const pptxgen = require("pptxgenjs");

const pres = new pptxgen();
pres.layout = "LAYOUT_16x9";
pres.title = "Ketamine: A Comprehensive Clinical Overview";
pres.author = "Orris Medical";

// ─── COLOR PALETTE ───────────────────────────────────────────
const BG_DARK   = "0D1B2A";   // deep navy  (title / section slides)
const BG_MID    = "1B2A3B";   // medium navy
const BG_LIGHT  = "F4F7FA";   // near-white  (content slides)
const ACCENT    = "E8A020";   // amber gold
const ACCENT2   = "4DC8B0";   // teal
const RED_WARN  = "D94040";
const TEXT_DARK = "1A1A2E";
const TEXT_GRAY = "4A5568";
const WHITE     = "FFFFFF";
const LINE_CLR  = "2A4A6A";

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function addHeader(slide, title, subtitle) {
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      fontSize: 13, color: ACCENT, fontFace: "Calibri", align: "right", valign: "middle", margin: 0
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}

// helper: content bullet
function bullet(text, level = 0, bold = false, color = TEXT_DARK) {
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function lastBullet(text, level = 0, bold = false, color = TEXT_DARK) {
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// helper: pill / badge shape
function addPill(slide, label, x, y, w, h, fillColor, textColor = WHITE) {
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}

// helper: info box
function addBox(slide, title, body, x, y, w, h, boxColor = BG_MID) {
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}

// ═══════════════════════════════════════════════════════════
// SLIDE 1 — TITLE
// ═══════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  s.background = { color: BG_DARK };
  // vertical accent bar left
  s.addShape(pres.ShapeType.rect, { x: 0, y: 0, w: 0.18, h: "100%", fill: { color: ACCENT } });
  // large title
  s.addText("KETAMINE", {
    x: 0.45, y: 1.1, w: 9.1, h: 1.4,
    fontSize: 64, bold: true, color: WHITE, fontFace: "Calibri", charSpacing: 8
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  s.addText("A Comprehensive Clinical Overview", {
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    fontSize: 22, color: ACCENT, fontFace: "Calibri", italic: true
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  s.addText("For Anesthesiologists & Clinicians", {
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  s.addText("June 2026", {
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  addPill(s, "Dissociative Anesthetic", 3.2, 3.75, 2.3, 0.38, "1A3A5C");
  addPill(s, "DEA Schedule III", 5.65, 3.75, 1.9, 0.38, "5A2020");
  // sources footnote
  s.addText("Sources: Miller's Anesthesia 10e · Goodman & Gilman's · Rosen's EM · Roberts & Hedges' · Kaplan & Sadock's · Harriet Lane Handbook", {
    x: 0.45, y: 5.2, w: 9.1, h: 0.3, fontSize: 8.5, color: "4A6A8A", fontFace: "Calibri"
  });
}

// ═══════════════════════════════════════════════════════════
// SLIDE 2 — OVERVIEW / AGENDA
// ═══════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  s.background = { color: BG_LIGHT };
  addHeader(s, "Presentation Overview");

  const topics = [
    ["01", "History & Classification"],
    ["02", "Mechanism of Action"],
    ["03", "Pharmacokinetics & Pharmacodynamics"],
    ["04", "Dosing — All Routes & Indications"],
    ["05", "Systemic Effects (CVS, CNS, Respiratory)"],
    ["06", "Clinical Uses & Indications"],
    ["07", "Contraindications & Precautions"],
    ["08", "Adverse Effects & Management"],
    ["09", "Drug Interactions"],
    ["10", "Special Populations"],
    ["11", "Ketamine in Psychiatry (TRD / Esketamine)"],
    ["12", "Monitoring & Practical Tips"],
  ];

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    });
  });
}

// ═══════════════════════════════════════════════════════════
// SLIDE 3 — HISTORY & CLASSIFICATION
// ═══════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  s.background = { color: BG_LIGHT };
  addHeader(s, "History & Classification");

  // Timeline
  const timeline = [
    { year: "1956", text: "Phencyclidine (PCP) synthesized by Parke-Davis — parent compound" },
    { year: "1962", text: "Calvin Stevens synthesizes ketamine as a safer PCP derivative" },
    { year: "1964", text: "First human trials in Michigan volunteers — 'dissociative anesthesia' coined" },
    { year: "1970", text: "FDA approves ketamine (Ketalar®) for clinical use" },
    { year: "1970s–80s", text: "Widespread battlefield use during Vietnam War; standard in field anesthesia" },
    { year: "2000s", text: "Sub-anesthetic doses explored for acute & chronic pain; antidepressant interest" },
    { year: "2019", text: "FDA approves Esketamine (Spravato®) for treatment-resistant depression" },
  ];

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  s.addText("Classification: Arylcyclohexylamine  |  Phencyclidine congener  |  NMDA receptor antagonist  |  DEA Schedule III Controlled Substance  |  WHO Essential Medicine", {
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  });
}

// ═══════════════════════════════════════════════════════════
// SLIDE 4 — MECHANISM OF ACTION
// ═══════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  s.background = { color: BG_LIGHT };
  addHeader(s, "Mechanism of Action");

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    { title: "NMDA Antagonism", body: "Blocks glutamate-gated ion channel inside open receptor\nPrevents Ca²⁺ / Na⁺ influx → disrupts thalamocortical & limbic signalling\nResults in 'dissociative' state: analgesia, amnesia, catalepsy", color: "1A3A5C" },
    { title: "μ-Opioid Agonism", body: "Weak partial agonist at μ and κ opioid receptors\nContributes to analgesia independent of NMDA blockade\nS(+) enantiomer has higher opioid receptor affinity", color: "1A4A3C" },
    { title: "Monoamine Reuptake\nInhibition", body: "Inhibits reuptake of dopamine, norepinephrine, serotonin\n→ Sympathomimetic effects: ↑HR, ↑BP, ↑CO\nCocaine-like inhibition of neuronal catecholamine uptake", color: "2A2A4A" },
    { title: "Sigma Receptor\nActivation", body: "Agonist at σ₁ receptors → psychotomimetic effects\nContributes to emergence delirium & hallucinations\nRelation to antidepressant effect under study", color: "4A2A2A" },
    { title: "mAChR & nAChR\nAntagonism", body: "Muscarinic & nicotinic acetylcholine receptor antagonism\n→ Bronchodilation, ↑secretions (salivation, bronchorrhoea)\nPreserved airway protective reflexes", color: "1A3A4A" },
    { title: "Voltage-Gated Na⁺\nChannel Block", body: "Local anaesthetic-like membrane stabilization\nContributes to analgesia at peripheral sites\nLower potency than traditional local anaesthetics", color: "2A3A1A" },
  ];

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  });
}

// ═══════════════════════════════════════════════════════════
// SLIDE 5 — PHARMACOKINETICS
// ═══════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  s.background = { color: BG_LIGHT };
  addHeader(s, "Pharmacokinetics & Pharmacodynamics");

  // PK table
  const rows = [
    [{ text: "Parameter", options: { bold: true, color: WHITE, fill: BG_DARK, fontSize: 12, fontFace: "Calibri" } }, { text: "Value / Details", options: { bold: true, color: WHITE, fill: BG_DARK, fontSize: 12, fontFace: "Calibri" } }],
    ["Bioavailability", "IV: 100% | IM: ~93% | Oral: ~16–20% (extensive first-pass) | IN: ~25–50%"],
    ["Protein Binding", "~47%"],
    ["Volume of Distribution (Vd)", "~3 L/kg — highly lipophilic, rapid CNS penetration"],
    ["Onset", "IV: 30–60 sec | IM: 3–5 min | Oral: 15–30 min | IN: 5–10 min"],
    ["Duration (dissociation)", "IV: 10–20 min | IM: 15–30 min"],
    ["Full Recovery", "IV: 1–2 h | IM: 60–140 min | Oral/IN: longer"],
    ["Metabolism", "Hepatic CYP3A4 (major), CYP2B6, CYP2D9 → Norketamine (active, ~20% potency)"],
    ["Elimination", "Urine (~91%) and bile, as hydroxylated conjugates"],
    ["Half-life (t½)", "Distribution: 10–15 min | Elimination: 2–3 h"],
    ["Clearance", "~1.3 L/kg/h — suitable for continuous infusion"],
    ["Enantiomers", "Racemic mixture of S(+) and R(-). S(+) is 2-4× more potent (NMDA) with fewer side effects"],
    ["Hepatic impairment", "Reduce dose; prolonged effect due to reduced CYP metabolism"],
  ];

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  // PD note
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  });
}

// ═══════════════════════════════════════════════════════════
// SLIDE 6 — DOSING TABLE
// ═══════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  s.background = { color: BG_LIGHT };
  addHeader(s, "Dosing — All Routes & Indications", "Adults & Paediatrics");

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    [
      { text: "Indication", options: { bold: true, color: WHITE, fill: BG_DARK, fontSize: 11, fontFace: "Calibri" } },
      { text: "Route", options: { bold: true, color: WHITE, fill: BG_DARK, fontSize: 11, fontFace: "Calibri" } },
      { text: "Adult Dose", options: { bold: true, color: WHITE, fill: BG_DARK, fontSize: 11, fontFace: "Calibri" } },
      { text: "Paediatric Dose", options: { bold: true, color: WHITE, fill: BG_DARK, fontSize: 11, fontFace: "Calibri" } },
      { text: "Notes", options: { bold: true, color: WHITE, fill: BG_DARK, fontSize: 11, fontFace: "Calibri" } },
    ],
    // Induction
    ["Anaesthetic Induction", "IV", "1–2 mg/kg (over 30–60 sec)\n(range 1–4.5 mg/kg)", "1.5–2 mg/kg IV", "Inject slowly to avoid apnoea"],
    ["Anaesthetic Induction", "IM", "6.5–13 mg/kg IM\n(single dose)", "4–7 mg/kg IM\n(neonates: 2–4 mg/kg)", "Onset 3–5 min; useful uncooperative pts"],
    // Maintenance
    ["Anaesthetic Maintenance", "IV infusion", "0.1–0.5 mg/min or\n50% of induction dose PRN", "0.5–2 mg/kg/h infusion", "Often combined with propofol or benzo"],
    // Dissociative sedation (PSA)
    ["Procedural Sedation (PSA)", "IV", "0.5–1 mg/kg (over 30–60 sec)\nRepeat: 0.25–0.5 mg/kg q5–10 min PRN", "0.5–1.5 mg/kg IV\n(dissociation at ≥1 mg/kg)", "Sub-dissociative: 0.3–0.5 mg/kg"],
    ["Procedural Sedation (PSA)", "IM", "4–5 mg/kg IM", "3–5 mg/kg IM\n(threshold: 3–4 mg/kg)", "Preferred in children when no IV access"],
    // Analgesia
    ["Sub-anaesthetic Analgesia", "IV", "0.1–0.5 mg/kg bolus or\n0.1–0.3 mg/kg/h infusion", "0.1–0.5 mg/kg IV", "Multimodal; reduces opioid requirements ~33%"],
    ["Perioperative analgesia", "IV infusion", "0.1–0.3 mg/kg/h intraop\n0.05–0.1 mg/kg/h postop", "0.1–0.2 mg/kg/h", "Small-dose: 20–60 mg total"],
    // RSI
    ["RSI (critically ill)", "IV", "1–2 mg/kg IV\n(0.5–1 mg/kg in shock)", "1.5 mg/kg IV", "Preferred in bronchospasm, haemodynamic instability"],
    // Pain states
    ["Acute Pain (ED)", "IV", "0.3–0.5 mg/kg over 15 min\n(sub-dissociative)", "0.3–0.5 mg/kg IV", "Comparable to morphine in fracture pain"],
    // Status epilepticus
    ["Refractory Status Epilepticus", "IV infusion", "1–5 mg/kg bolus then\n0.5–5 mg/kg/h infusion", "1–5 mg/kg/h infusion", "Last resort; adjunct to other AEDs"],
    // Bronchospasm
    ["Severe Bronchospasm / RSI-asthma", "IV", "1.5–2 mg/kg for induction", "1.5–2 mg/kg IV", "Preferred induction agent in status asthmaticus"],
    // Epidural
    ["Epidural / Caudal Adjunct", "Epidural", "0.5–1 mg/kg (preservative-free S+ only)", "0.5 mg/kg caudal", "Regulatory approval pending in many regions"],
    // Intranasal
    ["Procedural Sedation / Analgesia", "Intranasal (IN)", "0.5–1 mg/kg per nostril\n(max volume ~1 mL/nostril)", "0.5–0.75 mg/kg IN", "Use concentrated formulation (50 mg/mL)"],
    // Oral
    ["Premedication / Pain", "Oral/PO", "3–6 mg/kg PO", "6–10 mg/kg PO", "Low bioavailability; unpredictable; rarely used"],
    // TRD
    ["Treatment-Resistant Depression (off-label)", "IV infusion", "0.5 mg/kg over 40 min\nUp to twice weekly × 6 weeks", "Not established", "Psychiatry setting; monitor for dissociation"],
    // Esketamine TRD
    ["TRD — Esketamine (Spravato®)", "Intranasal", "56 mg IN (titrate to 84 mg)\nWeeks 1–4: twice weekly\nWeeks 5–8: weekly\nWeek 9+: weekly or q2 weeks", "Not approved < 18 yrs", "REMS program required; 2-h post-dose monitoring"],
  ];

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    border: { pt: 0.4, color: "C0CDD8" },
    fill: { color: BG_LIGHT },
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    autoPageRepeatHeader: true,
    autoPageHeaderRows: 1,
    autoPageLineColor: "C0CDD8",
    autoPageCharWeight: 0,
    newSlideStartY: 0.88,
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}

// ═══════════════════════════════════════════════════════════
// SLIDE 7 — CARDIOVASCULAR EFFECTS
// ═══════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  s.background = { color: BG_LIGHT };
  addHeader(s, "Systemic Effects — Cardiovascular System");

  const boxes = [
    { title: "Haemodynamic Stimulation (dominant)", body: "↑ Heart rate, ↑ Arterial BP, ↑ Cardiac output\n↑ Pulmonary artery pressure\n↑ Myocardial O₂ consumption\nMechanism: sympathetic activation, catecholamine release, NE reuptake inhibition\nOnset/offset of cardiac effect: t½ = 1–2 min", color: "1A3A5C", accent: ACCENT },
    { title: "Direct Myocardial Depression", body: "Intrinsic negative inotropic effect (direct)\nUsually masked by sympathetic activation\nUnmasked when catecholamine stores depleted:\n  → repeated large doses\n  → catecholamine-depleted septic shock\n  → end-stage heart failure", color: "4A2020", accent: RED_WARN },
    { title: "S(+) Ketamine — Specific", body: "S(+) isomer: cardiac output ↑1 L/min at ~243 ng/mL\nAfter S+ infusion ends → transient ↓CO below baseline\nMore pronounced pulmonary vs systemic vascular resistance rise", color: "1A3A4A", accent: ACCENT2 },
    { title: "Ideal For", body: "✓ Haemodynamic instability / hypovolaemic shock\n✓ Cardiac tamponade (preserves HR & RAP)\n✓ Restrictive pericarditis\n✓ Congenital heart disease (no significant shunt change)\n✓ Septic shock (catecholamine replete)\n✓ Malignant hyperthermia (safe)", color: "1A4A2A", accent: ACCENT2 },
    { title: "Caution / Avoid", body: "✗ Ischaemic heart disease (↑MVO₂)\n✗ Severe hypertension / aortic aneurysm\n✗ Congestive heart failure\n✗ Mitral valve disease (↑PAP disproportionately)\n✗ Tachyarrhythmias", color: "4A2A2A", accent: RED_WARN },
    { title: "How to Blunt Haemodynamic Response", body: "Benzodiazepines (midazolam, diazepam): most effective\nPropofol co-infusion\nInhalation anaesthetics\nContinuous slow infusion technique\n(β-blockers can be used if needed)", color: "2A2A4A", accent: ACCENT },
  ];

  boxes.forEach((b, i) => {
    const col = i % 3;
    const row = Math.floor(i / 3);
    const x = 0.35 + col * 3.15;
    const y = 0.88 + row * 2.15;
    s.addShape(pres.ShapeType.roundRect, { x, y, w: 3.05, h: 2.05, fill: { color: b.color }, line: { color: b.accent, pt: 1 }, rectRadius: 0.08 });
    s.addText(b.title, { x: x + 0.1, y: y + 0.07, w: 2.85, h: 0.38, fontSize: 11.5, bold: true, color: b.accent, fontFace: "Calibri" });
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  });

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  s.addText("Ref: Miller's Anesthesia 10e (pp. 2559–2562) — 'The centrally mediated sympathetic responses to ketamine usually override the direct depressant effects.'", {
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  });
}

// ═══════════════════════════════════════════════════════════
// SLIDE 8 — CNS & RESPIRATORY EFFECTS
// ═══════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  s.background = { color: BG_LIGHT };
  addHeader(s, "Systemic Effects — CNS & Respiratory");

  // CNS column
  s.addShape(pres.ShapeType.rect, { x: 0.35, y: 0.88, w: 4.55, h: 0.38, fill: { color: "1A2A4A" }, line: { color: ACCENT, pt: 1 } });
  s.addText("CNS Effects", { x: 0.45, y: 0.88, w: 4.45, h: 0.38, fontSize: 14, bold: true, color: ACCENT, fontFace: "Calibri", valign: "middle" });

  const cnsItems = [
    "Dissociative state: thalamocortical–limbic disconnection",
    "↑ CBF (~14% at sub-anaesthetic, ~36% at anaesthetic doses) — S(+) enantiomer",
    "↑ ICP concern (historical) — now reconsidered; systematic reviews show no ICP ↑ in head injury when co-administered with sedatives",
    "↑ CMR (~25% globally with subanesthetic doses, mainly frontal & anterior cingulate)",
    "EEG: suppresses alpha, ↑ theta/gamma; at hypnotic doses → slow waves alternating with gamma bursts",
    "Raises seizure threshold for most but lowers at very high doses",
    "Effective in refractory status epilepticus",
    "Nystagmus, roving eye movements, catalepsy, amnesia",
    "Emergence delirium/hallucinations: ~10–30% adults, rare in children",
    "Antidepressant effect via NMDA blockade & AMPA pathway activation",
  ];
  s.addText(cnsItems.map((t, i) => ({ text: `• ${t}`, options: { fontSize: 11, color: TEXT_DARK, fontFace: "Calibri", paraSpaceAfter: 3, breakLine: i < cnsItems.length - 1 } })),
    { x: 0.4, y: 1.3, w: 4.45, h: 4.1 });

  // Respiratory column
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  const respItems = [
    "Spontaneous respiration largely preserved at clinical doses",
    "Rapid IV bolus can cause transient apnoea → always inject over 30–60 sec",
    "Protective airway reflexes maintained (cough, swallow, pharyngeal tone)",
    "Potent bronchodilator: relaxes bronchial smooth muscle (indirect sympathomimetic + direct)",
    "Drug of choice for induction in status asthmaticus / reactive airway disease",
    "↑ Tracheobronchial & salivary secretions ('hypersalivation') — consider glycopyrrolate only if excessive",
    "Laryngospasm: rare (0.3% in paediatric PSA meta-analysis)",
    "Transient apnoea: 0.8% in paediatric PSA (none required intubation)",
    "Respiratory depression possible with rapid infusion or large doses",
    "Pulmonary compliance and functional residual capacity relatively maintained",
  ];
  s.addText(respItems.map((t, i) => ({ text: `• ${t}`, options: { fontSize: 11, color: TEXT_DARK, fontFace: "Calibri", paraSpaceAfter: 3, breakLine: i < respItems.length - 1 } })),
    { x: 5.15, y: 1.3, w: 4.45, h: 4.1 });

  s.addShape(pres.ShapeType.line, { x: 4.97, y: 0.88, w: 0, h: 4.6, line: { color: "C0CDD8", pt: 1.2 } });
}

// ═══════════════════════════════════════════════════════════
// SLIDE 9 — CLINICAL INDICATIONS
// ═══════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  s.background = { color: BG_LIGHT };
  addHeader(s, "Clinical Uses & Indications");

  const indications = [
    { icon: "⚡", title: "General Anaesthesia", detail: "Induction & maintenance\nHaemodynamically unstable patients\nCardiac tamponade, restrictive pericarditis\nCongenital heart disease (neonates)\nMalignant hyperthermia-susceptible patients\nTotal IV anaesthesia (TIVA) with propofol" },
    { icon: "🏥", title: "Procedural Sedation (PSA)", detail: "ED procedural sedation (adults & children)\nOrthopedic reductions, wound care, burns\nIM route in non-cooperative paediatric patients\nDental/minor surgery in field settings\nVetinary & military/resource-limited settings" },
    { icon: "💉", title: "Rapid Sequence Intubation", detail: "Preferred RSI agent:\n• Haemodynamic instability / shock\n• Severe bronchospasm / asthma\n• Trauma with blood loss\n• Tension pneumothorax pre-airway\nDose: 1–2 mg/kg IV (0.5 mg/kg in profound shock)" },
    { icon: "🩹", title: "Acute & Perioperative Pain", detail: "Sub-dissociative dose (0.3–0.5 mg/kg IV)\nMultimodal analgesia — reduces opioid use ~33%\nFracture pain, sickle cell crisis\nCancer pain, neuropathic pain\nPrevention of opioid tolerance / hyperalgesia\nPostoperative pain infusion 0.05–0.1 mg/kg/h" },
    { icon: "🧠", title: "Neurological Emergencies", detail: "Refractory status epilepticus\n  (1–5 mg/kg bolus; 0.5–5 mg/kg/h infusion)\nRaised ICP: can use cautiously WITH propofol/benzo\nNo longer absolutely contraindicated in head injury\nTBI: decreases ICP at 1.5–5 mg/kg (with propofol)" },
    { icon: "🌬️", title: "Critical Care / Sedation", detail: "ICU procedural sedation\nVentilator weaning/adjunct\nBurn dressing changes\nDrug-resistant bronchospasm in ventilated patients\nPreserves haemodynamics in catecholamine-replete septic shock" },
    { icon: "💊", title: "Psychiatry (TRD)", detail: "Treatment-resistant depression\nIV ketamine 0.5 mg/kg/40 min — rapid onset\n(response within hours; antidepressant ~7–14 days)\nEsketamine (Spravato® IN) — FDA-approved 2019\nAcute suicidality in some protocols\nFDA REMS program required for esketamine" },
    { icon: "💫", title: "Other Uses", detail: "Premedication in paediatrics (oral/IM)\nEpidural adjunct (preservative-free S+ only)\nChronic pain: CRPS, phantom limb, fibromyalgia\nIntranasal analgesia in pre-hospital/ED\nSpace / austere environment anaesthesia\nAsthma: bronchodilator of last resort" },
  ];

  indications.forEach((ind, i) => {
    const col = i % 4;
    const row = Math.floor(i / 4);
    const x = 0.32 + col * 2.37;
    const y = 0.88 + row * 2.2;
    s.addShape(pres.ShapeType.roundRect, { x, y, w: 2.27, h: 2.1, fill: { color: row === 0 ? "1A2E4A" : "0D2035" }, line: { color: row === 0 ? ACCENT : ACCENT2, pt: 0.8 }, rectRadius: 0.07 });
    s.addText(`${ind.icon}  ${ind.title}`, { x: x + 0.1, y: y + 0.05, w: 2.1, h: 0.4, fontSize: 11, bold: true, color: row === 0 ? ACCENT : ACCENT2, fontFace: "Calibri" });
    s.addText(ind.detail, { x: x + 0.1, y: y + 0.44, w: 2.1, h: 1.58, fontSize: 9.5, color: WHITE, fontFace: "Calibri", valign: "top", wrap: true });
  });
}

// ═══════════════════════════════════════════════════════════
// SLIDE 10 — CONTRAINDICATIONS & PRECAUTIONS
// ═══════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  s.background = { color: BG_LIGHT };
  addHeader(s, "Contraindications & Precautions");

  // Absolute
  s.addShape(pres.ShapeType.rect, { x: 0.35, y: 0.88, w: 4.55, h: 0.38, fill: { color: RED_WARN }, line: { color: RED_WARN } });
  s.addText("ABSOLUTE Contraindications", { x: 0.45, y: 0.88, w: 4.45, h: 0.38, fontSize: 13.5, bold: true, color: WHITE, fontFace: "Calibri", valign: "middle" });

  const abs = [
    "Active psychosis or mania",
    "Known hypersensitivity to ketamine",
    "Conditions where ↑BP is hazardous:\n  • Aortic dissection\n  • Severe uncontrolled hypertension\n  • Recent myocardial infarction (relative)",
    "Procedures requiring intact pharyngeal/laryngeal reflexes for safety (e.g., posterior pharynx procedures)",
    "Age < 3 months (manufacturer; immature CNS, unpredictable response)",
  ];
  s.addText(abs.map((t, i) => ({ text: `✗  ${t}`, options: { fontSize: 11.5, color: RED_WARN, fontFace: "Calibri", paraSpaceAfter: 5, breakLine: i < abs.length - 1 } })),
    { x: 0.4, y: 1.3, w: 4.45, h: 2.2 });

  // Relative
  s.addShape(pres.ShapeType.rect, { x: 0.35, y: 3.58, w: 4.55, h: 0.38, fill: { color: ACCENT }, line: { color: ACCENT } });
  s.addText("RELATIVE Contraindications", { x: 0.45, y: 3.58, w: 4.45, h: 0.38, fontSize: 13.5, bold: true, color: BG_DARK, fontFace: "Calibri", valign: "middle" });

  const rel = [
    "Ischaemic heart disease / coronary artery disease",
    "Congestive heart failure",
    "Elevated ICP (use WITH sedative co-admin; see evidence)",
    "Elevated intraocular pressure (glaucoma, penetrating eye injury)",
    "Thyroid disease (sympathomimetic effect amplified)",
    "Porphyria",
    "History of substance abuse / dependence",
    "Severe hepatic impairment",
  ];
  s.addText(rel.map((t, i) => ({ text: `⚠  ${t}`, options: { fontSize: 11, color: "7A4A00", fontFace: "Calibri", paraSpaceAfter: 4, breakLine: i < rel.length - 1 } })),
    { x: 0.4, y: 4.0, w: 4.45, h: 1.4 });

  // Evidence update box
  s.addShape(pres.ShapeType.roundRect, { x: 5.1, y: 0.88, w: 4.55, h: 2.3, fill: { color: "1A3A5C" }, line: { color: ACCENT2, pt: 1 }, rectRadius: 0.1 });
  s.addText("Updated Evidence: Ketamine & ICP", { x: 5.2, y: 0.95, w: 4.35, h: 0.35, fontSize: 13, bold: true, color: ACCENT2, fontFace: "Calibri" });
  s.addText(
    "Historical concern: ketamine raises ICP and CBF.\n\nCurrent evidence (systematic reviews):\n• Ketamine does NOT increase ICP in mechanically ventilated head-injury patients when used with adequate sedation\n• ICP actually DECREASES with large doses (1.5–5 mg/kg) in TBI patients receiving propofol\n• Autoregulation and CO₂ responsiveness preserved\n\nPractical recommendation:\nCan use cautiously with benzodiazepine or propofol in critically ill; avoid as sole agent in unventilated raised-ICP.",
    { x: 5.2, y: 1.32, w: 4.35, h: 1.78, fontSize: 10.5, color: WHITE, fontFace: "Calibri", valign: "top", wrap: true }
  );

  // Key point box
  s.addShape(pres.ShapeType.roundRect, { x: 5.1, y: 3.28, w: 4.55, h: 2.1, fill: { color: "1A3A2A" }, line: { color: ACCENT2, pt: 1 }, rectRadius: 0.1 });
  s.addText("The 'Safe Airway' Distinction", { x: 5.2, y: 3.35, w: 4.35, h: 0.35, fontSize: 13, bold: true, color: ACCENT2, fontFace: "Calibri" });
  s.addText(
    "• Ketamine preserves airway reflexes and muscle tone\n• 40+ years of use: no documented clinically significant aspiration in patients without established contraindications\n• May be preferred when fasting cannot be ensured (emergency situations)\n• Airway compromise risk: laryngospasm 0.3%, transient apnoea 0.8% (paediatric meta-analysis n=8282)",
    { x: 5.2, y: 3.75, w: 4.35, h: 1.55, fontSize: 10.5, color: WHITE, fontFace: "Calibri", valign: "top", wrap: true }
  );
}

// ═══════════════════════════════════════════════════════════
// SLIDE 11 — ADVERSE EFFECTS
// ═══════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  s.background = { color: BG_LIGHT };
  addHeader(s, "Adverse Effects & Their Management");

  const adverseData = [
    { effect: "Emergence Delirium / Hallucinations", freq: "10–30% adults\n<5% children", management: "Benzodiazepine (midazolam 0.03 mg/kg IV) — modestly reduces (NNB = 6)\nQuiet room, minimal stimulation during recovery\nDoes NOT require routine benzo prophylaxis in children", sev: RED_WARN },
    { effect: "Nausea & Vomiting (PONV)", freq: "8.4% paediatric\n(IM > IV)", management: "Ondansetron 0.15 mg/kg IV (max 4 mg) reduces incidence (NNB = 13)\nNot mandatory prophylaxis; typically late in recovery\nHigher risk in early adolescents", sev: ACCENT },
    { effect: "Hypersalivation / ↑ Secretions", freq: "Common\n(~5–10%)", management: "Glycopyrrolate 0.01 mg/kg IV 10 min before only if airway exam planned\nNot routinely recommended; no evidence reduces airway events", sev: ACCENT },
    { effect: "Transient Apnoea", freq: "0.8% (paediatric\nPSA meta-analysis)", management: "Administer IV dose slowly (over 30–60 sec)\nBag-mask ventilation if occurs; self-limiting\nNone required intubation in meta-analysis (n=8282)", sev: ACCENT },
    { effect: "Laryngospasm", freq: "0.3% (paediatric\nPSA)", management: "Position, jaw thrust, CPAP\nSuccinylcholine 0.5–1 mg/kg if does not resolve\nFrequency ↑ with rapid IV injection or excessive secretions", sev: RED_WARN },
    { effect: "Hypertension / Tachycardia", freq: "Common\n(sympathomimetic)", management: "Benzodiazepine pre-treatment; slow infusion\nPropofol/inhalational agent combination\nAvoid in uncontrolled HTN; use β-blocker if needed", sev: ACCENT },
    { effect: "Recovery Agitation", freq: "7.6% mild\n1.4% pronounced\n(paediatric)", management: "Quiet environment, parental presence\nMidazolam for significant agitation\nDifferentiate from pain (assess and treat)", sev: ACCENT },
    { effect: "Diplopia / Blurred Vision", freq: "Transient\n(common)", management: "Usually resolves without intervention\nWarn patient and family pre-procedure", sev: "6A8A3A" },
    { effect: "↑ ICP / IOP", freq: "Historical concern\n(dose-dependent)", management: "Use with sedative co-administration\nPreserved autoregulation per systematic reviews\nAvoid sole use in spontaneously breathing raised-ICP patients", sev: ACCENT },
    { effect: "Ketamine Cystopathy (chronic use)", freq: "Rare in clinical\n(drug abuse doses)", management: "Dose-limiting; reduce or stop ketamine\nUrological follow-up; cessation may reverse early changes", sev: "4A4A4A" },
    { effect: "Potential Neuroapoptosis (neonatal)", freq: "Animal data only\n(high doses)", management: "Animal models used very high doses\nClinical doses for induction in neonates appear safe\nBeneficial effects in pain models also reported", sev: "4A4A4A" },
    { effect: "Drug Dependence / Abuse Potential", freq: "Schedule III;\nrecreational use", management: "Monitor for misuse in chronic pain programs\nLimit outpatient prescribing; use structured protocols", sev: RED_WARN },
  ];

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    [
      { text: "Adverse Effect", options: { bold: true, color: WHITE, fill: BG_DARK, fontSize: 10.5, fontFace: "Calibri" } },
      { text: "Frequency", options: { bold: true, color: WHITE, fill: BG_DARK, fontSize: 10.5, fontFace: "Calibri" } },
      { text: "Management", options: { bold: true, color: WHITE, fill: BG_DARK, fontSize: 10.5, fontFace: "Calibri" } },
    ],
    ...adverseData.map(d => [d.effect, d.freq, d.management])
  ];

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    x: 0.3, y: 0.86, w: 9.4,
    fontSize: 10, fontFace: "Calibri",
    colW: [2.4, 1.4, 5.6],
    border: { pt: 0.4, color: "C0CDD8" },
    fill: { color: BG_LIGHT },
    rowH: 0.4,
    autoPage: true,
    autoPageRepeatHeader: true,
    autoPageHeaderRows: 1,
    autoPageLineColor: "C0CDD8",
    newSlideStartY: 0.88,
  });
}

// ═══════════════════════════════════════════════════════════
// SLIDE 12 — DRUG INTERACTIONS
// ═══════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  s.background = { color: BG_LIGHT };
  addHeader(s, "Drug Interactions");

  const interactions = [
    { drug: "Benzodiazepines\n(midazolam, diazepam)", effect: "↓ Emergence reactions\n↓ Haemodynamic stimulation\n↓ Hallucination frequency", clinical: "Synergistic; often deliberately co-administered\nMay prolong recovery", severity: "BENEFICIAL" },
    { drug: "Opioids\n(fentanyl, morphine)", effect: "Profound sedation, respiratory depression, coma\nProlonged recovery time", clinical: "Use lowest effective doses; monitor carefully\nSynergistic analgesia", severity: "CAUTION" },
    { drug: "Propofol", effect: "Attenuates haemodynamic stimulation\nReduced ketamine dose needed", clinical: "'Ketofol' combination widely used in TIVA/PSA\nBlunts emergence reactions", severity: "BENEFICIAL" },
    { drug: "MAOIs", effect: "Risk of severe hypertension\nHyperpyrexia risk", clinical: "Co-administer with extreme caution\nClose monitoring of vital signs; avoid if possible", severity: "MAJOR" },
    { drug: "Theophylline /\nAminophylline", effect: "↓ Seizure threshold\nConvulsions reported", clinical: "Avoid combination if possible\nMonitor for seizures; use with extreme caution", severity: "MAJOR" },
    { drug: "Sympathomimetics\n(epinephrine, vasopressin)", effect: "Additive haemodynamic stimulation\nSevere hypertension / tachycardia", clinical: "Closely monitor vitals; dose-adjust individually", severity: "CAUTION" },
    { drug: "CNS Depressants\n(alcohol, barbiturates)", effect: "Additive CNS/respiratory depression", clinical: "Reduce ketamine dose; extended monitoring", severity: "CAUTION" },
    { drug: "Halothane\n(volatile agents)", effect: "↓ HR & BP response to ketamine\nNegative inotropic effect may emerge", clinical: "Attenuates cardiovascular stimulation — used therapeutically", severity: "MODERATE" },
    { drug: "Thyroid hormones", effect: "↑ Hypertension and tachycardia\n(amplified sympathomimetic effects)", clinical: "Monitor; may need antihypertensive coverage", severity: "CAUTION" },
    { drug: "Muscle relaxants\n(NMBAs)", effect: "Ketamine itself provides some muscle relaxation via central mechanisms but does NOT replace NMBAs for intubation", clinical: "Standard NMBA dosing required for intubation; no dose change needed", severity: "NEUTRAL" },
    { drug: "Dexmedetomidine", effect: "Synergistic sedation/analgesia\nAttenuates sympathomimetic response", clinical: "'KetoDex' increasingly used; reduces emergence reactions", severity: "BENEFICIAL" },
  ];

  const sevColor = { BENEFICIAL: "1A4A2A", MAJOR: "5A1010", CAUTION: "4A3010", MODERATE: "2A3A4A", NEUTRAL: "2A2A4A" };
  const sevText = { BENEFICIAL: ACCENT2, MAJOR: RED_WARN, CAUTION: ACCENT, MODERATE: "7AB0D4", NEUTRAL: "9090A0" };

  const tableRows = [
    [
      { text: "Drug / Class", options: { bold: true, color: WHITE, fill: BG_DARK, fontSize: 11, fontFace: "Calibri" } },
      { text: "Effect", options: { bold: true, color: WHITE, fill: BG_DARK, fontSize: 11, fontFace: "Calibri" } },
      { text: "Clinical Note", options: { bold: true, color: WHITE, fill: BG_DARK, fontSize: 11, fontFace: "Calibri" } },
      { text: "Severity", options: { bold: true, color: WHITE, fill: BG_DARK, fontSize: 11, fontFace: "Calibri" } },
    ],
    ...interactions.map(r => [r.drug, r.effect, r.clinical,
      { text: r.severity, options: { bold: true, color: WHITE, fill: sevColor[r.severity] || BG_DARK, fontSize: 10, fontFace: "Calibri", align: "center" } }
    ])
  ];

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    x: 0.3, y: 0.86, w: 9.4,
    fontSize: 10, fontFace: "Calibri",
    colW: [1.85, 2.5, 3.7, 1.35],
    border: { pt: 0.4, color: "C0CDD8" },
    fill: { color: BG_LIGHT },
    rowH: 0.4,
    autoPage: true,
    autoPageRepeatHeader: true,
    autoPageHeaderRows: 1,
    newSlideStartY: 0.88,
  });
}

// ═══════════════════════════════════════════════════════════
// SLIDE 13 — SPECIAL POPULATIONS
// ═══════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  s.background = { color: BG_LIGHT };
  addHeader(s, "Special Populations");

  const pops = [
    {
      title: "Paediatrics",
      color: "1A3A5C",
      accent: ACCENT2,
      points: [
        "Ideal agent for painful ED procedures (IM option avoids IV access)",
        "IM dose: 3–5 mg/kg (dissociation at ≥3–4 mg/kg); IV: 1–1.5 mg/kg",
        "Emergence reactions uncommon in children & usually mild",
        "Benzodiazepine co-admin NOT routinely recommended in children",
        "Emesis higher in early adolescents; ondansetron reduces (NNB=13)",
        "Neonatal induction (cardiovascular instability): 2 mg/kg IV or 4–7 mg/kg IM",
        "Theoretical neuroapoptosis concern (animal data only; not confirmed clinically at standard doses)",
      ]
    },
    {
      title: "Elderly",
      color: "1A3A2A",
      accent: ACCENT2,
      points: [
        "No accepted maximum age cut-off for ketamine",
        "Weigh unrecognised CAD risk (sympathomimetic effects ↑MVO₂)",
        "Reduce dose (CYP metabolism may be reduced)",
        "More sensitive to psychomimetic effects — use lower doses, slower infusion",
        "Combination with low-dose opioid/benzo reduces haemodynamic response",
        "Beneficial as opioid-sparing agent in elderly surgical patients",
      ]
    },
    {
      title: "Pregnancy",
      color: "3A1A4A",
      accent: ACCENT,
      points: [
        "Not recommended as sole agent in obstetric anaesthesia at full dose (↑uterine tone at >1.5 mg/kg)",
        "Sub-anaesthetic doses (0.25–0.5 mg/kg) used for obstetric analgesia",
        "Crosses placenta readily — use with caution in first trimester",
        "Can be used cautiously for emergency C-section in resource-limited settings",
        "Haemodynamic stability valuable in haemorrhaging parturients",
      ]
    },
    {
      title: "Haemodynamic Instability / Shock",
      color: "4A2020",
      accent: RED_WARN,
      points: [
        "Preferred induction agent in hypovolaemia, haemorrhagic shock, sepsis",
        "Reduce dose to 50% (0.5–1 mg/kg IV) in profound refractory shock",
        "Catecholamine-depleted patients: direct myocardial depression may emerge",
        "Cardiac tamponade / restrictive pericarditis: drug of choice (preserves HR and RAP)",
        "Ensure adequate volume resuscitation before induction",
      ]
    },
    {
      title: "Hepatic Impairment",
      color: "2A3A1A",
      accent: ACCENT,
      points: [
        "Extensive hepatic metabolism via CYP3A4 → norketamine",
        "Severe hepatic impairment: prolonged effect and recovery",
        "Reduce maintenance dose; monitor extended recovery",
        "Acute liver failure: use with caution; norketamine accumulation",
      ]
    },
    {
      title: "Reactive Airway Disease / Asthma",
      color: "1A2A4A",
      accent: ACCENT2,
      points: [
        "Drug of choice for RSI in status asthmaticus",
        "Potent bronchodilator via sympathomimetic + direct smooth muscle relaxation",
        "Dose: 1.5–2 mg/kg IV for induction",
        "↑ Secretions may worsen mucous plugging — consider glycopyrrolate",
        "Caution: tachycardia in cardiac-compromised asthmatic patients",
      ]
    },
  ];

  pops.forEach((p, i) => {
    const col = i % 3;
    const row = Math.floor(i / 3);
    const x = 0.32 + col * 3.18;
    const y = 0.88 + row * 2.2;
    s.addShape(pres.ShapeType.roundRect, { x, y, w: 3.07, h: 2.1, fill: { color: p.color }, line: { color: p.accent, pt: 0.8 }, rectRadius: 0.08 });
    s.addText(p.title, { x: x + 0.1, y: y + 0.05, w: 2.87, h: 0.38, fontSize: 11.5, bold: true, color: p.accent, fontFace: "Calibri" });
    s.addText(
      p.points.map((pt, pi) => ({ text: `• ${pt}`, options: { fontSize: 9.5, color: WHITE, fontFace: "Calibri", paraSpaceAfter: 2, breakLine: pi < p.points.length - 1 } })),
      { x: x + 0.1, y: y + 0.43, w: 2.87, h: 1.6 }
    );
  });
}

// ═══════════════════════════════════════════════════════════
// SLIDE 14 — KETAMINE IN PSYCHIATRY
// ═══════════════════════════════════════════════════════════
{
  const s = pres.addSlide();
  s.background = { color: BG_DARK };
  addHeader(s, "Ketamine in Psychiatry — TRD & Esketamine");

  // Mechanism in depression
  s.addShape(pres.ShapeType.roundRect, { x: 0.35, y: 0.88, w: 9.3, h: 0.55, fill: { color: "1A2A4A" }, line: { color: ACCENT, pt: 1 }, rectRadius: 0.07 });
  s.addText("Proposed Mechanism in Depression: NMDA blockade → rapid synaptic AMPA activation → ↑BDNF (brain-derived neurotrophic factor) → rapid synaptogenesis & antidepressant effect within hours", {
    x: 0.5, y: 0.88, w: 9.1, h: 0.55, fontSize: 11.5, color: WHITE, fontFace: "Calibri", valign: "middle", align: "center"
  });

  const depBoxes = [
    { title: "IV Racemic Ketamine (off-label)", body: "Dose: 0.5 mg/kg IV over 40 min\nFrequency: up to 2× weekly × 6 weeks\nOnset: antidepressant effect within 1–4 hours\nDuration: typically 7–14 days\nSetting: clinic/hospital monitoring required\nResponse rate TRD: ~50–70% (rapid; not sustained without repeats)\nNot FDA-approved for depression", accent: ACCENT },
    { title: "Esketamine (Spravato® — FDA-approved 2019)", body: "S(+) enantiomer intranasal spray\nInduction (wk 1–4): 56 mg IN twice weekly\n  → titrate to 84 mg based on response\nMaintenance (wk 5–8): 56 or 84 mg weekly\nWeek 9+: weekly or q2 weeks\nPatient must self-administer under direct clinical observation\nMonitor ≥2 h post-dose (sedation, dissociation risk)\nREMS program mandatory (certified sites only)\nCo-prescribed with oral antidepressant", accent: ACCENT2 },
    { title: "Safety & Monitoring", body: "Common AEs: dissociation, dizziness, nausea, sedation\nBlood pressure ↑ common — measure pre-dose & post-dose\nDo not drive/operate machinery on day of administration\nRisk of abuse potential (Schedule III)\nSuicide monitoring: watch closely initially (paradoxical concern early)\nContraindicated: active psychosis, mania, aneurysmal vascular disease, uncontrolled HTN\nLong-term cystopathy risk if used at high/frequent doses", accent: RED_WARN },
  ];

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// ═══════════════════════════════════════════════════════════
// SLIDE 15 — MONITORING & PRACTICAL TIPS
// ═══════════════════════════════════════════════════════════
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    "IV access secured (for IV route)",
    "Continuous pulse oximetry + cardiac monitoring",
    "Capnography if airway management anticipated",
    "Age, weight, allergy, contraindication check",
    "Equipment: bag-mask, suction, airway adjuncts, succinylcholine available",
    "Informed consent: warn about emergence, hallucinations",
    "Fasting: recommended but not mandatory in emergency PSA",
    "Baseline BP measured (ketamine will ↑ BP)",
    "Pre-treatment with midazolam (0.03 mg/kg IV) optional in adults for emergence",
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    "IV: inject over 30–60 sec (0.5 mg/kg/min) — prevents apnoea",
    "Use concentrated formulation for IM/IN (50 mg/mL) to minimize volume",
    "Oral/rectal: mix with cola or juice to mask bitter taste",
    "Epidural: use only preservative-free S(+) formulation",
    "Reduce dose 50% in haemodynamically depleted/shock patients",
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    "SpO₂ continuously; ETCO₂ if ventilated",
    "Continuous ECG: watch for tachyarrhythmias",
    "BP every 1–3 min: expect ↑15–30% — treat if necessary",
    "Depth of anaesthesia monitors (BIS, Entropy): ketamine causes SPURIOUS elevation of indices — interpret with caution",
    "EEG: loss of alpha, ↑ gamma — not consistent with hypnotic drugs",
    "Neuraxial / epidural: dermatomal sensory testing",
    "Eye protection: nystagmus is expected; protect cornea if prolonged procedure",
  ];
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  const rec = [
    "IV discharge: typically 50–110 min; IM: 60–140 min",
    "Quiet, low-stimulation recovery environment",
    "Assess orientation, vital signs, swallow reflex before discharge",
    "Warn about post-discharge PONV and drowsiness",
    "No driving or complex decisions for 24 h after ketamine",
    "Esketamine: mandatory 2-h monitored post-dose observation",
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// ═══════════════════════════════════════════════════════════
// SLIDE 16 — SUMMARY / KEY TAKEAWAYS
// ═══════════════════════════════════════════════════════════
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    { icon: "🔬", text: "Mechanism: NMDA antagonist → dissociative state; also opioid agonism, NE reuptake inhibition, sigma receptor activation" },
    { icon: "💉", text: "Induction dose: 1–2 mg/kg IV (over 30–60 s) or 4–7 mg/kg IM; inject slowly to prevent apnoea" },
    { icon: "❤️", text: "CVS: stimulatory (↑HR, BP, CO) dominates; ideal in shock/tamponade; avoid in ischaemic heart disease" },
    { icon: "🌬️", text: "Preserves airway reflexes and respiratory drive; potent bronchodilator — preferred in asthma/RSI" },
    { icon: "🧠", text: "ICP concern now reconsidered — no ↑ICP in ventilated TBI patients when combined with adequate sedation" },
    { icon: "⚠️", text: "Emergence delirium 10–30% adults — mitigated by midazolam (optional); rare in children" },
    { icon: "🚫", text: "Absolute contraindications: active psychosis, uncontrolled hypertension, aortic dissection, known hypersensitivity" },
    { icon: "💊", text: "Antidepressant: IV 0.5 mg/kg/40 min (off-label TRD); Esketamine IN (Spravato®) FDA-approved 2019" },
    { icon: "📊", text: "Sub-anaesthetic analgesia (0.1–0.5 mg/kg) reduces opioid use ~33%; strong evidence for multimodal pain" },
    { icon: "⚡", text: "Ketamine is a WHO Essential Medicine — unique among anaesthetics in preserving haemodynamics & airway" },
  ];

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// ═══════════════════════════════════════════════════════════
// WRITE
// ═══════════════════════════════════════════════════════════
pres.writeFile({ fileName: "/home/daytona/workspace/ketamine-pptx/Ketamine_Clinical_Overview.pptx" })
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