1. Lead Poisoning: Clinical Effects- A pediatric emergency medicine perspective Regional New York State Lead Conference The Children’s Hospital at Montefiore Medical Center November 2, 2018
Fred M. Henretig, MD
Section of Clinical Toxicology
Division of Emergency Medicine
Children’s Hospital of Philadelphia

2. Overview Review of background and pathophysiology of lead toxicity
Pediatric exposures
Adult exposures
Treatment considerations
ED issues
Questions

3. Lead: Sources, Uses silvery gray, soft metal, AW 207
widely distributed, most abundant ore is galena ( PbS)
very malleable, good for water-proofing and electrical / radiation shielding
one of first metals used by human society
today most widely-used non-ferrous metal, global production 9,000,000 tons/yr

4. Lead uses - 2 Electric batteries: Other
metallic lead (grid) and lead oxide ( paste) = ~2/3 of annual US usage
recycled batteries large source of occupational lead exposure
Other
alloys: printing, solder, radiation / electrical shielding
ammunition
lead compounds in paint, glazes, pvc plastics, crystal glass
TEL in gasoline

5. Lead and plumbism: ancient history
Lead-based paints and artifacts from 40,000-6,000 BC
Romans used it extensively, esp in pipes, cooking utensils, ceramic glazes, and “sapa”- grape syrup simmered in lead vessels
Pliny: beware the dangers of inhaled lead fumes from smelting
perhaps: caused the fall of the Roman empire!

6. Lead: 18th century
Industrial revolution led to marked increase in use and recognized toxicity
Ben Franklin, 1763
“Dry gripes” - abdominal colic
“Dangles - wrist drop
Observed among tinkers, painters, and typesetters.

7. Lead: 19th century
Charles Dickens 1863
The Uncommercial Traveler

8. Lead Poisoning: Dickens
Dickens describes a hunched-over mill worker…
“And tis the lead, sur.”
“The what?”
“The lead, sur. Sure, tis the lead mills, where the woman gets took on at eighteen pence a day, sur…and her constitooshun is lead-poisoned, bad as can be, sur; and her brain is coming out her ear and it hurts dreadful…”

9. Lead: late 19th-20th century
Recognition of children at risk…
Turner AJ , 1897
Childhood poisoning linked to lead based paint in Australia.
Byers and Lord, 1943
Childhood plumbism often assoc’d with severe neuro sequelae
Needleman HL , 1979
Deficit in intellectual function observed even among asymptomatic children with hi tooth lead vs low lead

10. Lead poisoning today - 1
Kids- wide concern re subtle neurocognitive effects from low-level environmental exposure
lead paint in/around old homes
toys from China!
air ( mostly 3rd world)
leaded gasoline
proximity to lead smelters, etc

11. Lead poisoning today - 2
Children: rare case reports of symptomatic plumbism
US: usually, lead paint exposure
Pica
House dust in home, soil
US: sometimes exotic source, eg, swallowed lead object
3rd world: above, + air/water/food, + occupational / home exposures

14. Lead poisoning today - 3 Adults:
Occ’l symptomatic cases from occ/ rec exposures
More and more: are some “diseases of aging” exacerbated, by occult plumbism?
Hypertension
Renal failure
CV disease
Cataracts
Dementia

15. Adult lead exposures Lead refining, smelting, etc
Battery production, reclamation
Painting, construction, metal cutting/welding, etc
Shipwrecking
Firing range work or hobby
Artists, home remodelers, target shooting
Retained bullets, etc
Many misc exotic sources!
Residual childhood exposure

16. Lead: toxicology - 1
Absorption via GI ( esp kids) and inhalation (esp adults) primarily; transplacental
Distribution to blood; soft tissues ( most of toxic effects); and bone ( 75% in kids, 90% in adults)
Elimination: very slow, 65% renal, 35% hepatic: T 1/2 for blood 1-10 mos, bone yrs!

17. Lead: toxicology - 2
Gen: strong affinity for many biologic ligands, esp -SH groups, w/ consequent effects on structural and enzymatic proteins
Similar to Ca++ and interferes in many Ca-mediated intracellular and 2nd messenger systems

18. Lead: toxicology - 3 CNS PNS
Acute encephalopathy w/ neuronal damage, cerebral edema
Subtle neurocognitive effects prob related to neurotransmitter dysfunction and mild morphologic changes in developing brain
Also: protein kinase stim, altered neuronal cell adhesion
PNS
Demyelination and axonal degeneration
Primarily motor nerves

19. Lead toxicology - 4 Hematologic
heme synth pathway inhib, elev EP, microcytic anemia; increased hemolysis
Renal
nephropathy w/ Fanconi syndrome
hypertension in adults
“saturnine” gout
Reproductive: dec’d fertility, m and f
GI: anorexia, N/V, constip, pain ( lead colic)
Endocrine:dec thyroid, adrenopit
Immunologic: dec’d cellular imm markers

20. Heme synthesis inhibition

21. Case presentation-1 3 y.o. boy to ED in status epilepticus
Required several doses diazepam, then ETT
VS p ETT: T 38.3, HR 120, BP 84/53
Atraumatic, card, pulm, abd exam neg
Neuro: obtunded, interm w/drawal to pain vs ext posturing, pupils 3mm, sluggish, nl fundi, inc DTRs w/ ankle clonus

22. Case presentation-2 Labs:
CBC- wbc 11,300 plt 473,000, hgb 6.6, basophilic stippling noted
Chem’s ~ wnl exc sl inc glu, ALT, AST
CSF- 3 wbc, prot 96
Xray of abd, wrist done, and head CT

23. Case presentation-3

24. Case presentation-4 BLL 220
Further rx with phenytoin, phenobarb, midaz and pentobarb infusions for persistant sx activity
Chelation w/ BAL and CaNa2EDTA
PICU 23 days, then transfer to a chronic rehab unit
Marked hypotonia, chorea, dec’d hearing and vision, severe cerebral/cerebellar atrophy

25. Case presentation-5
Follow-up mri day 22

26. Clinical presentation: children-1
Severe ( usually BLL > 100)
CNS: encephalopathy w/ coma, sx’s, papilledema, Cr N palsies, inc’d ICP
GI: pernicious vom’g often prodromal
Heme: pallor (anemia)

27. Clinical presentation: children-2
Mild/Mod (BLL ~ )
CNS: irritable, lethargy, dec’d play
GI: occ’l vomiting, constipation, abd pain
Asymptomatic ( BLL ~ 10-70)
impaired cognition, behavior
possible subtle impaired fine-motor coord, hearing, growth

28. Exceptions to the rule…
BLL ~200 !

29. Low-level lead in kids-1
BLLs intensively studied
Most appear asympt to parents, MDs
Cross-sectional studies find strong asssoc’s of inc’g BLL w/ dec’g IQ or similar markers of cog function1
Maybe even effect at 0-10, esp in very young2
Lead has no physiologic role!
1Needleman NEJM Canfield NEJM 2003

30. Low-level lead in kids-2
Always some doubt re confounding variables, but most authorities believe there is some causality likely
Unfortunately, little data to suggest benefit of chelation rx, tho reduced exposure and enrichment activity may be helpful

31. Low-level lead: Rogan et al
Rogan et al. NEJM 2001 *
Background
Low lead levels do injure developing brain.
Objective
To see if DMSA improves cognitive functioning among young children with moderate blood lead levels.
* Disclosure: ( CHOP and FH ) participated…

32. Lead: Rogan Study-2 Methods
Randomized, double-blinded, placebo control
780 children, age 1-3, 4 clinical centers
BLL g/dL
Home environment remediated
Up to three 26-day courses of DMSA
Neurocognitive testing over 36 months

33. Lead: Rogan Study-3 Results - I 90% drug compliance by parental report
76% drug compliance by pill count
Lead Levels
 11 g/dL at 1 week with DMSA
 g/dL at 6 months with DMSA
 g/dL at 1 year with DMSA

34. Lead: Rogan Study-4
Blood
Lead
Level
over
Time

35. Lead: Rogan Study-5 Results - II No differences noted in... WPPSI-R
Wechsler Preschool and Primary Scales of Intelligence
NEPSY
Developmental Neuropsychological Assessment CPRS-R
Conners’ Parent Rating Scale

36. Lead: Rogan Study-6
Treatment Effect on Neuro Testing

37. Lead: Rogan Conclusions
DMSA did not improve neuro testing among children with moderate plumbism.
DMSA was associated with a small reduction in linear growth.

38. Lead: Rogan Criticisms
Study Flaws
Little BLL reduction at 6 mos; none at 1 yr.
No EP data (marker of soft tissue effect).
Mean maternal IQ = 80.
Only DMSA studied.
Only one dosing regimen.

39. Low-level lead in kids-Summary
Lead is a neurotoxin, even at low levels.
Childhood lead burden has  over 30 yrs.
Still, too many children remain lead poisoned.
Lack evidence that chelation
can prevent or reverse neuro injury.
Pediatricians and parents
must advocate for the environment.
Keep the Lead Out
is better than
Get the Lead Out!

40. Case presentation-2
A 50-something man presents with gen’d sx, after prodrome of being confused for several days
Postictally is agitated and combative
Occ. Hx: he scavenges bullets at Phila shooting ranges, has hx of prior rx for lead toxicity some yrs before
After a few days of BAL and EDTA has quite a tale to tell…

41. Clinical Presentation: adults-1
Severe (BLL usually > 150)
CNS: encephalopathy
PNS: wrist drop, foot drop
GI: colic, “lead lines”
Heme: pallor ( anemia)
Renal: nephropathy

42. Clinical Presentation: adults-2
Moderate
CNS: headache, memory loss, dec’d libido, insomnia
GI: abd pain, anorexia, constipation, met taste, “lead lines”
Renal: hypertension, mild nephropathy
Misc: mild anemia, arthralgias, myalgias, weakness
Mild
CNS: tiredness, moody, etc
Misc: ? Impaired repro, hypertension

43. Treatment guidelines-kids
Ssx or BLL > 70: BAL (im) and Ca Na2EDTA (iv)
BLL 45-69: DMSA (po) or Ca Na2EDTA (iv)
BLL 10-44: close follow-up, consider DMSA in some
All: reduce exposure as much as possible!
Consider GI decon prn

44. Before WBI After WBI

45. Treatment guidelines-adults
Generally, chelation reserved for symptomatic pts, or “very high” BLLs (>70-100)
BAL and Ca Na2EDTA for encephalopathy
DMSA for mild ssx, or hi BLL w/o ssx
Controversy: value of chelation in pregnancy re fetal protection; in gen’l, rx as for non-pregnant woman; rarely, might consider induction of labor.
Also: reduce exposure as possible; must not allow chelation to substitute for worksite contamination correction, avoidance…

46. Special ED Considerations
Could it be lead encephalopathy?
Kids:
Age 1-5
Pica
Suspicious prodrome?
Old house, other exposure source?
Stat labs: micro anemia, baso stippling, inc’d EP, abn’l u/a, xray wrists, axr
Adults
Occupational hx of note
PMH
Stat labs: micro anemia, baso stippling, inc’d EP, abn’l u/a
“Stat” BLL ( usually 1-2 days in Phila…)
Exposure reduction, consider empiric rx, pursue ddx

47. Unusual challenge of exposure reduction!

48. An old problem…
1874 Boston Medical and Surgical Journal, aka…?

49. Retained bullets, shot, etc
Usually benign in subcut, muscle
Problematic when bathed by acidic body fluids, eg, serosal, synovial, CSF
Risk also related to particle size/ total lead surface area and intercurrent illness, acidosis, infection, etc.
Chelation unlikely to reduce body burden significantly unless bullet(s) can be removed; surgery may warrant perioperative chelation?
(Dr Haroz ??)

50. Another challenge: “macro-pica”
Beware swallowed lead foreign bodies, can lead to very high BLLs within 1-2 weeks of ingestion, faster if in fine particles…

51. Lead - summary
Ubiquitous element in earth’s crust, many industrial uses
Long history of toxicity
Toxic effects on many organ systems, esp CNS and heme in pts of all ages, and renal in adults
Treatment: reduce exposure, including retained or swallowed FB’s if possible; chelation prn
Defining asymptomatic pts who might benefit has been problematic