Toxicity of Ammonia

from docx import Document
from docx.shared import Pt, Inches, RGBColor
from docx.enum.text import WD_ALIGN_PARAGRAPH
from docx.enum.table import WD_TABLE_ALIGNMENT
from docx.oxml.ns import qn
from docx.oxml import OxmlElement
import datetime

doc = Document()

# Default style
style = doc.styles["Normal"]
style.font.name = "Calibri"
style.font.size = Pt(11)

DARK_BLUE = RGBColor(0x1F, 0x3A, 0x5F)
ACCENT = RGBColor(0x2E, 0x74, 0xB5)
GREY = RGBColor(0x59, 0x59, 0x59)

def set_cell_shading(cell, color_hex):
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def add_heading(text, level=1, color=DARK_BLUE, size=None):
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def add_table(headers, rows, col_widths=None):
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# ---------------- TITLE PAGE ----------------
title = doc.add_paragraph()
title.alignment = WD_ALIGN_PARAGRAPH.CENTER
r = title.add_run("CLINICAL SUMMARY")
r.font.size = Pt(28)
r.font.bold = True
r.font.color.rgb = DARK_BLUE

subtitle = doc.add_paragraph()
subtitle.alignment = WD_ALIGN_PARAGRAPH.CENTER
r2 = subtitle.add_run("Ammonia Toxicity: Recognition and Management")
r2.font.size = Pt(18)
r2.font.color.rgb = ACCENT
r2.bold = True

meta = doc.add_paragraph()
meta.alignment = WD_ALIGN_PARAGRAPH.CENTER
r3 = meta.add_run(f"Prepared for clinical education / quick-reference use\nDate: {datetime.date.today().strftime('%B %d, %Y')}")
r3.font.size = Pt(10)
r3.font.color.rgb = GREY

doc.add_paragraph()
note = doc.add_paragraph()
note.alignment = WD_ALIGN_PARAGRAPH.CENTER
rn = note.add_run("For educational/clinical reference only. Always follow institutional protocols, "
                   "poison control guidance, and current drug labeling.")
rn.italic = True
rn.font.size = Pt(9)
rn.font.color.rgb = GREY

doc.add_page_break()

# ---------------- 1. OVERVIEW ----------------
add_heading("1. Overview", level=1)
doc.add_paragraph(
    "Ammonia toxicity presents in two clinically distinct forms that share a common downstream mechanism of "
    "central nervous system injury but differ markedly in etiology, route, and initial management:"
)
add_bullets([
    ("Endogenous hyperammonemia", " - elevated blood ammonia (NH3) due to failure of hepatic urea-cycle "
     "clearance or an inborn error of metabolism. Presents as encephalopathy, often without a history of "
     "chemical exposure."),
    ("Exogenous ammonia exposure", " - inhalation, dermal, or ocular contact with ammonia gas or liquid "
     "(anhydrous or aqueous), producing corrosive/alkaline chemical injury to mucosa, airway, skin, and eyes."),
])
doc.add_paragraph(
    "This document summarizes recognition, workup, and stepwise management for both presentations, "
    "with reference values, drug dosing, and disposition thresholds."
)

# ---------------- 2. ETIOLOGY ----------------
add_heading("2. Etiology / Causes", level=1)
add_heading("2a. Endogenous hyperammonemia", level=2, color=ACCENT, size=13)
add_bullets([
    "Acute or chronic liver failure / cirrhosis (impaired urea cycle capacity) - hepatic encephalopathy",
    "Inherited urea cycle enzyme deficiencies (e.g., OTC deficiency, citrullinemia, carbamoyl phosphate "
    "synthetase deficiency, HHH syndrome) - typically unmasked by catabolic stress, illness, or high protein load",
    "Drug-induced: valproic acid (impairs mitochondrial ureagenesis and increases renal ammonia production; "
    "can occur with normal liver enzymes and normal valproate levels)",
    "Rare organic acidemias / N-acetylglutamate synthetase deficiency",
    "Portosystemic shunting, severe dehydration/catabolic states, GI bleeding (protein load), infection/sepsis",
])
add_heading("2b. Exogenous exposure", level=2, color=ACCENT, size=13)
add_bullets([
    "Occupational/industrial: refrigeration systems, fertilizer production, cleaning agents, chemical "
    "manufacturing - anhydrous ammonia is among the most commonly stored hazardous chemicals in the US",
    "Household: mixing ammonia-based cleaners with bleach (generates chloramine gas) or with other chemicals",
    "Agricultural: clandestine methamphetamine production, livestock/fertilizer facilities",
    "Transportation incidents (tanker/rail leaks)",
])

# ---------------- 3. PATHOPHYSIOLOGY ----------------
add_heading("3. Pathophysiology (brief)", level=1)
add_bullets([
    ("CNS toxicity (hyperammonemia): ", "Astrocytes detoxify ammonia by converting glutamate to glutamine via "
     "glutamine synthetase. Excess intracellular glutamine creates an osmotic gradient causing astrocyte "
     "swelling and cerebral edema. Ammonia also impairs glutamatergic/GABAergic neurotransmission, contributing "
     "to altered mental status, seizures, and (in severe cases) herniation."),
    ("Corrosive injury (exposure): ", "Ammonia gas is highly water-soluble and hygroscopic; on contact with "
     "moist mucosa it forms alkaline ammonium hydroxide, causing liquefactive/alkaline chemical burns to "
     "conjunctiva, cornea, upper and lower airway epithelium, and skin. Liquid anhydrous ammonia additionally "
     "causes cryogenic (frostbite-like) injury on contact."),
])

# ---------------- 4. CLINICAL PRESENTATION ----------------
add_heading("4. Clinical Presentation", level=1)
add_table(
    ["System / Setting", "Findings"],
    [
        ["Hyperammonemia (early)", "Nausea, vomiting, irritability, lethargy"],
        ["Hyperammonemia (progressive)", "Confusion, asterixis, ataxia, seizures, cerebral edema, coma"],
        ["Pediatric / neonatal UCD crisis", "Poor feeding, vomiting, tachypnea, lethargy progressing to coma; often triggered by illness/catabolism"],
        ["Ocular exposure", "Pain, tearing, blepharospasm, corneal burns, risk of blindness"],
        ["Skin/liquid contact", "Alkaline burn plus cryogenic (freeze) injury from anhydrous liquid"],
        ["Inhalation - mild/moderate", "Eye/nose/throat irritation, cough, bronchospasm (onset even at ~50 ppm)"],
        ["Inhalation - severe", "Laryngeal edema, upper airway obstruction, stridor, pulmonary edema (may be delayed hours), ARDS, secondary infection"],
    ],
    col_widths=[2.2, 4.3]
)

# ---------------- 5. DIAGNOSTIC WORKUP ----------------
add_heading("5. Diagnostic Workup", level=1)
add_bullets([
    "Venous or arterial ammonia level (free-flowing draw, no tourniquet stasis, transport on ice, analyze promptly - false elevation is common with poor technique)",
    "Basic metabolic panel, glucose, LFTs, coagulation studies (INR), lactate",
    "Arterial blood gas (acid-base status; consider concomitant metabolic acidosis in inborn errors)",
    "Urine organic acids, plasma amino acids, and acylcarnitine profile if inborn error of metabolism suspected (especially in infants/children)",
    "Valproic acid level if on this medication, regardless of level (hyperammonemia can occur even with therapeutic/normal valproate levels)",
    "For inhalation exposure: pulse oximetry/ABG, chest imaging if respiratory symptoms, direct laryngoscopy if stridor/voice change to assess airway edema",
    "Ocular exposure: fluorescein exam, pH testing of conjunctival surface until neutralized",
])
p = doc.add_paragraph()
r = p.add_run("Reference: normal blood ammonia is approximately 10-40 micromol/L. Levels >200 micromol/L are "
              "associated with increased risk of intracranial hypertension in acute liver failure; levels "
              ">500 micromol/L are a commonly cited threshold for considering hemodialysis in acute severe "
              "hyperammonemia (e.g., pediatric urea cycle crisis).")
r.italic = True

# ---------------- 6. MANAGEMENT ----------------
add_heading("6. Management", level=1)

add_heading("6a. Endogenous Hyperammonemia - General Approach", level=2, color=ACCENT, size=13)
add_bullets([
    "Identify and treat the precipitant: stop protein intake temporarily, treat infection/GI bleed/dehydration, "
    "discontinue valproate or other offending drugs, correct catabolic state",
    "Reverse catabolism: IV dextrose to provide calories and halt endogenous protein breakdown; avoid steroids "
    "(they increase protein turnover and worsen ammonia)",
    "Airway/neuro protection: manage seizures, elevate head of bed, treat cerebral edema if present, frequent neuro checks",
    "Nitrogen-scavenging drugs (below) started early, in parallel with definitive therapy",
    "Escalate to renal replacement therapy if ammonia remains markedly elevated or rising despite medical therapy",
])

add_heading("6b. Ammonia-Scavenging / Nitrogen-Diversion Drugs", level=2, color=ACCENT, size=13)
add_table(
    ["Agent", "Mechanism", "Typical Use"],
    [
        ["Sodium benzoate", "Conjugates with glycine -> hippurate, excreted in urine (diverts 1 N per mole)",
         "Acute hyperammonemia / urea cycle disorders; IV in crisis (e.g., as part of Ammonul with sodium phenylacetate)"],
        ["Sodium phenylbutyrate / phenylacetate", "Converted to phenylacetate, conjugates with glutamine -> "
         "phenylacetylglutamine, excreted in urine (diverts 2 N per mole)", "Acute and chronic urea cycle disorder management; oral (chronic) or IV (acute crisis, as Ammonul)"],
        ["L-arginine / L-citrulline", "Urea cycle intermediate replacement, restores cycle flux (except in arginase deficiency)",
         "Adjunct in most urea cycle disorders"],
        ["L-carnitine", "Combines with accumulated organic acids to form excretable acylcarnitines", "Empiric adjunct in suspected organic acidemia (e.g., 100 mg/kg or ~400 mg IV/IO in pediatric protocols)"],
        ["Lactulose", "Acidifies colon, traps NH3 as NH4+, cathartic effect reduces gut absorption",
         "Hepatic encephalopathy (cirrhosis); not proven effective in valproate-induced hyperammonemic encephalopathy"],
        ["Rifaximin / neomycin", "Reduces ammoniagenic gut flora", "Adjunct/maintenance in hepatic encephalopathy"],
        ["L-ornithine L-aspartate (LOLA)", "Substrate for urea cycle and glutamine synthetase", "Adjunct in hepatic encephalopathy"],
    ],
    col_widths=[1.6, 2.8, 2.3]
)

add_heading("6c. Renal Replacement Therapy", level=2, color=ACCENT, size=13)
add_bullets([
    "Indicated when ammonia is very high (commonly cited threshold >500 micromol/L, especially pediatric UCD crisis) "
    "or when levels fail to fall with medical therapy within hours",
    "Intermittent hemodialysis is the most efficient modality for rapid ammonia clearance",
    "Continuous veno-venous hemofiltration/hemodialysis (CVVH/D) is an alternative, particularly in hemodynamically unstable patients or where intermittent HD access is not immediately available",
    "Exchange transfusion and peritoneal dialysis are not effective for ammonia clearance and should not be relied upon",
])

add_heading("6d. Hepatic Encephalopathy (Cirrhosis-Related)", level=2, color=ACCENT, size=13)
add_bullets([
    "First line: lactulose titrated to 2-3 soft stools/day; add rifaximin for recurrent/breakthrough episodes",
    "Identify and correct precipitants: infection (SBP), GI bleeding, electrolyte disturbance, sedative/diuretic overuse, constipation, dehydration",
    "Protein restriction is not routinely recommended; adequate protein intake supports recovery",
    "Consider LOLA, flumazenil (if benzodiazepine-related), and airway protection in advanced-grade encephalopathy",
])

add_heading("6e. Valproic Acid-Induced Hyperammonemic Encephalopathy", level=2, color=ACCENT, size=13)
add_bullets([
    "Discontinue or reduce valproate dose - usually resolves clinically and biochemically after withdrawal",
    "L-carnitine supplementation is commonly used, particularly with concurrent hepatotoxicity or carnitine deficiency risk factors",
    "Lactulose is not established as effective in this specific etiology",
    "Hemodialysis effectively clears valproate and can be considered in severe/refractory cases or significant overdose",
])

add_heading("6f. Exogenous Exposure (Gas / Liquid Ammonia) - Prehospital and ED", level=2, color=ACCENT, size=13)
add_bullets([
    "Scene safety first: rescue only by personnel with appropriate PPE/SCBA; remove victim to fresh air",
    "ABCs: assess airway patency early - laryngeal edema can progress rapidly; have a low threshold for early "
    "intubation in significant exposure (avoid blind nasotracheal intubation)",
    "Supplemental humidified/warmed oxygen; assist ventilation with bag-valve-mask if needed",
    "Decontamination: remove contaminated clothing; flush skin/hair with copious plain water for several minutes "
    "then wash with mild soap and rinse; cover open wounds before decontamination (ammonia absorbs readily through abraded skin)",
    "Liquid anhydrous ammonia contact: first thaw with water before removing adherent clothing/PPE to avoid "
    "additional tissue trauma",
    "Ocular exposure: copious irrigation (preferably isotonic saline) until conjunctival pH normalizes, "
    "followed by ophthalmology evaluation",
    "Bronchodilators for bronchospasm; monitor for delayed pulmonary edema (may develop hours after exposure) - "
    "observe/admit even initially asymptomatic-appearing significant exposures",
    "Management is largely supportive; there is no specific antidote for inhalation/dermal ammonia injury",
])

# ---------------- 7. DISPOSITION ----------------
add_heading("7. Disposition and Monitoring", level=1)
add_bullets([
    "Asymptomatic gas-only exposure: may be released with return precautions and instructions to seek care if symptoms develop",
    "Symptomatic inhalation, ocular, or significant dermal/liquid exposure: admit for observation given risk of delayed pulmonary edema and progressive airway edema",
    "Any patient with altered mental status or ammonia >150-200 micromol/L: admit, trend ammonia levels serially, involve critical care/toxicology/metabolic genetics as appropriate",
    "Pediatric suspected inborn error of metabolism with hyperammonemia: urgent transfer to a center capable of emergent hemodialysis and metabolic/genetics consultation",
])

# ---------------- 8. KEY REFERENCE VALUES ----------------
add_heading("8. Key Reference Values", level=1)
add_table(
    ["Parameter", "Value / Threshold"],
    [
        ["Normal blood ammonia", "~10-40 micromol/L"],
        ["Mild airborne ammonia irritation threshold", "~50 ppm (eye/nose/throat irritation, bronchospasm)"],
        ["Ammonia level associated with increased ICP risk (ALF)", ">200 micromol/L"],
        ["Common hemodialysis threshold (severe hyperammonemia)", ">500 micromol/L, or rising despite medical therapy"],
        ["Anhydrous liquid ammonia storage temperature", "~-28 F / -33 C (cryogenic injury risk)"],
    ],
    col_widths=[3.5, 3.2]
)

# ---------------- 9. RECENT EVIDENCE NOTE ----------------
add_heading("9. Recent Evidence Notes", level=1)
doc.add_paragraph(
    "Recent systematic reviews/meta-analyses (2023-2025) on valproic acid-induced hyperammonemic encephalopathy "
    "(PMID: 39873559, PMID: 37126830) reinforce that this diagnosis should be considered even with normal liver "
    "enzymes and therapeutic valproate levels, and that withdrawal of the drug remains the cornerstone of "
    "treatment. A 2024 systematic review/meta-analysis (PMID: 39226259) found that blood ammonia correlates "
    "with hepatic encephalopathy severity but should be interpreted alongside other markers (e.g., IL-6, "
    "sodium, albumin) rather than in isolation, since ammonia level alone does not perfectly predict "
    "encephalopathy grade."
)

# ---------------- 10. REFERENCES ----------------
add_heading("10. Sources", level=1)
refs = [
    "Ammonia Toxicity - Miller's Anesthesia, 10th ed.",
    "Disorders of the Urea Cycle - Basic Medical Biochemistry: A Clinical Approach, 6th ed.",
    "Urea Cycle Defects - Harrison's Principles of Internal Medicine, 22nd ed.",
    "Clinical Features (Hepatic Encephalopathy) - Robbins, Cotran & Kumar Pathologic Basis of Disease",
    "Ammonia Metabolism / Urea Cycle Defects - Tietz Textbook of Laboratory Medicine, 7th ed.",
    "Ammonia - Henry's Clinical Diagnosis and Management by Laboratory Methods",
    "Ammonia (Respiratory Toxicity) - Fishman's Pulmonary Diseases and Disorders",
    "Clinical Features / Fluid Resuscitation / Eliminate Toxic Metabolites / Additional Therapies - Tintinalli's Emergency Medicine, Comprehensive Study",
    "Acute Liver Failure - Current Surgical Therapy, 14th ed.",
    "Treatment - Sleisenger and Fordtran's Gastrointestinal and Liver Disease",
    "Enzyme Inhibition / Diversion - Thompson & Thompson Genetics and Genomics in Medicine, 9th ed.",
    "Other Enzyme Deficiency Disorders - Kaplan & Sadock's Comprehensive Textbook of Psychiatry",
    "Techniques (Dialysis) - The Harriet Lane Handbook, 23rd ed.",
    "Treatment (Valproic Acid Hyperammonemic Encephalopathy) - The Washington Manual of Medical Therapeutics",
    "Hepatic Encephalopathy - Bradley and Daroff's Neurology in Clinical Practice",
    "Questions and Answers, Metabolic Derangements - ROSEN's Emergency Medicine, Concepts and Clinical Practice",
    "Case 9: Elevated Ammonia - Biochemistry, Lippincott Illustrated Reviews, 8th ed.",
    "TABLE 8-2 Most Common Chemicals Stored in the US / Hazmat Decontamination - Tintinalli's Emergency Medicine",
    "Classification of Asphyxiants - The Essentials of Forensic Medicine and Toxicology, 36th ed.",
    "CDC/ATSDR Medical Management Guidelines for Ammonia (wwwn.cdc.gov/tsp/MMG)",
    "CHEMM Ammonia Emergency Department/Hospital Management (chemm.hhs.gov)",
    "Ammonia Toxicity Treatment & Management - Medscape/eMedicine",
    "StatPearls - Ammonia Toxicity (NCBI Bookshelf)",
    "Wong YJ et al. Valproic Acid-Associated Hyperammonemia: A Systematic Review. J Clin Psychopharmacol 2023. PMID: 37126830",
    "Huang TK et al. Valproic acid-induced hyperammonemia with encephalopathy in adults: A meta-analysis. Int J Clin Pharmacol Ther 2025. PMID: 39873559",
    "Sepehrinezhad A et al. Correlation of ammonia and blood laboratory parameters with hepatic encephalopathy: A systematic review and meta-analysis. PLoS One 2024. PMID: 39226259",
]
for ref in refs:
    p = doc.add_paragraph(style='List Bullet')
    p.add_run(ref).font.size = Pt(9.5)

doc.add_paragraph()
disclaimer = doc.add_paragraph()
d = disclaimer.add_run(
    "Disclaimer: This summary is for clinical education and quick reference. It does not replace institutional "
    "protocols, poison control/toxicology consultation, or current product labeling. Verify all doses locally "
    "before clinical use."
)
d.italic = True
d.font.size = Pt(9)
d.font.color.rgb = GREY

doc.save("/tmp/workspace/ammonia-toxicity/Ammonia_Toxicity_Clinical_Summary.docx")
print("saved")