eye is the prevention of scarring and infection (Sidell et al., 1997). Eyes exposed to HD should be irrigated to remove traces of vesicant. Severe ocular involvement requires topical antibiotics (such as tobramycin OD) applied several times a day. Topical steroids may be useful in the first 48 h after exposure. Temporary loss of vision may also occur after mustard exposure (Motakallem, 1988; Azizi

and Amid, 1990; Sidell et al., 1997). The patient should

be reassured that vision loss is not permanent and is due

to palpebral edema, not corneal damage.

Respiratory System

The conducting and ventilation portions of the respiratory tract are affected with HD vapor, necessitating a pulmonary examination (Azizi and Amid, 1990; Sidell et al., 1997; Dompeling et al., 2004). Bronchodilators are useful to diminish hyperreactive airways and should be used if a prior history of asthma or hyperreactive airways is documented. Further support with humidiied oxygen may be required. Ventilatory support may be required for severe cases of HD vapor exposure before laryngeal spasm makes intubation difficult. Bronchoscopy is critical for diagnosis, therapeutic dilation against HD-induced tracheobronchial stenosis, and removal of

pseudomembranes that cause airway obstruction. Since the toxic bronchitis produced by HD is nonbacterial, antibiotic therapy should not be given during the first 3–4 days (Sidell et al., 1997). Continuous monitoring of sputum for Gram’s stain and culture growth is necessary to identify the specific organism responsible for the late-developing superinfection. The presence of leukopenia in children, a grave sign of HD exposure, will require aggressive support with combination antibiotic treatment.

Gastrointestinal Tract

Atropine or common antiemetics can be given to provide relief from nausea and vomiting, early signs of HD intoxication (Yu et al., 2003). Excellent choices for pediatric-speciic antiemetics include medications such as promethazine, metoclopramide, and ondansetron (Sidell et al., 1997). Persistent vomiting and diarrhea are later signs of systemic toxicity requiring prompt fluid replacement.

Bone Marrow Suppression

As a radiomimetic, HD affects rapidly dividing tissues like bone marrow in addition to the gastrointestinal tract (Sidell et al., 1997; Graham et al., 2005). HD destroys hematopoietic precursor cells; WBCs have the shortest life span and decrease in number first, followed by red blood cells (RBCs) and thrombocytes. The bone marrow suppression that is sometimes seen can be treated with ilgrastim injections. This medication stimulates the bone marrow to create and release WBCs.

Other Treatment Considerations

Fluid status, electrolytes, and urine output should be monitored in the HD-intoxicated patient. Tetanus prophylaxis should also be administered because fatal tetanus may occur even after a small, partial-thickness burn (Marshall et al., 1972).

Summary

Pediatric exposures to vesicants can be quite toxic; however, in contrast to nerve agent exposures, HD causes significantly greater morbidity than mortality. While mustard did not cause many deaths in World War I, death from HD exposure is usually due to massive pulmonary damage, complicated by infection (broncho-pneumonia) and sepsis. Children often show a quicker onset and greater severity of toxicity. Skin and eye toxicity occurs in the form of blisters or irritation that can

result in blindness for the most severe cases. Except for Lewisite, vesicant exposures must be managed with supportive care and rapid decontamination.

Pulmonary Agents

Introduction

In January 2002, a CIA report stated that terrorist groups may have less interest in biological materials than in chemicals such as cyanide, chlorine, and phosgene (DCI, 2002), which are able to contaminate food and water supplies (Sidell et al., 1997; Graham et al., 2005). The targeting of children has the potential to destabilize governments and create widespread terror.   Industrial chemicals, such as chlorine and phosgene*, have advantages that make them potential candidates to be used by terrorists in the future. Both chlorine and phosgene are fairly easy to manufacture and handle, prompting national concern over their future use. In the United States alone, millions of tons of chlorine and phosgene are produced annually toward the manufacture of various products (Burklow et al., 2003). A detailed discussion of the general mechanisms of chlorine and phosgene toxicity can be found elsewhere in this book and will not be explored further here.

*smells like musty hay

EXHIBIT D

P E D I AT R I C C A S E H I S T O R I E S — V E S I C A N T S

Mustard Gas Exposure in 14 Children and Teenagers from Halabja, Iraq

Mustard gas was used on the civilian population during the Iraq–Iran War (1980–1988). A case series of 14 children and teenagers affected by mustard gas was reported by Momeni and Aminjavaheri (1994). They found that facial involvement was the most frequent disorder (78%), followed by genital (42%) and trunk and axillar lesions (both 14%). The most prominent laboratory abnormality was eosinophilia (in 12% of patients). As far as the time course of toxicity, skin lesions appeared 4–18 h after exposure, and then erythema developed within 20–30 h. After the erythema, blisters appeared. The authors concluded that the time of onset of toxicity was shorter and more severe in children and teenagers compared with adults (Momeni and Aminjavaheri, 1994.)

Clinical Cases from Moid Medical Center

(Mustard Exposure Following the Halabja

Attack on March 17, 1988)

A 3-year-old male presented to Moid Medical Center 8 days after the Halabja chemical attack with fever (39.5°C),

tachycardia (140 bpm), and tachypnea (respiratory rate (RR)

60). Cutaneous skin lesions were mild, but erythema and edema covered 45% of his skin surface area. Ocular and respiratory findings were as previously described. Laboratory findings were unremarkable except for a mild anemia. Chest roentograms revealed hilar congestion and consolidation bilaterally. The fever continued despite antibiotic therapy. On day 10 of admission (18 days after exposure), the patient developed leukocytosis with 82% polymorphonuclear neutrophils (PMNs) and worsening respiratory distress. The patient finally died 21 days after exposure.

An 8-year-old Iranian male presented at 5:30 p.m. with fever (40°C), severe agitation, delirium, and somnolence 24 h after exposure to chemical agents the previous day in Halabja. BP was 110/70 mm Hg, and the patient was notably tachycardic (120 bpm), and tachypneic (RR 42). The patient was noted to have serious dermatologic, ocular, and respiratory impairment.   Erythema, vesicles, erosions, bullae, ulcerations, and edema were present on 35% of the body. Ocular manifestations included conjunctivitis and palpebral edema. At this point, the patient was working hard to breathe, as evidenced from accessory muscles of respiration (sternocleidomastoid). On physical examination of the lungs, wheezing and crepitation were noted throughout the lung field. Laboratory findings were the following: Na + 139, K + 4.1 mEq/L, BUN 25 mg/dL, cal-

cium 7.3 mg/dL, and WBC 9,900/mm 3 , with 90% neutro-

phils. Arterial blood gases (ABGs) were as follows: pH

7.30, pCO 2 31, pO 2 65, and HCO 3 15.1. Chest roentograms

showed bilateral iniltrates. The patient died 24 h after

admission and 48 h after exposure, despite receiving sup-

portive care (Azizi and Amid, 1990).

…..............

…........................

…....................................

The targeting of children has the potential to destabilize   governments and create widespread terror. Industrial chemicals, such as chlorine and phosgene, have advantages that make them potential candidates to be used by terrorists in the future. Both chlorine and phosgene are fairly easy to  manufacture and handle, prompting national concern over their future use. In the United States alone, millions of tons of chlorine and  Phosgene are produced annually toward the manufacture of various products (Burklow et al., 2003). A detailed discussion of the general mechanisms of chlorine and Phosgene toxicity can be found elsewhere in this book and will not be explored further here.

Clinical Presentation

Pediatric signs and symptoms of chlorine gas exposure include predominantly ocular, nasal, oropharyngeal, and pulmonary irritation of membranes (Burklowet al., 2003). The hallmark of intoxication by these choking agents involves respiratory complaints. Minor chlorine exposures can lead to burning of the eyes and throat, which indicate mucous membrane irritation. More severely exposed patients may complain of cough, choking, sore throat, shortness of breath, chest tightness, dificulty breathing, and other respiratory-related complaints. Clinical findings may also include lacrimation, rhinorrhea, laryngeal edema, hoarseness, aphonia, stridor, expiratory wheezing, tracheitis, and cyanosis (Güloğlu et al., 2002; Traub et al., 2002). Tachypnea may develop as a direct result of pulmonary irritation, and tachycardia has been demonstrated in some studies. Many pediatric patients with a prior history of reactive airway disease are at increased risk of chlorine-induced bronchospasm (Burklow et al., 2003).

Pulse oximetry may indicate low oxygen saturation (Traub et al., 2002). While ABGs usually indicate hypoxemia, carbon dioxide levels have been shown to be decreased, increased, or normal (Güloğlu et al., 2002;Traub et al., 2002.) A hyperchloremic metabolic acidosis may show up on blood chemistries due to systemic absorption of hydrochloric acid. Pulmonary edema, the most significant morbidity from pulmonary agents, can be seen on chest roentograms (Burklow et al., 2003). Pulmonary edema may develop as early as 2–4 h after exposure; radiographic

evidence typically appears later. Pulmonary edema may progress to the point of producing Kerley B lines on chest x-rays. These lines are often described as rungs of a ladder running perpendicular to the lateral margin of the lungs beginning at the costophrenic angle. Chest radiographs will often show opacities of acute lung injury. Pneumomediastinum has also been reported in chlorine gas exposure (Traub et al., 2002.) Pulmonary function tests (PFTs) are not helpful (Pherwani et al., 1989; Traub et al., 2002) in this circum stance. A study of schoolchildren exposed to a chlorine gas leak reported a predominantly obstructive pattern on PFTs. This could be explained by congestion and edema narrowing the central airways rather than smaller ones.

Pediatric Vulnerability

Chlorine is a pungent green–yellow gas, twice as heavy as air (Güloğlu et al., 2002) and settles near the ground (Traub et al., 2002; Burklow et al., 2003). This poses a problem for children, leading to increased exposure for this population in the event of release, either accidentally or via an act of terror. Children can be

exposed as a result of the following activities: inhaling chlorine vapors at swimming pools (Burklow et al.2003), mixing of household bleach (sodium hypochlorite) with acidic cleaning agents (Traub et al., 2002), andindustrial accidents (Pherwani et al., 1989). Phosgene, a dense gas heavier than air, is a more lethal pulmonary agent than chlorine. While the smell of chlorine is associated with swimming pools, phosgene odor is described

as smelling like freshly mown hay (Burklow et al., 2003.)

Initially, both agents cause intense irritation of the mucosal membranes (Burklow et al., 2003) and coughing (Güloğlu et al., 2002; Traub et al., 2002). This is typically followed by a feeling of suffocation (Burklow et al., 2003.) Morbidity from pulmonary agents is the direct result of pulmonary edema, appearing 2–4 h after chlorine exposures. Since children have a smaller fluid reserve (Rotenberg and Newmark, 2003), pulmonary edema can

cause rapid dehydration or even shock (Burklow et al.2003). Due to the higher respiratory rates and minute volumes of children (Rotenberg and Newmark, 2003), exposure to pulmonary agents will be greater (Burklow et al., 2003). Concerning the effects on children exposed to pulmonary agents and subsequent treatment, there are many documented clinical case studies in the lit-

erature looking at accidental exposures and industrial accidents (Pherwani et al., 1989; Güloğlu et al., 2002; Traub et al., 2002.)

Treatment

The first line of treatment for children exposed to pulmonary agents is decontamination. Decontamination can be as simple as removing the victim from the source to fresh air, followed by the removal of contaminated clothing (Burklow et  al.2003.)  Supportive care includes administration of humidified air, supplemental oxygen, water irrigation, and high-low oxygen delivered via positive pressure for pulmonary edema (Traub et al.,

2002; Burklow et al., 2003). Further treatment may include surgical debridement and supportive care with medications, such as albuterol for bronchospasm, corticosteroids for inflammation, and antibiotics for any secondary bacterial infections. Antidotes or specific postexposure treatments do not exist for this class of

agents. Supportive treatment recommendations are shown in Table 68.6.

Summary

Chlorine and Phosgene are two chemicals that can cause severe pulmonary toxicity due to pulmonary edema and direct damage to the lungs. Treatment involves decontamination and supportive care. Special care needs to be provided for exposed children because they are at higher risk for toxicity because of their unique vulnerabilities.

Cyanide
Introduction

Cyanide is used in plastic processing, electroplating of metals, metal tempering, extraction of gold and silver, fumigants, and photographic development (Baskin and Brewer, 1997; Rotenberg, 2003a). It is also found in vehicle exhaust, tobacco smoke, certain fruit pits, and bitter almonds. The major cyanide-containing compounds used by the military in World War I werehydrogen cyanide, cyanogen chloride, and cyanogen bromide. Cyanide is also liberated during the combustion or metabolism of nitrogen-containing polymers of natural and synthetic origin (Riordan et al., 2002.)

Cyanides can cause lethality through the inhalation of cyanide vapor or ingestion (Prajapati et al., 1992.) Cyanide poisoning leads to death in minutes, but it can be effectively treated with antidotes if diagnosed quickly. Pediatricians, medical first-responders, and fireighters need to recognize victims of cyanide poisoning in order to initiate immediate intervention (Baskin and

Brewer, 1997; Rotenberg, 2003a). Cyanide is one of the few chemicals for which an effective antidote exists.

Mechanism of Toxicity

The cyanide ion kills aerobic organisms by shutting down oxidative phosphorylation in the mitrochondria, and therefore the utilization of oxygen in cells (Baskin and Brewer, 1997; Riordan et al., 2002). Cyanide has a propensity to affect certain organs (e.g., brain, heart and lungs) more than others (Baskin and Brewer, 1997; Rotenberg, 2003a). Significant exposure can lead to central respiratory arrest and myocardial depression. Cyanide also acts as a direct neurotoxin (Rotenberg, 2003a), disrupting cell membranes and causing excitatory injury in the CNS (Baskin and Brewer, 1997; Riordan et al., 2002.)

Clinical Presentation

Cyanide is an uncommon cause of childhood poisoning. In 2006, there were only 12 reported cases of cyanide exposure in the pediatric population (<19 years) (Bronstein et al., 2007). Since the signs of toxicity (see Exhibit F) are so similar to carbon monoxide poisoning, which accounts for the largest group of poisoning deaths among children, clinicians must have a high index of suspicion to make the diagnosis (Prajapati et al., 1992;

Riordan et al., 2002). Rotenberg describes a typical toxidrome induced by cyanide (Rotenberg, 2003a), which includes a rapid progression from hyperpnea, hanxiety, restlessness, unconsciousness, seizures, apnea, and finally reaching death. Skin, blood, and fundi may be cherry red upon physical examination due to the inability of mitochondria to extract oxygen. In reported casesof accidental cyanide ingestion by children, other signs of toxicity included nausea, vomiting, abdominal pain, headache, lethargy, slurred speech, ataxia, stupor, coma, and respiratory depression. In addition, delayed vomiting occurred due to the slow metabolization of the chemical compound acetonitrile to cyanide, a process that can take 6–14 h after the ingestion (Geller et al., 2006.)

Laboratory Findings

ABGs can provide clues of cyanide exposure. Classic cases are presented with severe metabolic acidosis, elevated anion gap, and high lactate concentrations (Rotenberg, 2003a). Impaired cellular respiration will lead to a high oxygen content in venous blood (Riordan et al., 2002; Rotenberg, 2003a). Thus, a reduced arte-

rial-venous oxygen saturation difference suggests this diagnosis. Blood cyanide levels are confirmatory (Baskin and Brewer, 1997; Riordan et al., 2002; Rotenberg, 2003a) but will only delay the diagnosis, which must be based on the initial clinical presentation. Immediate therapeutic intervention with provision of 100% supplemental oxygen and administration of specific antidotes is paramount. An almond-like odor on the breath may alert a clinician that a person may have been exposed to cyanide, but up to 40% of the general population is unable to detect this odor.

Cyanide Terrorist Attack:

Pediatric Vulnerability

Children are especially vulnerable to cyanide attacks (Rotenberg, 2003a). A larger exposure to cyanide vapor occurs due to the higher respiratory rates and higher surface-to-volume ratios in children. Cyanide liquid causes greater and more rapid absorption when it comes against the immature skin barrier of children. Lower body mass and immature metabolic processes can render children more susceptible than adults to toxicity from cyanide exposure. It has also been noted that children seem more susceptible to ingestion poisoning, as demonstrated by various cassava and apricot pit exposures where the severity of toxicity was greater than that seen in adults who were also ingesting these products. In fact, it has been theorized that due to children’s higher gastric acidity, which leads to greater absorption, they experience more severe toxicity than adults when cassava is ingested (Geller et al., 2006). A case report of potassium cyanide ingestion among 10 children reported that the initial symptoms included abdominal pain, nausea, restlessness, and giddiness (Prajapati et al., 1992). Cyanosis and drowsiness were also noted, but the signature cherry-red skin color was not reported. Postmortem examination of the 2 children that died showed bright red blood and congested tissues. These 2 children consumed powder packets of potassium cyanide mixed in water, while the other 8 children licked the powder, leading to less toxicity. The survivors were managed with aggressive supportive care, including gastric lavage, oxygen, and IV fluids.

Treatment
The mainstay of treatment in cases of cyanide toxicity in the United States consists of supportive treatment and use of a multistage antidote kit (Baskin and Brewer, 1997; Riordan et al., 2002; Rotenberg, 2003a). Table 68.7 details pediatric doses used for the medications in this kit, which contains amyl nitrite, sodium nitrite, and sodium thiosulfate. Antidotes should be provided only for significantly symptomatic patients, such as those with impaired consciousness, seizures, acidosis, hypotension, hyperkalemia, or unstable vital signs (Goldfrank et al.,1998). Even when patients are rendered comatose by the inhalation of hydrogen cyanide gas, antidotes may not be necessary if the exposure is rapidly terminated, the patient has regained consciousness on arrival to the hospital, and there is no acidosis or abnormality of the vital signs (Peden et al., 1986).
Supportive Therapy
Regardless of the antidote available, treatment will always consist of supportive therapy (Rotenberg, 2003a).

Supportive therapy alone may reverse the effects of cyanide even in the face of apnea (Peden et al., 1986; Baskin and Brewer, 1997; Rotenberg, 2003a). Supportive therapy includes decontamination, which includes gastric lavage and  administration    of activated charcoal if appropriate, oxygen, hydration, and anticonvulsants.

Decontamination measures should take place prior to patient transport to a medical center. First-responders and healthcare professionals should in turn take precautions not to intoxicate themselves through direct mouth-to-mouth resuscitative efforts (Riordan et al., 2002.)

They must also wear personal protective equipment when transporting the victims to areas with adequate ventilation (Rotenberg, 2003a). Clothes are an obvious source for recontamination of the victim, so they must be removed. Subsequently, the skin should be flushed with copious amounts of water. The temperature of the water becomes a major consideration for children, who may not tolerate the extremes. Depending on the hospital size, antidote kits may or may not be available. Therefore, the time when supportive care is implemented becomes extremely important.

Antidotal Therapy

The US standard cyanide antidote kit uses a small inhaled dose of amyl nitrite followed by IV sodium nitrite and sodium thiosulfate (Anon, 1998; Rotenberg, 2003a). This antidote converts a portion of the hemoglobin’s iron from ferrous iron to ferric iron, converting the hemoglobin into methemoglobin. Cyanide is more strongly drawn to methemoglobin than to the cytochrome oxidase of cells, effectively pulling the cyanide off the cells and onto the methemoglobin (Berlin, 1970; Baskin and Brewer, 1997). Once bound with the cyanide, the methemoglobin becomes cyanmethemoglobin (Anon, 1998). Therapy with nitrites is not innocuous, since methemoglobin cannot transport oxygen in the blood. The doses given to an adult can potentially cause a fatal methemoglobinemia in children or may cause profound hypotension. Treatment of children affected with cyanide intoxication must be individualized based upon their body weight and hemoglobin concentration. Once an ampule of amyl nitrite has been broken one at a time into a handkerchief, the

contents should be held in front of the patient’s mouth for 15 s, followed by 15 s of rest. This should be reapplied using this interrupted schedule until sodium nitrite can be administered. Continuous use of amyl nitrite may prevent adequate oxygenation. Taylor Pharmaceuticals, the manufacturer of the kit, recommends the dose for children of sodium nitrite to be 6–8 mL/m 2 (approximately 0.2 mL/kg body weight), but not to exceed an adult dose of 10 mL of a 3% solution (approximately 300 mg). While excessive sodium nitrite can cause methemoglobinemia, it should be noted that in the 70-year history of using the kit, the only reported fatality of such toxicity from using the kit involved a child without serious cyanide poisoning who was given two adult doses of sodium nitrite (Berlin, 1970; Hall and Rumack, 1986).

In fact, the scientific literature recommends pediatric dosing based on monitoring hemoglobin levels. The next part of the cyanide antidote kit is sodium thiosulfate, which is administered intravenously (Hall and Rumack, 1986; Baskin and Brewer, 1997; Anon, 1998; Rotenberg, 2003a). The sodium thiosulfate and cyanmethemoglobin become thiocyanate, releasing hemoglobin; thiocyanate is excreted by the kidneys. Table 68.8 provides a dosing chart for the safe dosing of sodium nitrite and sodium thiosulfate, with continuous monitoring of hemoglobin levels. Before treating pediatric patients with nitrites, it is imperative that prescribers inquire about conditions that may predispose a victim to anemia and, if there are concerns, doses should be decreased. Methemoglobin levels must be monitored sequentially in children and should not exceed 20% (Rotenberg, 2003a). Due to concerns about the excessive methemoglobinemia, along with the complicated administration procedures associated with the cyanide antidote kit, experts have suggested that alternative therapies, such as hydroxocobalamin, may be preferable to use in children (Geller et al., 2006).

Alternative Strategies

Alternative methods of treating cyanide intoxication are used in other countries. For example, the antidote used primarily in France is hydroxocobalamin (a form of vitamin B 12 ), which combines with cyanide to form the harmless vitamin B 12a cyanocobalamin (Baskin and Brewer, 1997; Rotenberg, 2003a). In France, this medication is used for children at a dose of 70 mg/kg. A study of 41 French children with ire smoke inhalation showed a prehospital mortality rate of 4% for those given hydroxo

cobalamin and not found in cardiac arrest (Geller et al.2006). The authors of the study noted that for those children found in cardiac arrest by paramedics, administration of hydroxocobalmin did not prevent mortality. Another case series detailed 8 pediatric patients exposed to cassava, where 4 of the most severely affected children were given the cyanide antidote kit, while the others were given 500 mg of hydroxocobalamin. All the children improved regardless of which therapy they were given and were discharged from the hospital with no sequelae. This medication appears to have a good safety profile; adverse effects reported such as transient reddish-brown discoloration of the urine and mucous membranes. Some elevations in blood pressure and rash have also been reported (Geller et al., 2006). The FDA approved hydroxocobalamin for use in the United States in December 2006 to treat cyanide exposure victims in a product called Cyanokit, manufactured by EMD Pharmaceuticals, Inc. The package insert for this medication provides adult dosing and a statement that the safety and effectiveness of Cyanokit has not been established in the pediatric population. However, there is a reference to the 70 mg/kg dose that is used in Europe (Anon, 2006).

Summary

Cyanide is found in a wide variety of industrial processes and has been explored by Al Qaeda for use as a weapon of terror (Rotenberg, 2003a). Whether ingested or inhaled, cyanide is very lethal. Cyanide produces toxicity through impairment of mitochondrial enzymes, disrupting the electron transport chain, and preventing their utilization of oxygen. The mainstay of treatment of cyanide toxicity consists of the use of a multistage

antidote kit. The management of children with cyanide toxicity should include appropriate antidote dose adjustments and proper monitoring to prevent fatal methemoglobinemia. Another antidote, hydroxocobalamin, may gain favor over time as the treatment of choice for pediatric cyanide exposures, due to its preferable safety proile and its ease of administration (Geller et al., 2006).

DECONTAMINATION OF CHILDREN

Decontamination after a chemical terrorist attack needs to be well-planned, efficient, and cognizant of the special needs of children. It is well-recognized that the unique vulnerabilities of children may lead to a disproportionate number of pediatric victims after a chemical attack. Without proper planning and consideration as to how children will be decontaminated, the potential for preventable pediatric casualties is increased due to time loss and confusion. It is highly recommended for pediatricians to be involved in the development of each hospital’s plans for decontamination. Over the last several years, many advances have been made in the management of the critically injured child. In fact, studies have shown that children managed in a PICU have better outcomes than children managed in an adult intensive care unit (ICU; Wheeler and Poss, 2003). Not all hospitals have the resources to have their own PICU, but they

need to be able to provide the initial resuscitation and stabilization of pediatric victims of a terrorist attack. It is

highly recommended that predetermined, written transfer agreements exist between emergency departments in community hospitals and centers that specialize in pediatric care. These agreements will allow the rapid transport of critically injured children to the sites that can ensure the best outcomes. The first step in the decontamination process is the appropriate triage of patients (Burklow et al., 2003). If this step is done quickly and accurately, patients will be appropriately managed and outcomes will improve. The key to triage is the ability to ration care when resources are limited. Victims are usually classified into tiered

categories. The classic categories that have been used on the battlefield include minimal, delayed, immediate, and expectant. Patients in the minimal category have minor injuries that may not require medical care or can be managed with self-care. However, it should be noted that it is difficult for children to manage themselves, in addition to the fact that the category they are placed within can change more rapidly than for adults. The delayed category describes patients who have injuries that will require medical intervention, but the injuries are not immediately life-threatening. Logically, the immediate category describes patients who are critically injured and need medical intervention to save life or limb. Finally, the expectant category describes those patients who are so critically injured that they are

not expected to survive. The expectant category poses a special challenge to civilian healthcare workers, who are used to expending vast resources and personnel to maximize survival. 

Note:

In a mass casualty event, clinicians need to come to

grips with the fact that the most ill may not be treated.

Although the classic categories of triage are fairly well known, they are not consistently used among hospitals. Some categories are developed specific to chemical attacks. An example of this are triage categories that separate patients as “exposed” and “not exposed.” At the University of Maryland Medical Center, the biochemical response triage categories differentiate between exposed and not exposed individuals. Furthermore, recognizing that not all exposed individuals will necessarily be symptomatic but may still need to be isolated, the categories differentiate between those who are exposed and symptomatic, exposed and asymptomatic, and those with unrelated emergent conditions. Regardless of what categories get utilized, triage must focus on the fact that the best outcome is achieved for the greatest number of victims. To achieve this outcome, appropriate identification of the causative agent is critical. This can be a challenge because often, full identification is delayed. To protect those involved in triage, full personal protective equipment is highly recommended. Working in full personal equipment can be cumbersome and uncomfortable, but when triage is done correctly, unnecessary decontamination can be avoided. After triage, the decontamination process should begin (Wheeler and Poss, 2003). All workers who are involved in this process must be appropriately protected with butyl rubber aprons and gloves, double layers of latex gloves, waterproof aprons, and chemical-resistant jumpsuits. Personal protective equipment should also include an appropriately selected air-purifying or atmosphere-supplying respirator, depending upon how well the threat environment has been categorized. It is important to note that this equipment often needs to be changed to prevent healthcare worker exposure. The setup and use of the decontamination area must be carefully thought out. Often, the area is split into different zones (Rotenberg et al., 2003). At a minimum, there must be a dirty contaminated zone and a clean decontaminated zone. It is critical to emphasize that traffic must go one way between zones. This will eliminate the possibility of a cleaned patient becoming cross-contaminated or an exposed patient entering a healthcare facility before being decontaminated. Security personnel must be utilized to make sure that patients do not consciously or unconsciously violate the rules. A secondary triage will be needed as patients enter the clean zone to allow patients to receive antidotes or be referred for further care. Keep in mind that for severely ill patients, antidote administration may precede decontamination. The selection of the appropriate decontamination agent is important. The gold standard for decontamination is plain water (Rotenberg et al., 2003). Other agents that have been used for decontamination include carbonaceous adsorbent powder, dilute (0.5%) hypochlorite solution, water with soap, and dry decontaminants such as flour or talcum powder. For children, the use of water

or water with soap is preferred. In addition to agents used to decontaminate, other cornerstones to management include exposure to fresh air (when patients have been exposed to chemicals in the gaseous form), a change of clothing, and showers.

Conducting decontamination in children can be especially difficult. At every step of the process, special considerations need to be addressed (Rotenberg et al. 2003). Starting at triage, clinicians need to understand how chemical toxicities manifest in children; also, an understanding of what normal vital signs should be for a child will be critical. Pediatric-specific triage tools often consider different vital signs, such as heart rate and respiratory rate parameters and the varying ability of patients to communicate. It is important for the triage to include the examination of a child’s mouth and eyes because of frequent hand-to-mouth and hand-to-eye activity. If antidote administration is needed, pediatric references should be readily available, and an understanding of pediatric doses will be needed. When there is a lack of experience with managing children, the otherwise efficient decontamination process can get bogged down. Some hospitals have decided to set up pediatric-specific areas to address the specific needs of children. Clinicians may need to handle uncooperative or non-verbal children. This becomes especially challenging when an IV line needs to be started. Placing a line in a child while in full protective equipment is no small feat. Also, keep in mind that the unfamiliar presence of a clinician in full personal protective equipment can cause fear and distress in a child.  Children undergoing decontamination will benefit from a parent or guardian to guide them through and reassure them. For those children who present alone, a guardian will need to be appointed and a system for parental identification will be needed. Hospitals will need to plan for this extra resource. In fact, one Israeli hospital has employed social workers to participate in their disaster preparation to help manage patient/family needs and psychological distress (Rosenbaum, 1993). It is recommended not to separate parents and children during a time of crisis. Plans should be made for the decontamination and treatment of parent–child pairs (Rotenberg et al., 2003.) A range of specially sized supplies is needed to appropriately manage children, which range from pediatric-sized emergency equipment to basic needs, such as formula for feeding and diapers. Since decontamination often includes disrobing, child-sized clothing would be needed. For children who may need to be observed for hours, toys will be needed. Also, the agents used to decontaminate children should be carefully selected. (Rotenberg et al., 2003). Water is the gold standard for decontamination. When employing water in decontamination, the temperature of the water must be considered. Children, especially newborns and infants, are prone to hypothermia and emodynamic instability from cold water. Water at a comfortable temperature is recommended, along with a good supply of blankets that can be used to quickly warm up pediatric patients after water decontamination. In some situations, indoor sprinkler systems have been used when outdoor conditions were inhospitable.

EXHIBIT E

P E D I AT R I C C A S E H I S T O RY —

P U L M O N A RY A G E N T S

Chlorine Gas Exposure in an Adolescent

A 14-year-old male, previously healthy except for a history of asthma, was exposed to chlorine gas by mixing household bleach with vinegar. Immediately, he began to cough and have difficulty breathing. His symptoms worsened over the next hour, leading to an admission to the local emergency room. Upon admission, the physical exam revealed that the patient was in respiratory distress, with bilateral crackles and diffuse

wheezing. He also had conjunctival irritation. Vital signs were pulse 100 bpm, blood pressure 130/80 mm Hg, respiratory rate 20 breaths/min, and temperature 97°F. His initial oxygen saturation while breathing room air was 92%. A venous blood gas suggested mild CO 2 retention with a pH of 7.35, PCO 2 of 53 mm Hg, and a PO 2 of 33 mm Hg. Chest radiograph showed

bilateral alveolar iniltrates with a normal heart size, which is indicative of acute lung injury. Sinus tachycardia was demonstrated on the ECG. The patient was treated with oxygen, multiple doses of nebulized albuterol, and oral prednisone. Despite these measures, his overall respiratory status continued to decline, and a repeat pulse oximetry while on 50% oxygen showed a saturation of 85%. Due to his worsening condition, he was intubated and transported to another hospital with a PICU. Upon intubation, it was noted that the patient had copious secretions. After admission to the

PICU, the patient developed acute respiratory distress syndromes (ARDS) and needed ventilatory management for 19 days, along with additional doses of albuterol and methylprednisolone. After extubation, he was placed on a prednisone taper and discharged with no evidence of residual pulmonary dysfunction (Traub et al., 2002.)

VIII. PROPHYLACTIC, THERAPEUTIC AND COUNTERMEASURES

Effects Of Specific Agents

Clinical Presentation

Pediatric signs and symptoms of chlorine gas exposure include predominantly ocular, nasal, oropharyngeal, and pulmonary irritation of membranes (Burklow et al., 2003). The hallmark of intoxication by these choking agents involves respiratory complaints. Minor chlorine exposures can lead to burning of the eyes and throat, which indicate mucous membrane irritation. More severely exposed patients may complain of cough, choking, sore throat, shortness of breath, chest tightness, dificulty breathing, and other respiratory-related complaints. Clinical indings may also include lacrimation, rhinorrhea, laryngeal edema, hoarseness, aphonia,

stridor, expiratory wheezing, tracheitis, and cyanosis (Güloğlu et al., 2002; Traub et al., 2002). Tachypnea may develop as a direct result of pulmonary irritation, and tachycardia has been demonstrated in some studies.

Many pediatric patients with a prior history of reactive

airway disease are at increased risk of chlorine-induced

bronchospasm (Burklow et al., 2003).

Pulse oximetry may indicate low oxygen saturation (Traub et al., 2002). While ABGs usually indicate hypoxemia, carbon dioxide levels have been shown to be decreased, increased, or normal (Güloğlu et al., 2002; Traub et al., 2002). A hyperchloremic metabolic acidosis may show up on blood chemistries due to systemic absorption of hydrochloric acid.

Pulmonary edema, the most significant morbidity from pulmonary agents, can be seen on chest roentograms (Burklow et al., 2003). Pulmonary edema may develop as early as 2–4 h after exposure; radiographic evidence typically appears later. Pulmonary edema may progress to the point of producing Kerley B lines on chest x-rays. These lines are often described as rungs of a ladder running perpendicular to the lateral margin of the lungs beginning at the costophrenic angle. Chest

radiographs will often show opacities of acute lung injury. Pneumomediastinum has also been reported in chlorine gas exposure (Traub et al., 2002.)

Pulmonary function tests (PFTs) are not helpful (Pherwani et al., 1989; Traub et al., 2002) in this circumstance. A study of schoolchildren exposed to a chlorine gas leak reported a predominantly obstructive pattern on PFTs. This could be explained by congestion and edema narrowing the central airways rather than smaller ones.

Pediatric Vulnerability

Chlorine is a pungent green–yellow gas, twice as heavy as air (Güloğlu et al., 2002) and settles near the ground (Traub et al., 2002; Burklow et al., 2003). This poses a problem for children, leading to increased exposure for this population in the event of release, either accidentally or via an act of terror. Children can be exposed as a result of the following activities: inhaling Chlorine vapors at swimming pools (Burklow et al.2003), mixing of household bleach (sodium hypochlorite) with acidic cleaning agents (Traub et al., 2002), and industrial accidents (Pherwani et al., 1989). Phosgene, a dense gas heavier than air, is a more lethal pulmonary agent than Chlorine. While the smell of chlorine is associated with swimming pools, Phosgene odor is described as smelling like freshly mown hay (Burklow et al., 2003.) Initially, both agents cause intense irritation of the

mucosal membranes (Burklow et al., 2003) and coughing   (Güloğlu et al., 2002; Traub et al., 2002). This is typically

followed by a feeling of suffocation (Burklow et al., 2003.)

Morbidity from pulmonary agents is the direct result of pulmonary edema, appearing 2–4 h after chlorine exposures. Since children have a smaller fluid reserve (Rotenberg and Newmark, 2003), pulmonary edema can cause rapid  dehydration or even shock (Burklow et al. 2003). Due to the higher respiratory rates and minute volumes of children (Rotenberg and Newmark, 2003), exposure to pulmonary agents will be greater (Burklow et al., 2003). Concerning the effects on children exposed to pulmonary agents and subsequent treatment, there are many documented clinical case studies in the literature looking at accidental exposures and industrial accidents (Pherwani et al., 1989; Güloğlu et al., 2002;

Traub et al., 2002.)

Treatment

The first line of treatment for children exposed to pulmonary agents is decontamination. Decontamination can be as simple as removing the victim from the source to fresh air, followed by the removal of contaminated clothing (Burklow et al., 2003). Supportive care includes administration of humidified air, supplemental oxygen, water irrigation, and high-low oxygen delivered via positive pressure for pulmonary edema (Traub et al. 2002; Burklow et al., 2003). Further treatment may include surgical debridement and supportive care with

medications, such as albuterol for bronchospasm, corticosteroids for inflammation, and antibiotics for any

secondary bacterial infections. Antidotes or specific

postexposure treatments do not exist for this class of agents. Supportive treatment recommendations are shown in Table 68.6.

Summary

Chlorine and phosgene are two chemicals that can cause severe pulmonary toxicity due to pulmonary edema and direct damage to the lungs. Treatment involves decontamination and supportive care. Special care needs to be provided for exposed children because they are at higher risk for toxicity because of their unique vulnerabilities.

Cyanide

Introduction

Cyanide is used in plastic processing, electroplating of metals, metal tempering, extraction of gold and silver, fumigants, and photographic development (Baskin and Brewer, 1997; Rotenberg, 2003a). It is also found in vehicle exhaust, tobacco smoke, certain fruit pits, and bitter almonds. The major cyanide-containing compounds used by the military in World War I were hydrogen cyanide, cyanogen chloride, and  cyanogen bromide. Cyanide is also liberated during the combus

tion or metabolism of nitrogen-containing polymers of natural and synthetic origin (Riordan et al., 2002).

Cyanides can cause lethality through the inhalation of cyanide vapor or ingestion (Prajapati et al., 1992). Cyanide poisoning leads to death in minutes, but it can be effectively treated with antidotes if diagnosed quickly. Pediatricians, medical first-responders, and firefighters need to recognize victims of cyanide poisoning in order to initiate immediate intervention (Baskin and Brewer, 1997; Rotenberg, 2003a). Cyanide is one of the few chemicals for which an effective antidote exists.

Mechanism of Toxicity

The cyanide ion kills aerobic organisms by shutting down oxidative phosphorylation in the mitrochondria, and therefore the utilization of oxygen in cells (Baskin and Brewer, 1997; Riordan et al., 2002). Cyanide has a propensity to affect certain organs (e.g., brain, heart, and lungs) more than others (Baskin and Brewer, 1997; Rotenberg, 2003a). Significant exposure can lead to central respiratory arrest and myocardial depression. Cyanide also acts as a direct neurotoxin (Rotenberg, 2003a), dis

rupting cell membranes and causing excitatory injury in the CNS (Baskin and Brewer, 1997; Riordan et al., 2002).

TABLE 68.6 Management of Pulmonary Agent Exposures

Pulmonary

Agents Symptoms Treatment

Chlorine

● Lacrimation

● Rhinorrhea

● Conjunctival irritation

● Cough

● Sore throat

● Hoarseness

● Laryngeal edema

● Dyspnea

● Stridor

● ARDS

● Pulmonary edema

Decontamination: Copious water irrigation of the skin, eyes, and mucosal membranes to prevent continued irritation and injury Symptomatic care (no antidote): Warm/moist air, supplemental oxygen, positive pressure O 2 for pulmonary edema Bronchospasm: Beta-agonists (albuterol) Severe bronchospasm: Corticosteroids (prednisone) (also used for PTS with H/O asthmabut use unproven) Analgesia and cough: Nebulized lidocaine (4% topical solution) or nebulized sodium

bicarbonate (use unproven)

Phosgene

● Transient irritation (eyes,

nose, throat, and sinus)

● Bronchospasm

● Pulmonary edema

● Apnea

● Hypoxia

Decontamination: Wash away all residual liquid with copious water, remove clothing

Symptomatic care: ABCs, hydrate, positive pressure O 2 for pulmonary edema

Bronchospasm: Beta-agonists (albuterol), corticosteroids INH/IV, furosemide contraindicated

Hypoxia: Oxygen

[In each instance above, please refer to the accompanying tables to appreciate how each specific symptom must be treated.
In the above instance, please refer to Table 68.6.]

Cyanide
Introduction

Cyanide is used in plastic processing, electroplating of metals, metal tempering, extraction of gold and silver, fumigants, and photographic development (Baskin and Brewer, 1997; Rotenberg, 2003a). It is also found in vehicle exhaust, tobacco smoke, certain fruit pits, and bitter almonds. The major cyanide-containing

compounds used by the military in World War I were hydrogen cyanide, cyanogen chloride, and cyanogen bromide. Cyanide is also liberated during the combustion or metabolism of nitrogen-containing polymers of natural and synthetic origin (Riordan et al., 2002). Cyanides can cause lethality through the inhalation of cyanide vapor or ingestion (Prajapati et al., 1992).

Cyanide poisoning leads to death in minutes, but it can be effectively treated with antidotes if diagnosed quickly. Pediatricians, medical first-responders, and fireighters need to recognize victims of cyanide poisoning in order to initiate immediate intervention (Baskin and Brewer, 1997; Rotenberg, 2003a). Cyanide is one of the few chemicals for which an effective antidote exists.

Mechanism of Toxicity

The cyanide ion kills aerobic organisms by shutting down oxidative phosphorylation in the mitrochondria, and therefore the utilization of oxygen in cells (Baskin and Brewer, 1997; Riordan et al., 2002). Cyanide has a propensity to affect certain organs (e.g., brain, heart, and lungs) more than others (Baskin and Brewer, 1997; Rotenberg, 2003a). Significant exposure can lead to central respiratory arrest and myocardial depression. Cyanide also acts as a direct neurotoxin (Rotenberg, 2003a), disrupting cell membranes and causing excitatory injury in

the CNS (Baskin and Brewer, 1997; Riordan et al., 2002).

TABLE 68.3 Management of Mild/Moderate Nerve Agent Exposures

P E D I AT R I C C A S E H I S T O RY — C YA N I D E

Case History: Cyanide Exposure in a Child

A 2-year-old, previously healthy, 12-kg male ingested an unknown quantity of an acetonitrile-containing sculptured nail remover. The product contains an aliphatic nitrile that releases inorganic cyanide upon human metabolization. The child was brought into the emergency room because of lethargy approximately 10 h after the ingestion. Although the child was acting normally at the time of ingestion, 8 h later he was found to be moaning, poorly responsive, and having just vomited. In the emergency room, he was pale and lethargic, responding only to deep pain. Abdomen and neck exam was normal, and the lung exam revealed bilateral coarse breath sounds with a normal chest roentgenogram. Extremities were mottled and cool, with a delayed capillary refill time. Vital signs showed a temperature of 36.9°C, pulse of 140 bpm, respiratory rate of 56/min, and blood pressure of 70/30 mmHg. 

ABG measurements showed a pH of 6.95, PCO 2 of 11 mm Hg, and PO 2 of 114 mm Hg. His electrolytes revealed the following levels: sodium of 137 mmol/L, potassium of 5.1 mmol/L, chloride of 114 mmol/L, bicarbonate of 4 mmol/L, serum creatinine of 70.7 μmol/L, glucose of 15.8 mmol/L, and blood urea nitrogen of 5 mmol/L. The WBC count was 9.5 × 10 9 /L, and the hematocrit was 31%. Sinus tachycardia, at a rate of 160 bpm, with normal intervals and axis, was observed on the ECG. Serial whole blood cyanide levels were obtained, with the initial level being 231 μmol/L (600 μg/dL) 12 h after exposure. The patient was given oxygen, sodium bicarbonate, and fluid resuscitation. Electrolyte and acid–base disturbances were corrected, and no antidotal therapy was administered due

to prompt response on supportive therapies. The patient was discharged from the hospital 3 days after admission in good condition (Caravati and Litovitz, 1988).

EXHIBIT D

P E D I AT R I C C A S E H I S T O R I E S — V E S I C A N T S

Mustard Gas Exposure in 14 Children and

Teenagers from Halabja, Iraq

Mustard gas was used on the civilian population during the Iraq–Iran War (1980–1988). A case series of 14 children and teenagers affected by mustard gas was reported by Momeni and Aminjavaheri (1994). They found that facial involvement was the most frequent disorder (78%), followed by genital (42%) and trunk and axillar lesions (both 14%). The most prominent laboratory abnormality was eosinophilia (in 12% of patients). As far as the time course of toxicity, skin lesions appeared 4–18 h after exposure, and then erythema developed within 20–30 h. After the erythema, blisters appeared. The authors concluded

that the time of onset of toxicity was shorter and more severe in children and teenagers compared with adults (Momeni and Aminjavaheri, 1994).

Clinical Cases from Moid Medical Center

(Mustard Exposure Following the Halabja

Attack on March 17, 1988)

A 3-year-old male presented to Moid Medical Center 8 days after the Halabja chemical attack with fever (39.5°C), tachycardia (140 bpm), and tachypnea (respiratory rate (RR) 60). Cutaneous skin lesions were mild, but erythema and edema covered 45% of his skin surface area. Ocular and respiratory indings were as previously described. Laboratory findings were unremarkable except for a mild anemia. Chest roentograms revealed hilar congestion and consolidation bilaterally. The fever continued despite antibiotic therapy. On day 10 of admission (18 days after exposure), the patient developed leukocytosis with 82% polymorphonuclear neutrophils (PMNs) and worsening respiratory distress. The patient finally died 21 days after exposure.

An 8-year-old Iranian male presented at 5:30 p.m. with fever (40°C), severe agitation, delirium, and somnolence 24 h after exposure to chemical agents the previous day in Halabja. BP was 110/70 mm Hg, and the patient was notably tachycardic (120 bpm), and tachypneic (RR 42). The patient was noted to have serious dermatologic, ocular, and respiratory impairment. Erythema, vesicles, erosions, bullae, ulcerations, and edema were present on 35% of the body. Ocular manifestations included conjunctivitis and palpebral edema. At this point, the patient was working hard to breathe, as evidenced from accessory muscles of respiration (sternocleidomastoid). On physical examination of the lungs, wheezing and crepitation were noted

throughout the lung ield. Laboratory indings were the following: Na + 139, K + 4.1 mEq/L, BUN 25 mg/dL, calcium 7.3 mg/dL, and WBC 9,900/mm 3 , with 90% neutro-

phils. Arterial blood gases (ABGs) were as follows: pH 7.30, pCO 2 31, pO 2 65, and HCO 3 15.1. Chest roentograms showed bilateral infiltrates. The patient died 24 h after admission and 48 h after exposure, despite receiving supportive care (Azizi and Amid, 1990).

EXHIBIT E

P E D I AT R I C C A S E H I S T O RY —

P U L M O N A RY A G E N T S

Chlorine Gas Exposure in an Adolescent

A 14-year-old male, previously healthy except for a history of asthma, was exposed to chlorine gas by mixing household bleach with vinegar. Immediately, he began to cough and have difficulty breathing. His symptoms worsened over the next hour, leading to an admission to the local emergency room. Upon admission, the physical exam revealed that the patient was in respiratory distress, with bilateral crackles and diffuse wheezing. He also had conjunctival irritation. Vital signs were pulse 100 bpm, blood pressure 130/80 mm Hg, respiratory rate 20 breaths/min, and temperature 97°F. His initial oxygen saturation while breathing room air was 92%. A venous blood gas suggested mild CO 2 retention with a pH of 7.35, PCO 2 of 53 mm Hg, and a PO 2 of 33 mm Hg. Chest radiograph showed bilateral alveolar infiltrates with a normal heart size, which is indicative of acute lung injury. Sinus tachycardia was demonstrated on the ECG. The patient was treated with oxygen, multiple doses of nebulized albuterol, and oral prednisone. Despite these measures, his overall respiratory status continued to decline, and a repeat pulse oximetry while on 50% oxygen showed a saturation of 85%. Due to his worsening condition, he was intubated and transported to another hospital with a PICU. Upon intubation, it was noted that the patient had copious secretions. After admission to the PICU, the patient developed acute respiratory distress syndromes (ARDS) and needed ventilatory manage-

ment for 19 days, along with additional doses of albuterol and methylprednisolone. After extubation, he was placed on a prednisone taper and discharged with no evidence of residual pulmonary dysfunction (Traubet al., 2002).

References

Abraham, R.B., Weinbroum, A.A., Rudick, V., et al., 2001. Perioperative care of
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Abraham, R.B., Rudick, V., Weinbroum, A.A., 2002. Practical guidelines for acute
care of victims of bioterrorism: conventional injuries and concomitant nerve
agent intoxication. Anesthesiology 97, 989–1004.

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Amitai, Y., Almog, S., Singer, R., et al., 1999. Atropine poisoning in children dur-
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