Table of contents : 

General toxicology Chemical elements hydrogen metabolic acidosis respiratory acidosis metabolic alkalosis respiratory alkalosis oxygen sodium hyponatremia  hypernatremia magnesium phosphorus chlorine potassium hypokalemia hyperkalemia calcium hypocalcemia hypercalcemia iron cuprum zinc arsenic iodine mercury Endogenous metabolites ketones lactic acid creatinine uric acid urea homocysteine catecholamines dyslipidemias triglycerides cholesterol glucose bilirubin

Naturally occurring toxins (taxonomic classification)  Bacteria (bacterial toxins) Eukarya (eukaryal toxins) Fungi (fungal toxins / mycotoxins) Viridiplantae (vegetal or botanical toxins / phytotoxins) Metazoa toxins Alveolata toxins Annelida toxins Bryozoa toxins Cnidaria toxins Porifera toxins Mollusca toxins Arthropoda toxins Chordata toxins Amphibia toxins Archosauria toxins Lepidosauria toxins Mammalia toxins Synthetic chemicals (classification according to use) synthetic polluttants air polluttants liquid solvents and vapors synthetic pesticides algaecides fungicides herbicides molluscicides insecticides ectoparasiticides piscicides rodenticides synthetic drugs of abuse (classification according to chemical structure) chemical weapons  Classification according to induced damage : carcinogens  endocrine disrupters Occupational toxicology Web resources

Chemical elements (below are listed alterations of plasma concentrations; see also alterations of urinary concentrations). When perfusion pressure falls, the homeostatic mechanisms of the human body tend to preserve euvolemia rather than concentration of solutes

• hydrogen (₁H)
• H⁺ ion

Algorithm : acidemia or alkalemia ? respiratory (acute or chonic ?) or metabolic disorder ? if metabolic acidosis, increased or normal anion gap ? if metabolic acidosis with increased anion gap, other acidoses ? if metabolic disorder, is respiratory apparatus adequately compensating it ?

• simple alterations
• alkalosis : pH > 7.45 in the blood (alkalemia) and most body tissues

Pathogenesis : decreased cerebral blood flow (CBF), less pronounced effect on other organs
Symptoms & signs : mental confusion, obtundation, delirium, seizures, muscular hyperexcitability and tetanus, decreased cardiovascular electrical stability, VF, increased sensitivity to digitalis glucosides, secondary systemic arterial hypertension, depression of inotropism, hypoventilation and decreased strength of respiratory muscles
Laboratory examinations : hypokalemia, hypocalcemia, hypophosphatemia, increased glycolysis, right shift in hemoglobin dissociation curve
• respiratory alkalosis : P_CO2 < 36 mmHg in the blood (hypocapnia / hypocarbia) and most body tissues

Aetiology : hyperventilation
• hypoxemia => stimulation of carotid and aortic chemoreceptors => stimulation of respiratory centres
• lung diseases (APE, PTE, fibrosis, pneumonia, etc.)
• CHF
• hypotension, severe anemia
• low atmospheric P_O2
• lung diseases => stimulation of juxtacapillary and paraepithelial receptors => vagus nerve => stimulation of respiratory centres
• direct stimulation of respiratory centres : high environmental P_CO2, hepatic failure, surgery, Gram negative sepsis, salicylate intoxication, hepatic encephalopathy, pulmonary embolism, fever, mechanical ventilation, anxiety, panic attack, less commonly in tetanus due to hypocalcemia or hypophosphatemia due to intracellular shift, post-acidemic alkalosis, progesterone in pregnancy and luteal stage of menstrual cycle
• compensated respiratory alkalosis : the pH of the blood has been returned toward normal through retention of acid or excretion of base by renal mechanisms
Predicted compensatory variations :
• acute : decrease of [HCO₃^-] (mmol/L) = - 0.2 ^. decrease of P_{CO2, art} (mmHg)
• chronic : decrease [HCO₃^-] (mmol/L) = - 0.4 ^. decrease of P_{CO2, art} (mmHg)
Laboratory examinations : hyponatremia, mild hypokalemia, hypophosphatemia, decreased free calcium (increased protein-bound calcium), hyperchloremia
Symptoms & signs : decreased cerebral blood flow => vertigo, mental confusion and convulsions; in anaesthetised or mechanically ventilated patients, cardiac output and arterial blood pressure fall due to effects of anaesthesia or positive pressure ventilation on heart rate, peripheral resistances and venous return. Bohr effect impairs O₂ cession from hemoglobin => cardiac arrhythmia in patients with myocardium ischemias; paraesthesias, perioral unsensitivity, chest constriction or pain, respiratory failure, tetany (rare); hyperventilation syndrome : a complex of symptoms that accompany hypocapnia caused by hyperventilation, including palpitations, shortness of breath, lightheadedness, profuse perspiration, and tingling sensations in the fingertips, face, or toes; prolonged overbreathing may result in vasomotor collapse and loss of consciousness. Hyperventilation unrecognized by the patient is a common cause of the subjective somatic symptoms associated with chronic anxiety or panic attacks.
Therapy :
• aetiological
• correction of hypophosphatemia
• psychological support or mild sedation
• breathe in an air bag (CO₂ rebreathing)
• b-AR blockers to treat hyperadrenergic symptoms
• metabolic alkalosis : [HCO₃^-] > 27 mEq/L in the blood (hyperbicarbonatemia) and most body tissues

Aetiology :
• exogenous HCO₃^- loads
• antiacids associated with ion exchange resins (aluminum hydroxide and sulfonated sodium polystirene)
• acute p.o. or i.v. HCO₃^-
• acetate (solutions for parenteral hyperfeeding)
• citrate (transfusions)
• milk-alkali syndrome
• hypovolemia, normotension, and hyperreninemic hyperaldosteronism
• loss of noncarbonic, or fixed (nonvolatile) acids :
• loss of Na⁺Cl^- and H⁺Cl^- due to prolonged gastric vomiting (also hypochloremia, hyponatremia, and hypokalemia)
• gastric aspiration
• congenital chloridorrhea
• villous adenoma
• administration of polystirene sodium sulfonate together with aluminum hydroxide
• retention of base
• diuretics inducing chloruresis without bicarbonaturia
• thiazide diuretics
• loop diuretics
• edema
• rebound after acute therapy of acidoses (worsened by acidosis-induced hypokalemia, renal new HCO₃^- production, and alkali therapy)
• post-hypercapnia
• post-lactic acidosis or ketoacidosis (lactate and ketones are metabolized to equivalent quantities of HCO₃^-)
• hypercalcemia or hypoparathyroidism
• nonreabsorbable anions (penicillin, carbenicillin) increase transepithelial voltage in distal renal tubule => increased potassium secretion
• hypokalemia
• juxtaglomerular cell hyperplasia / Bartter's syndrome
• hyperaldosteronism (hypervolemia, secondary systemic arterial hypertension)
• Liddle syndrome (hypervolemia, secondary systemic arterial hypertension, hyporeninemic hypoaldosteronism)
• compensated respiratory alkalosis : the pH of the blood has been returned toward normal through retention of acid or excretion of base by renal mechanisms
Pathogenesis : renal HCO₃^- retention
Predicted compensatory variation : increase in P_{CO2, art} (mmHg) =
• + 0.75 ^. increase [HCO₃^-]_plasma (mmol/L)
• + 0.6 ^. increase [HCO₃^-]_plasma (mmol/L)
... or P_{CO2, art} (mmHg) = [HCO₃^-]_plasma (mmol/L) + 15
Symptoms & signs : similar to hypocalcemia
Laboratory examinations : hypochloremia, hypophosphatemia and hypokalemia
Therapy :
• if renal function is preserved, pH < 7.5 and [HCO₃^-]_plasma < 39 mmol/L => hydratation and potassium correct alteration within 48 hrs
• if pH > 7.5 and [HCO₃^-]_plasma > 39 mmol/L => CAI (acetazolamide 200-400 mg i.v. every 4-6 hrs blocks renal HCO₃^- production)
• if renal failure : hemodialysis vs.dialyzed with low [HCO₃^-] and high [Cl^-]
• in neurological emergencies, central venous infusion of diluted HCl
Compensation : proximal renal tubule reabsorbs the standard quote of HCO₃^- (=> basic urine with pH = 8), while the distal tubule secretes H⁺ into plasma and HCO₃^- into tubule by "inverting" membrane domains (creating a pancreas-like arrangements but with Na⁺ channels replaced by K⁺ channels), without involving Na⁺ as the position of Na⁺/K⁺ ATPase is not inverted. Hypokalemia is a side effect.
• acidosis : pH < 7.35 in the blood (acidemia) and most body tissues
• compensated acidosis : pH = 7.38-7.40
• uncompensated acidosis : pH < 7.38
Pathogenesis :
• cellular effects : protein change, shape and function, increased protein breakdown, decreased energy metabolism (glycolysis and oxidative phosphorylation), decreased Ca²⁺ binding, change in dissociation rate of the weak acids and bases; decreased receptor number and function (insulin and catecholamines resistance)
• functional effects : vagal hypertone, reduced myocardial contractility, arteriolar dilatation, venoconstriction and centralization of blood volume, increased pulmonary vascular resistance; sensitization to reentrant arrhythmias and decreased threshold of VF (pH < 7.1 = cardiac arrest); decreased strength of respiratory muscle and promotion of muscle fatigue; inhibition of cerebral metabolism and cell volume regulation
• systemic effects : decreased cardiac output => decreased renal and hepatic flow, ventilatory failure, obtundation and coma despite hyperperfusion
• hypercapnic or respiratory acidosis : P_CO2 > 44 mmHg in the blood (hypercapnia / hypercarbia) and most body tissues. CO₂ is usually transported in blood ...
• dissolved (10%).
• PaCO₂ = 0.863 ^. (V^._CO2 / V^._A) = 36-44 mmHg = 4.7-6.0 kPa (low SD) (3-5% free CO₂, 5% HbCO₂, 90% HCO₃^-). It doesn't depend on patient's age.
• PvCO₂ = 41-49 mmHg
• bicarbonate (60%)
• bound to proteins (30%)
Aetiology :
• hypoventilation
• acute :
• inhibition of respiratory centre : drugs, trauma, O₂-therapy in COPD, cardiac arrest, shock central sleep apnea
• respiratory muscle diseases : myasthenia gravis, periodic palsy, GBS, aminoglycoside toxicity, hypophosphatemia, hypokalemia
• aspiration of foreign body or gastrointestinal content (regurgitation or vomiting), obstructive sleep apnea, laryngospasm
• impaired respiration : reacutizationof COPD, ARDS, APE, asthma, pneumonia, pneumothorax
• chronic :
• inhibition of respiratory centre : severe obesity, CNS injuries, respiratory alkalosis
• respiratory muscle disease : spinal injuries, poliomyelitis
• thoracic cage diseases : kyphoscoliosos, severe obesity
• impaired respiration : COPD, severe obesity
• mechanical ventilation

• high PEEP increases alveolar dead volume
• mechanical ventilation unappropiately regulated to face
• increased CO₂ production (fever, agitation, sepsis, excessive feeding)
• decreased alveolar ventilation (worsened pulmonary function)
• permissive hypercapnia : artificially induced hypercapnia in patients with acute respiratory distress syndrome or respiratory failure, done to lower the inspiratory pressure and tidal volume and thus the possibility of lung injury
• compensated respiratory acidosis : the pH of the blood has been returned toward normal by renal compensatory mechanisms.
Predicted compensatory variations : [HCO₃^-]_plasma < 38 mmol/L (> 38 mmHg in metabolic alkalosis)
• acute : increase of [HCO₃^-]_plasma (mmol/L) = - 0.1 ^. increase of P_{CO2, art} (mmHg)
• chronic : increase [HCO₃^-]_plasma (mmol/L) = - 0.35-0.4 ^. increase of P_{CO2, art} (mmHg)
Symptoms & signs :
• acute : anxiety, dyspnea, confusion, psychosis, hallucinations, coma
• chronic : sleep disturbances, amnesia, daysleeping, personality disorders, coordination and motory disturbances (tremors, myoclonus, asterixis, headache, pseudotumor cerebri)
Laboratory examinations : changing levels of CO₂ in the breath show that a patient is running into respiratory trouble and may need emergency intervention. In hospitals, doctors have sophisticated machinery to measure this vital sign, but emergency workers need smaller, portable equipment to use on the spot. To tackle this problem, Alexander Star of the technology company Nanomix in Emeryville, California, and his colleagues turned to carbon nanotubes. These are tiny, hollow tubes of carbon that conduct electricity and can be used as transistors. The team fused carbon nanotubes with custom-made polymers that detect CO₂. When the polymers react with CO₂, their electrical charge is altered and this in turn creates a measurable voltage change in the attached nanotubes. This is detected with an electronic sensor. A 10% rise in CO₂ levels altered the electrical conductance of the carbon nanotubes by 20%. The transistor's conductivity changed in parallel with the levels of CO₂.
Therapy : aetiological and mechanical ventilation
• nonrespiratory or metabolic acidosis : [HCO₃^-] < 23 mEq/L in the blood (hypobicarbonatemia) and most body tissues and anion gap > 30 mEq/L

Aetiology :
• metabolic acidosis with normal anion gap / hyperchloremic acidosis due to reciprocal variations of [Cl^-] and [HCO₃^-]
• gastrointestinal loss of HCO₃^-
• duodenal vomiting
• diarrhea
• external drainage of pancreas or small bowel
• ureterosigmoidostomy, jejunal loop, ileal loop
• calcium chloride (acidifier)
Symptoms & signs : metabolic acidosis and hypokalemia increase renal NH₄⁺ synthesis and excretion => urinary pH = 5-6
Laboratory examinations : negative urinary anion gap, no bicarbonaturia (EL_HCO3- < 10% FL, variable daily HCO₃^- requirement), hypokalemia
Therapy : aetiological
• renal tubular acidosis (RTA)
• with hypokalemia
• proximal RTA / type 2 RTA : caused by malfunction of the proximal tubules.

Aetiology :
• autosomal dominant
• autosomal recessive
• X-linked
• Fanconi's syndrome
• CAI
Pathogenesis : impaired  reabsorption => bicarbonaturia (EL_HCO3- > 15% FL, HCO₃^- requirement > 4 mmol/kg/die).
Laboratory examinations : urinary pH < 5.5, hypophosphatemia, hypercalciuria (=> hypocalcemia), normal or increased citraturia (reduced reabsorption in proximal tubule), hypovitaminosis 1a,25-(OH)₂-vitamin D₃, NaHCO₃ therapy increases renal K⁺ loss => worsened hypokalemia; after administration of 0.1 g (1.9 mmol) NH₄Cl/kg_{body weight}, pH urinary falls regularly
Therapy : thiazide diuretics, sodium-poor diet
• distal RTA / type 1 RTA : loss of the usual lowering of the pH of urine in the distal tubules
• type 3 RTA : self-limiting type 1 RTA with bicarbonaturia in babies (currently the term is no longer used)
Aetiology :
• autosomal dominant : mutations in SLC4A1
• autosomal recessive
• acquired
• Sjogren's syndrome
• hypergammaglobulinemia
• chronic active hepatitis
• systemic lupus erythematosus
Pathogenesis : excessive H⁺ retrodiffusion from collecting duct or inadequate H⁺ transport.
Laboratory examinations : urinary pH > 5.5 despite acidosis (low ammoniuria), no bicarbonaturia (EL_HCO3- < 10% FL, HCO₃^- requirement < 4 mmol/kg/die), hypercalciuria (=> hypocalcemia => mild secondary hyperparathyroidism) and hypocitraturia => nephrocalcinosis and phosphate calcium oxalate urolithiasis, polyuria; after administration of 0.1 g (1.9 mmol) NH₄Cl/kg_{body weight}, pH urinary doesn't fall below 5.5 despite worsening of acidemia (false positives during infections by urease⁺ bacteria)
Therapy : potassium.
• with hyperkalemia : generalized distal RTA / type 4 RTA

Aetiology : hypoaldosteronism
Laboratory examinations : urinary pH < 5.5 (despite impaired H⁺ excretion, as NH₃ excretion in proximal tubule is far more impaired by hyperkalemiaand cannot buffer the few protons in distal tubule), no bicarbonaturia (EL_HCO3- < 10% FL, HCO₃^- requirement < 4 mmol/kg/die)
Therapy : that for hyperkalemia
Laboratory examinations : mildly positive urinary anion gap,
• hyperkalemia associated to renal failure with 20 < GFR < 50 mL/min
• other causes
• exogenous acid intake
• lysine or arginine chloride
• hyperproteic diet
• ammonium chloride
• potential  loss : ketosis with ketone excretion
• expansion acidosis (rapid infusion of physiological solution)
• hippurate
• ion exchange resins
Therapy : HCO₃^- buffering to maintain HCO₃^- > 10 mmol/L and pH > 7.2. Dose to infuse = [body weight ^. 0.5 ^. (15 - [HCO₃^-]_{plasma, current}] / 2
• metabolic acidosis with increased anion gap / normochloremic acidosis : retention of acids other than HCO₃^- (fixed or nonvolatile acids)
• organic acids
• hyperuricemia
• azotemia
• advanced acute renal failure (GFR < 20 mL/min). Poor tolerance to pH fall.
• advanced chronic renal failure (GFR < 20 mL/min) (uremic acidosis) : the condition in uremic syndrome in which the ability to excrete acid is decreased). pH down to 7.3 are quite well tolerated.
Symptoms & signs : osteopenia, hypercalciuria
Therapy :
• p.o. Shohl solution or NaHCO₃. As citrate increases gastrointestinal aluminum absorption, it shouldn't be associated with antacids.
• hemodialysis
• hyperketonemia
• diabetic ketoacidosis (DKA) in patients with type 1 DM / IDDM

Pathogenesis => signs : hypoinsulinemia (expecially when insulin requests are increased as during concomitant disease), excess of contrainsular hormones (hyperglucagonemia, hypercatecholaminemia, hypercortisolemia, and hyper-GH) =>
• => increased protein catabolism => asthenia & azotemia
• =>
• diminished peripheral glucose uptake & increased gluconeogenesis => hyperglycemia => osmotic polyuria => loss of salts and water => dehydrated skin
• increased lipolysis in adipocytes => increased liver ketogenesis => ketosis => exhaustion of bicarbonate buffering increases ketoacidemia => metabolic acidosis => hyperkalemia, nausea and vomiting
=> ileus, gastric retention, anorexia
=> dehydratation => hypovolemia => heart failure => systemic arterial hypotension => hypovolemic shock => ketoacidotic coma
Laboratory examinations^ref :

	mild	moderate	severe
plasma glucose (mg/dl)	> 250; 400-1,000 mg/dL or > 17 mmol/L (increased)	> 250	> 250
arterial pH	7.25–7.30	7.00–7.24	<7.00 (>6.75)
serum bicarbonate (mEq/l)	15–18	10 to <15	< 10
urine ketones (nitroprusside reaction method)	positive	positive	positive
serum ketones (nitroprusside reaction method)	positive (3-27 mM/L (increased))	positive	positive
effective serum osmolality (mOsm/kg) = 2[measured Na (mEq/l)] + glucose (mg/dl)/18	variable = 310-380 mOsm/kg (normal or decreased)	variable	variable
anion gap = (Na+) - (Cl- + HCO3-) (mEq/l)	> 10	> 12	> 12
alteration in sensoria or mental obtundation	alert	alert/drowsy	stupor/coma
kalemia	3.5-7 mEq/L (normal or increased) (potassium deficit = 3-5 mEq/kg
natremia	125-140 mEq/L (normal) (sodium deficit = 7-10 mEq/kg)
bicarbonatemia	< 20 mEq/L
uremia	15-40 mg/dL
water deficit	6 (3-7) L = 100 ml/kg
chloride deficit	3-5 mEq/l
phosphate deficit	5-7 mmol/kg
magnesium deficit	1-2 mEq/kg
calcium deficit	1-2 mEq/kg

Therapy (chronological order):
• pediatric patients (< 20 years) : complete initial evaluation. Start i.v. fluids: 1.0 L of 0.9% NaCl per hour initially =>
• IV fluids => determine hydration status =>
• hypovolemic shock => administer 0.9% NaCl (20 ml/kg/h) and/or plasma expanders until shock resolved
• mild hypotension => administer 0.9% NaCl (10 ml/kg/h) for initial hour =>
• replace fluid deficit evenly over 48 h with 0.45-0.9% NaCl => when serum glucose reaches 250 mg/dl => change to 5% dextrose with 0.45-0.75% NaCl, at a rate to complete rehydration in 48 h and to maintain glucose between 150-250 mg/dl (10% dextrose with electrolytes may be required) => check glucose and electrolytes every 2-4 h until stable. Look for precipitating causes. After resolution of DKA, initiate SC insulin (0.5-1.0 U/kg/d given as 2/3 in the a.m. [1/3 short-acting, 2/3 intermediate-acting], 1/3 in p.m. [1/2 short-acting, 1/2 intermediate-acting]) or as 0.1-0.25 U/kg regular every 6-8 hours during the first 24 hours for new patients to determine insulin requirements
• rehydratation (total : 5.5 L)
• 0-30' : 1 L
• 30'-1 hr : 0.5 L
• 1-2 hr : 1 L
• 2-4 hr : 1 L
• 4-8 hr : 1 L
• 8-12 hr : 1 L
• insulin :
• IV route => IV insulin infusion : regular insulin 0.1 U/kg/h => continue until acidosis clears (pH > 7.3, HCO₃ > 15) => decrease to 0.05 U/kg/h until SC insulin replacement intiated
• IM (if no IV access) : regular insulin 0.1 U/Kg IV bolus followed by 0.1 U/kg/hr SC or IM
• potassium infusion :
• K⁺ < 2.5 mEq/l => administer 1 mEq/kg of KCL in IV over 1 h. Withhold insulin until K⁺> 2.5
• K⁺ 2.5-3.5 mEq/l => administer K⁺ 40-60 mEq/l in IV solution until K⁺ > 3.5. Monitor K⁺ hourly => check results of hourly K⁺ monitoring =>
• K⁺ < 2.5 mEq/l => see above
• K⁺ = 2.5-3.5 mEq/l => continue as above
• K⁺ > 3.5 mEq/l => see below
• K⁺ 3.5-5.5 mEq/l => administer K⁺ 30-50 mEq/l in IV solution to maintain serum K⁺ at 3.5-5.5 mEq/l
• K⁺ > 5.0 mEq/l => do not give IV K⁺. Monitor K⁺ hourly until K+ < 5.0 mEq/l => see above
• glucose infusion
• assess need for bicarbonate => administer slowly to prevent severe hypokalemia with reduced oxygen cession from hemoglobin to tissues and paradoxical reduction in pH_CSF
• pH < 7.0 => repeat pH after initial hydration bolus =>
• pH < 7.0 => over 1 h, administer NaHCO₃ (2 mEq/kg) added to NaCl to produce a solution that does not exceed 155 mEq/l of Na over 1 hr
• pH > 7.0 => see below
• pH > 7.0 => no HCO₃ indicated
• adult patients : complete initial evaluation. Start i.v. fluids: 1.0 L of 0.9% NaCl per hour initially (15-20 ml/kg/hr) =>
• IV fluids => determine hydration status =>
• hypovolemic shock => administer 0.9% NaCl (1 L/h) and/or plasma expanders
• mild hypotension => evaluate corrected natremia
• hypernatremia or normonatremia => 0.45% NaCl (4-14 ml/kg/hr depending on state of hydration => when serum glucose reaches 300 mg/dl => change to 5% dextrose with 0.45% NaCl at 150-250 ml/h with adequate insulin (0.05-0.1 units/kg/hr IV infusion or 5-10 units SC every 2 hr) to keep the serum glucose between 150-200 mg/dl until metabolic control is achieved => check electrolytes, BUN, creatinine, and glucose every 2-4 h until stable. After resolution of DKA, if the patient is NPO, continue IV insulin and supplement with SC regular insulin as needed. When the patient can eat, initiate a multidose insulin regimen and adjust as needed. Continue IV insulin infusion for 1-2 hr after SC insulin is begun to ensure adequate plasma insulin levels. Continue to look for precipitating cause(s)
• hyponatremia => 0.9% NaCl (4-14 ml/kg/hr) depending on state of hydration => when serum glucose reaches 300 mg/dl => change to 5% dextrose with 0.45% NaCl at 150-250 ml/h with adequate insulin (0.05-0.1 units/kg/hr IV infusion or 5-10 units SC every 2 hr) to keep the serum glucose between 150-200 mg/dl until metabolic control is achieved => check electrolytes, BUN, creatinine, and glucose every 2-4 h until stable. After resolution of DKA, if the patient is NPO, continue IV insulin and supplement with SC regular insulin as needed. When the patient can eat, initiate a multidose insulin regimen and adjust as needed. Continue IV insulin infusion for 1-2 hr after SC insulin is begun to ensure adequate plasma insulin levels. Continue to look for precipitating cause(s)
• cardiogenic shock => hemodynamic monitoring
• insulin
• IV route => regular insulin 0.15 U/kg as IV bolus => 0.1 U/kg/h IV insulin infusion
• SC/IM route => regular insulin 0.4 U/kg 1/2 IV bolus, 1/2 IM or SC => 0.1 U/kg/h regular insulin SC or IM
=> if serum glucose does not fall by 50-70 mg/dl in first hour =>
• double insulin infusion hourly
• give hourly IV insulin bolus (10 U)
... until glucose falls by 50-70 mg/dl. When serum glucose reaches 300 mg/dl => change to 5% dextrose with 0.45% NaCl at 150-250 ml/h with adequate insulin (0.05-0.1 units/kg/hr IV infusion or 5-10 units SC every 2 hr) to keep the serum glucose between 150-200 mg/dl until metabolic control is achieved => check electrolytes, BUN, creatinine, and glucose every 2-4 h until stable. After resolution of DKA, if the patient is NPO, continue IV insulin and supplement with SC regular insulin as needed. When the patient can eat, initiate a multidose insulin regimen and adjust as needed. Continue IV insulin infusion for 1-2 hr after SC insulin is begun to ensure adequate plasma insulin levels. Continue to look for precipitating cause(s)
• potassium => if initial serum
• K⁺ < 3.3 mEq/l => hold insulin and give 40 mEq K⁺ per h (2/3 KCL and 1/3 KPO₄) until K > 3.3 mEq/l
• K⁺ 3.3-5 mEq/l => give 20-30 mEq K⁺ in each liter of IV fluid (2/3 KCL and 1/3 KPO₄) to keep serum K⁺ at 4-5 mEq/l
• K⁺ > 5.0 mEq/l => do not give K⁺, but check K⁺ every 2 h
• assess need for bicarbonate =>
• pH < 6.9 => NaHCO₃ (100 mmol) dilute in 400 ml H₂O, infuse at 200 ml/h
• pH = 6.9-7.0 => NaHCO₃ (50 mmol) dilute in 200 ml H₂O, infuse at 200 ml/h
• repeat HCO₃ administration every 2 h until pH > 7.0. Monitor serum K⁺
• pH > 7.0 => no HCO₃ indicated :
• if kalemia < 3 mEq/L => administer 40 mEq/hr
• if 3 < kalemia < 4 mEq/L => administer 26 mEq/hr
• if 4 < kalemia < 5 mEq/L => administer 20 mEq/hr
• if 5 < kalemia < 6 mEq/L => administer 13 mEq/hr
• if kalemia > 6 mEq/L => interrupt infusion =>
Complications : edemas
• acute pulmonary edema due to excess of liquids
• cerebral edema due to excessive rapidity in normalization of hyperglycemia
Summary of major recommendations :
• initiate insulin therapy according to recommendations in position statement (level of evidence A)
• unless the episode of DKA is mild, regular insulin by continuous intravenous infusion is preferred (level of evidence B)
• assess need for bicarbonate therapy and, if necessary, follow treatment recommendations in position statement: bicarbonate may be beneficial in patients with a pH <6.9; not necessary if pH is >7.0°C
• studies have failed to show any beneficial effect of phosphate replacement on the clinical outcome in DKA. However, to avoid cardiac and skeletal muscle weakness and respiratory depression due to hypophosphatemia, careful phosphate replacement may sometimes be indicated in patients with cardiac dysfunction, anemia, or respiratory depression and in those with serum phosphate concentration <1.0 mg/dl (level of evidence A)
• studies of cerebral edema in DKA are limited in number. Therefore, to avoid the occurrence of cerebral edema, follow the recommendations in the position statement regarding a gradual correction of glucose and osmolality as well as the judicious use of isotonic or hypotonic saline, depending on serum sodium and the hemodynamic status of the patient (level of evidence C)
• initiate fluid replacement therapy based on recommendations in position statement (level of evidence A)
• starvation acidosis or ketoacidosis : a type of metabolic acidosis produced by accumulation of ketone bodies which may accompany a marasmus. This is the only case of metabolic acidosis in which excess protons are endogenous in origin.
• ethanol craving ketoacidosis

Symptoms & signs : abdominal pain, denutrition, hypovolemia
Laboratory examinations : low insulinemia, high triglycerids, cortisol, glucagon, and GH. Acetest may detect acetoacetate but not b-hydroxybutyrate leading to underevaluation of ketonemia and ketonuria
Therapy : i.v. 5% Glc in NaCl 0.9%; correct hypophosphatemia, hypokalemia, and hypomagnesemia
• hyperlactacidemia (lactic acidosis)
• type A (hypoxia)
• type B (aerobic disturbances)
• neoplasms
• diabetes mellitus
• renal failure
• liver failure (massive liver metastases)
• severe infections (cholera, malaria, HIV-1)
• convulsions
• drugs / toxins (biguanides, ethanol, methanol, isoniazid, AZT analogues, fructose)
• D-lactate acidosis : produced by intestinal bacteria in patients with
• jejunoileal bypass
• intestinal occlusion
Therapy :
• treatment of hypoperfusion or sepsis
• NaHCO₃ stimulates PFK and may depress cardiac functionality increasing lactacidemia. Fluid administration is poorly tolerated due to central venoconstriction. After removal of cause, blood lactate is converted to HCO₃^- and may cause rebound metabolic alkalosis
• toxins generating organic acids
• PEG (metabolytes : glycolic acid => glyoxylic acid => oxalic acid, other organic acids)
• methanol (metabolytes : formic and lactic acids)
• toluene (metabolytes : hippuric acid)
• salicylates (metabolytes : lactic acid and ketones)

Therapy : gastric washing with isotonic solution (without NaHCO₃) => active charcoal, i.v. NaHCO₃ (dangerous if respiratory alkalosis occurred) or CAI + HCO₃^- (to prevent systemic metabolic acidosis) until urinary pH > 7.5
Therapy : hemodialysis
Therapy :
• administration of physiological solution (Na:Cl 1:1)
• chlorinated acidifying salts (HCl)
• HCO₃^- and Na⁺ losses : H + Tr Na:Cl 1:1
• increase in organic acid and Na⁺ : H + Tr Na:Cl 1:1
• mucosal exchange : HCO₃^-/Cl^- + NH₄Cl
• glomerular-tubular disequilibrium : Tr Na:Cl 1:1
• compensated metabolic acidosis : the pH of the blood has been returned toward normal by respiratory compensatory mechanisms
Predicted compensatory variation : decrease in P_{CO2, art} (mmHg) = - 1.25 ^. decrease [HCO₃^-]_plasma (mmol/L)
... or :
• P_{CO2, art} (mmHg) = [HCO₃^-]_plasma (mmol/L) + 15
• P_{CO2, art} (mmHg) = (1.5 ^. [HCO₃^-]_plasma (mmol/L)) + 8
Classification according to H⁺ input rate
• 30-70 mmol/min (very fast acid) : hypoxia/ischemic lactic acidosis
• < 1 mmol/min (fast acid) : D-lactate acidosis, biguanides, toxics, DKA, AKA, intoxication (methanol, PEG, toluene, salicylates)
• 0.05 mmol/min (slow acid) : renal acidosis, renal or gastrointestinal HCO₃^- loss
Symptoms & signs : Kussmaul breathing, negative inotropic effect (normalized by incretion of catecholamines), peripheral arterial vasodilatation and central venoconstriction, reduction of central and pulmonary vascular compliance => acute pulmonary edema, headache, lethargy, stupor, impaired glucose tolarance
Therapy : [potential HCO₃^-]_plasma = D(anion gap) = (anion gap)_patient - 10. NaHCO₃ or Shohl solution p.o. or i.v.; check [K⁺]_plasma
Comparison among acidoses with normal anion gap :

	type 1 RTA	type 2 RTA	type 4 RTA	diarrhea
minimal urinary pH	> 5.5	< 5.5	< 5.5	5-6
% excretion of filtered HCO3-	< 10	> 15	< 10	< 10
potassiemia	hypokalemia	hypokalemia	hyperkalemia	hypokalemia
Fanconi's syndrome	no	yes	no	no
nephrolithiasis / nephrocalcinosis	yes	no	no	no
acid excretion in 24 hrs	low	normal	low	high
urinary anion gap (UAG)	positive urinary anion gap			negative
HCO3- requirement (mmol/kg/24 hrs)	< 4	> 4	< 4	variable

Compensation : proximal renal tubule reabsorbs all HCO₃^- filtered (kinetics limited by number of transporters) and distal tubule produces more : it keeps more CO₂ from plasma and produces both HCO₃^- (which outflows in interstitium) and H⁺ (which outflows into the tubule via Na⁺/H⁺ antiporter and eventually H⁺ ATPase and K⁺/H⁺ antiporter : in the latter case K⁺ is secreted back into the plasma by K⁺Cl^- symporter generating hyperkalemia. ATPases can create a tubular pH = 4.5 (DpH = 3), but H⁺ are buffered by HPO₄^2-, H₂PO₄^-, and NH₃, that have pK_a ~ pH_{distal tubule}. NH₃ (and 2 HCO₃^-) come from Gln and diffuse into the tubule : once accepted H⁺, NH₄⁺ can no longer come back into type A intercalated cell and acidic urine (pH 4.5) is generated. By titrating [NaH₂PO₄ + H₃PO₄ + NH₄⁺]_urine one can deduct pH_plasma coming from nonvolatile acids.
Therapy :
• HCO₃^- = ([HCO₃^-]_normal - [HCO₃^-]_observed) ^. volume of distribution_CO2 = base excess ^. body weight ^. 0.3 until pH = 7.2 or = 8-10 mEq/L (check effectiveness of ventilation)

Side effects : hypernatremia, overload, metabolic alkalosis, hypokalemia
• NaHCO₃ + Na₂CO₃ (Carbicarb) improves heart function and consumes CO₂, increasing [HCO₃^-]_extracelluar
• mixed alteration
• double alterations
• diabetic ketoacidosis (metabolic acidosis) causes sensory blur => hyperventilation (respiratory alkalosis) => compensated metabolic acidosis
• sepsis : hypoperfusion (metabolic acidosis) causes fever and hyperventilation (respiratory alkalosis) => compensated metabolic acidosis
• triple alterations
• alcoholic ketoacidosis (metabolic acidosis) => vomiting (=> metabolic alkalosis) and liver dysfunction or alcohol craving => hyperventilation (=> respiratory alkalosis)
The actual values are different from the predicted values for simple alterations, but the compensatory mechanism never overwhelms the primary alteration !
COPD patients always have high P_{CO2, art} (respiratory acidosis), so urgence should be evaluated only from pH and level of consciousness, verifying eventual metabolic acidosis. In chronic diseases, even if ABG shows respiratory acidosis, calculations should be done starting from the previous situation (considered as normal).
When pH is normal, an high anion gap may show metabolic acidosis compensated by metabolic alkalosis
• daily acid production
• 20,000 mmol/day of volatile acid (HCO₃^-)
• 70-100 mmol/day of fixed or nonvolatile acids (phosphates, urates, and H₂SO₃ from -SH groups of animal proteins => vegetarians have mild metabolic alkalosis)
• buffering
• chemical buffers (instantaneous control : they don't change mass but only partial pressures)
• extracellular fluid chemical buffers
• plasma chemical buffers : CO₂ + H₂O <=> H₂CO₃ <=> HCO₃^- + H⁺ => K_a = ([HCO₃^-] ^. [H⁺]) / ([CO₂] ^. [H₂O]) (pK_a = 6.1, distant from 7.4, low absolute concentrations, but relative concentrations can be precisely regulated !)
• urinary chemical buffers :
• NH₃ (pK_a = 9.2; absolute concentration >> P_i, but can be increased by Gln)
• HPO₄^2- and H₂PO₄^- (pK_a = 6.8, near to that of urine, where general urine concentration increases its absolute concentration)
• intracellular fluid chemical buffers
• inorganic phosphate (P_i : pK_a = 6.8, similar to that of cytosol, where it is more represented than in ECF)
• His in proteins, expecially HGB (it requires hours, but includes 70% of buffering activity)
• change in production of organic acids (OAs)
• lungs (require 3-12' to regulate pH after stimulation via peripheral => central chemoreceptors, but have a buffering power double than that of chemical buffers)
• kidneys (long-term buffering)
• H⁺ secretion into tubule
• to eliminate nonvolatile acids (other than H₂CO₃, mainly H₂SO₃)
• to reabsorb filtered HCO₃^-
• ex novo HCO₃^- production by excreting H⁺ into urine (then buffered by urinary chemical buffers)
Acid-base nomograms show 95% confidence interval for any simple acid-base alteration : anyway laboratory values falling within these areas can arise even from mixed alterations.
Web resources :
• GASNet
• The Virtual Anaesthesia Textbook
• Critical Patient.org
• Acid-Base Physiology
• lithium (₃Li)
• hyperlithemia : > 1.5 mEq/L

Sources : drug for treatment of mania (optimal plasma level = 0.5-0.8 mEq/L)
Symptoms & signs :
• acute renal failure
• reduced tubular resporption => polyuria
• primary polydipsia
• medullary hypoplasia
• hypothyroidism (interfers with synthesis and relase of thyroid hormones)
• EKG and EEG alterations
• sedation
• high-frequency hand tremors (> 1  mEq / L)
• ataxia
• psychomotory retardation
• hidradenitis
• primary hyperparathyroidism
• diarrhea and other gastrointestinal disorders
• dermatitis
• epilepsy
• sometimes disturbances of equilibrium
• it accelerates vasculopathies, CHF, and edemas
Overdose therapy : urea, sodium chloride, diuretics (< 2 mEq / L; mild symptoms; acetazolamide) => hemodialysis
• beryllium (₄Be)
• berylliosis / beryllium poisoning : a hypersensitivity response to beryllium, usually involving the lungs and less often the skin, subcutaneous tissues, lymph nodes, liver, or other structures. Beryllium fumes, its oxide and salts, and finely divided dust all may cause a tissue reaction when inhaled or implanted in the skin. 2 varieties are distinguished :
• acute berylliosis : an often fulminating reaction to inhalation of beryllium, characterized by a toxic or allergic pneumonitis, sometimes with rhinitis, pharyngitis, and tracheobronchitis. Symptoms may last for weeks, and serious cases can be fatal.
• chronic berylliosis : the usual form of berylliosis, characterized by beryllium granulomas and Schaumann's (conchoid) bodies, a diffuse inflammatory reaction that may be indistinguishable from sarcoidosis, and sometimes dyspnea and hypertrophic pulmonary osteoarthropathy. In time the granulomas may combine to form pulmonary nodules with fibrosis. Radiographically it is characterized by the development of either small rounded or occasionally irregular linear opacities usually confined to the bases.
• boron (₅B) : poisoning of humans or other animals by boron, boric acid, or a borate salt such as sodium borate (borax).

Symptoms & signs : weakness, ataxia, tremors, convulsions, and often death.
• carbon (₆C)
• charcoal : carbon prepared by charring wood or other organic material.
• activated charcoal / carbo activatus : the residue from the destructive distillation of various organic materials, treated to increase its adsorptive powers; used as a general purpose antidote
• animal charcoal / animal, ivory, or Paris black / bone-black : charcoal prepared from bone
• purified animal charcoal : charcoal prepared from bone and purified by removal of materials dissolved by hot hydrochloric acid and water; adsorbent and decolorizer.
Symptoms & signs : coal workers' pneumoconiosis (CWP) / black or coal miner's lung : a form caused by deposition of large amounts of coal dust in the lungs, and typically characterized by centrilobular emphysema. Different varieties of coal have different risks; those with certain types of contaminants may cause other types of pneumoconiosis.
• anthracosis : anthracite coal
• bituminosis : bituminous coal
Complications : progressive massive fibrosis (PMF)
Laboratory examinations : black induration (hardening and pigmentation of lung tissue)
• nitrogen (₇N)
• hypernitremia : excessive nitrogen in the blood
• hyponitremia : a low level of nitrogen in the blood, sometimes associated with protein malnutrition or overhydration
Total body nitrogen = 28,8 x lean body mass (LBM) (kg) + 2,28
Total daily nitrogen losses =
• ([urea]_{urine, 24 hrs} (mmol/day) x 0,06)/2,14 + 2
• Lee formula : [urea]_{urine, 24 hrs}  (g) x 0,58
• for patients with hyperazotemia : [urea]_{urine, 24 hrs} (g) x 0,58 + [increase in [urea]_plasma (g/l) x weight(kg) x 0,28]
• oxygen (₈O) :
• oxygen partial pressure :
• in inspirated air P_O2 = P_ATM ^.inhaled fraction O₂ (FiO₂) = 760 mmHg ^. 21 = 160 mmHg
• in alveolar (humidified) air P_O2 = 120 mmHg
• in arterial blood Pa_O2 = 100 mmHg, due to physiological dead volume and shunting of venous blood (bronchial arteries and veins). It depends on :
• age
• P_{O2, artery, expected} = 109 - (0.43 ^. age (yy)) [mmHg]
• 96 mmHg at age 30
• 77 mmHg at age 75
• P_{O2, artery, expected} = 103.5 - (0.42 ^. age (yy)) [mmHg]
• body temperature
• atmospheric P_O2 (if breathing 100% O₂, P_{O2, artery} may be > 500 mmHg)
• P_{O2, artery, standard (if patient wouldn't hyperventilate)} = [(P_{CO2, artery, measured} ^. 1.66) + P_{O2, artery, measured}] - 66.4 = 75-110 mmHg = 10.0-13.3 kPa
• P_{O2, artery, standard/expected}
• P_{O2, alveoli} - P_{O2, artery} = 5÷6 mmHg (low SD)
• in tissues P_O2 = 5-20 mmHg
• in venous blood Pv_O2 =

• hemoglobin O₂ saturation :
• in arterial blood (SaO₂) : 95-99%
• SaO_{2, aorta} = 98%
• in mixed venous blood (SvO₂) : 65-80%
• SvO_{2, inferior vena cava} = 80%
• SvO_{2, superior vena cava} = 65-75%
• total oxygen concentration or content :
• in arterial blood (CaO₂) = HGB^. SaO₂ ^. 1.39 + 0.0031 ^. Pa_O2 = 5 mL/ 100 mL blood
• O₂ content = [Hb (98%)] + [free plasma O₂ (2%)] = 19.8 mL / dL blood
• in mixed venous blood (CvO₂) : HGB^. SvO₂ ^. 1.39 + 0.0031 ^. Pv_O2 =
As 98% of oxygen is carried in blood as HbO₂ and only 2% is free in plasma, changes in SaO₂ have a greater impact on CaO₂ than changes in PaO₂ : e.g. a 50% decrease in SaO2 (from 15 mg/dL to 7.5 mg/dL) causes a 50% fall in CaO₂, while a 50% decrease in PaO₂ (from 90 to 45 mmHg) cause a 20% fall in CaO₂.
• oxygen availability (DO₂) = CO ^. CaO₂ = 13.4 ^. CI ^. HGB^. SaO₂ = 13.4 ^. (LVEDV - LVESV) ^. HR ^.HGB^. SaO₂ / BSA
• oxygen consumption (VO₂) = CO ^. (CaO₂ - CvO₂) = 13.4 ^. CI ^. HGB^. (SaO₂ - SvO₂) = 250 mL/min
• extraction rate (O₂ER) = 100 ^. VO₂/DO₂ = (CaO₂ - CvO₂)/CaO₂
• hyperoxia : an excess of O₂ in the system

Aetiology : exposure to high O₂ concentrations, especially to hyperbaric pressures of O₂
Symptoms & signs : oxygen poisoning or toxicity : the effects of hyperoxia due to the breathing of high partial pressures of oxygen for prolonged periods; they include serious, sometimes irreversible, damage to the pulmonary capillary endothelium, followed by cerebral edema and convulsions that can be fatal
• hypoxia : reduction of oxygen supply to tissue below physiological levels
• anoxia : a total lack of oxygen; often used interchangeably with hypoxia to mean a reduced supply of oxygen to the tissues.
Aetiology :
• hypoxic hypoxia : that due to insufficient oxygen reaching the blood
• anoxic anoxia : anoxia resulting from interference with the source of oxygen
• asphyxia [Gr. “a stopping of the pulse”] : pathological changes caused by lack of oxygen in respired air, resulting in hypoxia and hypercapnia
• acute respiratory failure
• alveolar hypoventilation
• asphyxiation / suffocation : the causing of or state of asphyxia
• traumatic asphyxia : asphyxia occurring as a result of sudden or severe mechanical injuries causing traumatic asphyxia of the thorax or upper abdomen, or both

Laboratory examinations :
• ecchymotic mask : cyanotic discoloration of the head and neck
• Tardieu's spots : spots of ecchymosis under the pleura following death by suffocation
Occurrence :
• fetal asphyxia : asphyxia in utero

Aetiology : fetal hypoxia : hypoxia in utero, caused by
• inadequate placental function (often abruptio placentae)
• preeclamptic toxicity
• prolapse of the umbilical cord
• complications from anesthetic administration
• anoxia neonatorum : anoxia of the newborn.
• birth or perinatal asphyxia : asphyxia in the infant

Aetiology :
• during labor (antepartum asphyxia)
• gestational diabetes mellitus
• chronic hypertension
• anemia
• isoimmunization
• previous fetal or neontal death
• during delivery (intrapartum asphyxia) (> 90%)
• during the immediate postnatal period (< 10%)
• CNS : IVH, drugs, seizures, hypoxic-ischemic encephalopathy, hernias, neuromuscular disorders, Leigh syndrome, cerebral infarction or anomalise (olivopontocerebellar atrophy)
• respiratory apparatus : pneumonia, obstructive airway lesions, atelectasis, extreme prematurity (< 1,000 g), laryngeal reflex, phrenic nerve paralysis, severe HMD, pneumothorax, hypoxia
• infections : sepsis, NEC, meningitis (bacterial, viral or mycotic), RSV, gastrointestinal infections, oral feeding, intestinal peristalsis, GERD, esophagitis, intestinal perforation
• metabolic causes : hypoglycemia, hypocalcemia, hypophosphoremia, hyponatremia or hypernatremia, hyperammoniemia, organic acidosis, increased room temperature, hypothermia
• cardiovascular causes : hypotension or hypertension, cardiac failure, anemia, hypovolemia, vagal hypertone
• idiopathic : immaturity of respiratory centres, sleep
Symptoms & signs : apnea neonatorum
Laboratory examinations : Apgar score (named in honor of one of the first pediatricians to specialise in newborn (neonatal) care, Dr. Virginia Apgar)

	0 points	1 point	2 points
Activity (muscle tone)	no movement, "floppy" tone	arms and legs flexed with little movement	active, spontaneous movement
Pulse	absent	< 100 bpm	> 100 bpm
Grimace (responsiveness or reflex irritability)	no response	facial movement only (grimace)	sneeze, cough, pulls away
Appearance (skin color)	normal color all over (hands and feet are pink)	normal color (but hands and feet are bluish)	bluish-gray or pale all over
Respiration (rate and effort)	absent	slow or irregular breathing	normal rate and effort or crying

A score is given for each sign the end of the first minute of extrauterine life and after 5'. If there are problems with the baby an additional score is given at 10 minutes. A score of 7-10 is considered normal, while 4-7 might require some resuscitative measures, and a baby with APGAR < 3 requires immediate resuscitation.
Limitation : poorly predictive for preterm newborns (skin is almost cyanotic, bradypnea, poor reactivity, flebile crying). Commonly only 3 parameters are used to establish if therapy is required (heart rate < 100 bpm; breath rate, cyanotic skin) independently of primary or secondary apnea.
Complications : postasphyxial hypoxic-ischemic encephalopathy (HIE) : Sarnat HB & Sarnat MS classification^ref :
• 1 (mild) : lasting < 24 hours, hyperalertness, uninhibited Moro and stretch reflexes, sympathetic effects, and a normal EEG; mild hypotonia (floppy infant syndrome), poor suction reflex, hypersympathicotonia (tachycardia, mydriasis). Prognosis : good
• 2 (moderate) : obtundation, hypotonia, strong distal flexion, multifocal seizures, lack of suction reflex.. The EEG showed a periodic pattern sometimes preceded by continuous delta activity. Prognosis : good in 50%, cerebral palsy in 25%, lesser handicap (dyslalia, dysgraphia) in 25%. Infants who do not enter stage 3 and who have signs of stage 2 for < 5 days appear normal in later infancy. Persistence of stage 2 for > 7 days or failure of the EEG to revert to normal is associated with later neurologic impairment or death.
• 3 (severe) : stuporous, severe hypotonia, and brain stem and autonomic functions were suppressed (coma, sustained convulsions, depression of respiratory centre). The EEG was isopotential or had infrequent periodic discharges. Prognosis : usually death, otherwise severe complications
Therapy :
• neonatal resuscitation
• mechanical ventilation
• cardiac massage
• cerebral hypothermia (lowered by 3-4°C for 72 hours after birth using a water-filled cap) can improve outcome of experimental perinatal hypoxia-ischaemia. Although induced head cooling is not protective in a mixed population of infants with neonatal encephalopathy, it could safely improve survival without severe neurodevelopmental disability in infants with less severe amplitude integrated electroencephalography (aEEG) changes^ref.
• in the following 2-3 days :
• decrease fluid intake by 20-30%
• ABPM
• normalization of P_CO2 (30-50 mmHg)
• euglycemia
• mannitol 1 g/kg 20' infusion every 4-6 hrs if intracranial hypertension
• AEDs
• neuroprotectors : useless when apoptosis has already occurred (i.e. after 8-24 hrs)
• NMDAR antagonists (ketamine, D-methorphan, PQQ)
• inhibitors of EAA secretion (lamotrigine, riluzole)
• K_ATP inhibitors (diazoxide, galanine)
• antiedemagenic (GR agonists, diuretics)
• CCBs (nifedipine, nicardipine, nimodipine) => Side effect : severe systemic arterial hypotension when the fetus is already hypotensive
• MgSO₄ (membrane hyperpolarization) => transient hypotonia and lethargy. Side effect : cerebral hemorrahges
• antioxidants (SOD, catalase, vitamin E, allopurinol, indomethacin) in reperfusion
• phenobarbital (antioxidant, CCBs and hyperpolarizer) : doubtful effectiveness in prevention
• asphyxia neonatorum : perinatal asphyxia in the newborn.
• asphyxia cyanotica or livida / blue asphyxia : perinatal asphyxia in which the skin is cyanotic from the lack of oxygen in the blood
• asphyxia pallida / white asphyxia : perinatal asphyxia attended with paleness of the skin
• secondary asphyxia : asphyxia recurring after apparent recovery from suffocation.
• high altitude anoxia or sickness : the condition resulting from difficulty in adjusting to diminished oxygen pressure at high altitudes. It may take the form of :
• high-altitude pulmonary edema (HAPE)
• high-altitude cerebral edema (HACE)
• mountain disease or sickness : a type of high altitude sickness caused by exposure to altitude high enough to cause hypoxia, occurring as a result of decreased atmospheric pressure with consequent lowering of arterial oxygen content. It occurs as :
• acute mountain sickness (AMS) / Acosta's disease : a type that appears a few hours after exposure to high altitude, characterized by fatigue, dizziness, breathlessness, headache, nausea and vomiting, insomnia, impairment of mental capacity, and prostration, ending with high-altitude cerebral edema (HACE)
• subacute mountain sickness (a.k.a. "Montezuma maledition") : a type milder than the chronic form and similar clinically to the acute form except for being persistent and amenable to cure by a descent in altitude.
• chronic mountain sickness / Andes disease / Monge's disease : a type characterized by loss of tolerance to hypoxia in a previously acclimatized person, with secondary polycythemia. It occurs in 2 types:
• emphysematous type in which dyspnea is the dominant symptom and bronchitis, laryngitis, and cyanosis are often present
• erythremic type in which there is an erythremic color that becomes cyanotic on mild exertion, with fatigue, headache, episodic stupor, paresthesias, anorexia, nausea and vomiting, and decreased visual acuity
SNPs in mtDNA of inhabitants that routinely dwell at altitudes of > 4,000 metres have been reported :
• indigens of the Tibetan plateau (colonized 23,000 years ago) have relatively low haemoglobin levels but breathe faster to take in more oxygen. Tibetans who live approximately 2-3 miles above sea level have significantly higher levels of glutathione-S-transferase and enoyl coenzyme A hydratase, and possess fewer mitochondria. Once non-genetic factors such as age, illness, or smoking were removed, a subset of Tibetan women has a blood-oxygen concentration that is 10% higher than normal. This trait is inherited in a way that suggests the difference is due to a single gene. The children of women with this putative gene are much more likely to survive to the age of 15, when they are old enough to have children of their own. In the low-oxygen group, each woman has on average 2.5 children that died during childhood. In the high-oxygen group, that average is just 0.4^ref. Maybe the trait allows the children to reach a higher birth weight or, if inherited, it might help children to survive bouts of respiratory illness that would otherwise prove fatal.
• indigens of the Ethiopian plateau (colonized about 50,000 years ago)
• indigens of the Andean Altiplano in Peru and Bolivia (10,000 years ago - after humans arrived in the New World) pump out more haemoglobin
Given enough time, they might all evolve the same adaptations to the high life. But it's perhaps more likely that they are all on their own genetic paths towards different adaptations
The subacute and chronic forms can be cured by descent to a lower altitude.
Climbers on Mount Everest could die because of sudden drops in air pressure triggered by high winds. The top of Mount Everest sits in the upper troposphere, a part of the atmosphere where winds travelling at 110 km an hour can pummel climbers. This region is also affected by jet streaks, extra fast bursts of wind within the jet streams that race around the Earth from west to east. Jet streaks can drag a huge draught of air up the side of the mountain, lowering the air pressure. This typically reduces the partial pressure of oxygen in the air by about 6%, which translates to a 14% reduction in oxygen uptake for the climbers. Air at that altitude already contains only 33% as much oxygen as sea-level air. At these altitudes climbers are already at the limits of endurance. The sudden drop in pressure could have driven some of these climbers into severe physiological distress. Intrepid mountaineers usually start their ascent of the world's highest mountain from a base camp at about 5000 m, trekking to the South Col at a height of around 8000 m. From there it is a full day's climb to the summit at 8850 m. On 8 May 1978, Reinhold Messner and Peter Habeler achieved the first ascent of Mount Everest without an oxygen supply. Since then, more and more climbers have opted to go to the highest place in the world without the support of oxygen cylinders.
Web resources :
• Everest Panorama
• Physiology on Everest
• National Geographic: Everest
• Jet Streaks
• MIT Weather Probe
• myocardial anoxia : failure of coronary blood flow to keep up with myocardial needs.
• anemic hypoxia => anoxia : hypoxia => anoxia due to severe anemia or defective hemoglobin
• stagnant hypoxia : that due to failure to transport sufficient oxygen because of inadequate blood flow, as in heart failure and shock
• stagnant anoxia : particularly severe stagnant hypoxia
• histotoxic hypoxia => anoxia : that due to impaired utilization of oxygen by tissues, as in CO or CN^- poisoning
• hypoxia-ischemia : the changes occurring in tissues when the blood supply is cut off, particularly in a fetus or infant with asphyxia
• hypoxemia : P_{O2, artery} < 80 mmHg or < [109 - 0.43 ^. age (yy)] [mmHg] or anyway P_{O2, artery} < 60 mmHg when measured outdoor at sea level.
• orthodeoxia : accentuation of arterial hypoxemia in the erect position, improved by assumption of a recumbent position

Aetiology : platypnea-orthodeoxia syndrome (POS)
• platydeoxia :

Aetiology : ascending aortic aneurysm compressing the right main pulmonary artery => right-to-left shunting, increased by supine position ^ref
Therapy : a pillow to maintain the lateral decubitus position during sleep prevent nighttime oxygen desaturation.
Pathogenesis : hypoxidosis (impaired cell function due to reduced supply of oxygen) => adaptation mechanisms => decrease in DO₂ causes a compensatory increase in O₂ER, so that VO₂ remains unchanged => when DO₂ < DO_2crit, also VO₂ decreases in a directly related manner => metabolic (lactic) or mixed acidosis => depletion of ATP => alterations in membrane pumps => circulation redistribution => loss of autoregulation in brain => cerebral vascular pressures relates to systemic arterial blood pressure => risk for cerebral hemorrhages in early stages and cerebral ischemia in later stages (hyperlactacidemia => neuronal membrane depolarization => IRI => increased excitatory amino acids => excitotoxicity) => decreased cardiac output, astrocyte and neuronal swelling, neuronal apoptosis (hippocampus, diencephalon, brainstem, cerebellum => cerebral palsy, intellectual deficiencies, epilepsy) => multiple organ failure (MOF). Hypoxic pulmonary vasoconstriction (HPV) (a reflex activated by hypoxia, acidosis or hypercapnia) shifts blood from unventilated to ventilated lobules. Anemia-, metahemoglobinemia- and carboxyhemoglobin-associated anemia doesn't cause hyperventilation because PO₂ remains normal in peripheral blood
Symptoms & signs :
• inspiratory dyspnea or irritative period (30"-1')
• expiratory dyspnea or convulsions period (1'-2') : expiration caused by hypercapnia => expiratory cramp, mydriasis, orthosympathetic secondary systemic arterial hypertension
• apneic period (2'-3') : cessation of respiratory movements, absolute loss of consciousness, deep coma, complete muscular relaxation and lack of reflexes while heartbeat persists (apparent death)
• gasping period (3'-5/6') : reappearance of irregular respiratory acts due to residual excitability of bulbar nervous centres, accompanied by intermittent movements of mouth and alae nasi
• death
Necroptic findings :
• external findings :
• delayed cadaver cooling (convulsions => hyperthermia)
• early rigor mortis due to muscular hyperactivity before death (convulsions)
• early, abundant and diffuse cadaveric ecchymoses due to blood hypoviscosity
• accelerated putrefaction due to blood hypoviscosity
• internal findings :
• dark blood due to hypoxemia
• persistent blood hypoviscosity
• pointed subpleural and subepicardial ecchymoses
• organ hyperemia (oligoemia in spleen due to orthosympathetic contraction of the capsule)
• acute pulmonary emphysema due to inspiratory and expiratory efforts
• in newborns : cerebral edema, status marmoratus of basal ganglia, thalamus (and eventually cortex), watershed infarction (parasagittal cerebral lesion : the commonest ischemic injury, between anterior, middle and posterior cerebral artery areas => spastic tetraplegia), focal or multifocal infarction => porencephalia (when multiple : multicystic encephalomalacia => hydranencephaly => spastic tetraparesis, epilepsy), periventricular leukomalacia (PVL) in trigoni (expecially in preterm newborns => spastic diplegia)
• fluoride (₉F)
• hypofluoremia
• hyperfluoremia

Epidemiology : historically, most cases of fluoride toxicity have followed accidental ingestion of insecticides or rodenticides. A power plant on the upper reaches of the Yuexi River in Sichuan province was to blame for the pollution, which prompted environmental officials to suspend water supplies to 20 000 people in Guanyin Town^ref since Wed 15 Feb 2006^ref. Water was being trucked in to residents, but it was insufficient to meet demand : the river had been polluted with chemicals, including fluoride and nitrogen. Earlier in Feb 2006, 3 tanks at a chemical company in the northwestern province of Shaanxi collapsed, discharging about 2000 tons of alkaline waste into a river which flows into the Yellow River, China's 2nd-longest. In one of the worst incidents, water supplies to millions of people in northeastern China were suspended after a blast at a chemical plant in November 2005 caused cancer-causing benzene compounds to leak into a major river. The chief of China's environment watchdog was forced to resign following that spill, which became an international incident, as the river flows into Russia. The Chinese government has promised to improve environmental safeguards and has spent billions of yuan on cleaning up the country's rivers, though experts warn some of it is misspent and ineffective.
Sources : exposure to excessive amounts of fluorine or its compounds, resulting from
• accidental or intentional ingestion of many common household products, including toothpaste (e.g., sodium monofluorophosphate), dietary supplements (e.g., sodium fluoride), glass-etching or chrome-cleaning agents (e.g., ammonium bifluoride), and certain insecticides and rodenticides (e.g., sodium fluoride)
• chronic inhalation of industrial dusts or gases
• prolonged ingestion of water containing large amounts of fluorides (used in fluoroprophylaxis) : fluoridation in Israel was first mooted in 1973 and finally incorporated into law in November 2002 obligating the Ministry of Health to add fluoride to the nation's water supply. Epidemiology studies in the USA have shown that the addition of 1 ppm of fluoride to the drinking water reduced the caries rate of children's teeth by 50-60% with no side effects. Both the WHO in 1994 and the American Surgeon General's report of 2000 declared that fluoridation of drinking water was the safest and most efficient way of preventing dental caries in all age groups and populations. Opposition to fluoridation has arisen from "antifluoridation" groups who object to the "pollution" of drinking water by the addition of chemicals and mass medication in violation of the "Patient's Rights" law and the Basic Law of Human Dignity and Liberty. However, none of the many independent professional committees reviewing the negative aspects of fluoridation have found any scientific evidence associating fluoridation with any ill-effects or health problems. In Israel, where dental treatment is not included in the basket of Health Services, fluoridation is the most efficient and cheapest way of reducing dental disease, especially for the poorer members of the population^ref. Sodium fluoride is a white, crystalline, water-soluble powder used in municipal water fluoridation systems, in various dental products, and in a variety of industrial applications. Toxicology and carcinogenesis studies were conducted with F344/N rats and B6C3F1 mice of each sex by incorporating sodium fluoride into the drinking water in studies lasting 14 days, 6 months, and 2 years. In addition, genetic toxicology studies were performed with Salmonella typhimurium, with mouse L5178Y cells, and with Chinese hamster ovary cells. 14-Day Studies: Rats and mice received sodium fluoride in drinking water at concentrations as high as 800 ppm. (Concentrations are expressed as sodium fluoride; fluoride ion is 45% of the sodium salt by weight.) In the high-dose groups, 5/5 male and 5/5 female rats and 2/5 male mice died; one female rat was given 400 ppm in the drinking water also died before the end of the studies. No gross lesions were attributed to sodium fluoride administration. 6-Month Studies: Rats received concentrations of sodium fluoride in drinking water as high as 300 ppm, and mice as high as 600 ppm. No rats died during the studies; however, among the mice, 4/9 high-dose males, 9/11 high-dose females, and 1/8 males in the 300 ppm group died before the end of the studies. Weight gains were less than those of controls for rats receiving 300 ppm and mice receiving 200 to 600 ppm. The teeth of rats and mice receiving the higher doses of sodium fluoride were chalky white and chipped or showed unusual wear patterns. Mice and male rats given the higher concentrations had microscopic focal degeneration of the enamel organ. Rats receiving 100 or 300 ppm sodium fluoride had minimal hyperplasia of the gastric mucosa of the stomach, and one high-dose rat of each sex had an ulcer. Acute nephrosis and/or lesions in the liver and myocardium were observed in mice that died early, and minimal alterations in bone growth/remodeling were observed in the long bones of mice receiving sodium fluoride at concentrations of 50 to 600 ppm. The sodium fluoride concentrations selected for the 2-year studies in both rats and mice were 0, 25, 100, and 175 ppm in the drinking water. These concentrations were selected based on the decreased weight gain of rats at 300 ppm and of mice at 200 ppm and above, on the incidence of gastric lesions in rats at 300 ppm in the 6-month studies, and on the absence of significant toxic effects at sodium fluoride concentrations as high as 100 ppm in an earlier 2-year study. Body Weights and Survival in the 2-Year Studies: Mean body weights of dosed and control groups of rats and mice were similar throughout the 2-year studies. Survival of rats and mice was not affected by sodium fluoride administration. Survival rates after 2 years were: male rats-control, 42/80; 25 ppm, 25/51; 100 ppm, 23/50; 175 ppm, 42/80; female rats-59/80; 31/50; 34/50; 54/81; male mice-58/79; 39/50; 37/51; 65/80; female mice-53/80; 38/52; 34/50; 52/80. Neoplastic and Nonneoplastic Effects in the 2-Year Studies: The teeth of rats and mice has a dose-dependent whitish discoloration, and male rats had an increased incidence of tooth deformities and attrition leading on occasion to malocclusion. The teeth of male and, to a lesser degree, female rats had areas of microscopic dentine dysplasia and degeneration of ameloblasts. Dentine dysplasia occurred in both dosed and control groups of male and female mice; the incidence of this lesion was significantly greater in high-dose than in control male mice. Osteosclerosis of long bones was increased in female rats given drinking water containing 175 ppm sodium fluoride. No other significant nonneoplastic lesions in rats or mice appeared related to sodium fluoride administration. Osteosarcomas of bone were observed in 1/50 male rats in the 100 ppm group and in 3/80 male rats in the 175 ppm group. None were seen in the control or 25 ppm dose groups. One other 175 ppm male rat had an extraskeletal osteosarcoma arising in the subcutaneous tissue. Osteosarcomas occur in historical control male rats at an incian incidence of 0.5%; (range 0-6%). The historical incidence is not directly comparable with the incidences observed in this study because examination of bone was more comprehensive in the sodium fluoride studies than in previous NTP studies of other chemicals, and the diet used in previous studies was not controlled for fluoride content. In the current study, although the pairwise comparison of the incidence in the 175 ppm group versus that in the controls was not statistically significant, osteosarcomas occurred with a statistically significant dose-response trend, leading to the conclusion that a weak association may exist between the occurrence of these neoplasms and the administration of sodium fluoride. No other neoplastic lesions in rats or mice were considered possibly related to chemical administration. Genetic Toxicology: Sodium fluoride was negative for gene mutation induction in Salmonella typhimurium strains TA100, TA1535, TA1537, and TA98 with and without S9. In two laboratories, sodium fluoride was tested for induction of trifluorothymidine resistance in mouse L5178Y lymphoma cells; results were positive both with and without S9. Sodium fluoride was tested for cytogenetic effects in Chinese hamster ovary (CHO) cells in two laboratories. In the first laboratory, the sister chromatid exchange (SCE) test was negative with and without S9, and the chromosomal aberration (Abs) test was positive in the absence of S9; in the second laboratory, the SCE test was positive with and without S9, but no induction of Abs was observed. The laboratory that reported a negative result for Abs tested at doses below that shown to be positive at the other laboratory. Similarly, the positive SCE result was obtained at a higher dose and longer harvest time than used by the laboratory reporting the negative SCE response. Conclusions: Under the conditions of these 2-year dosed water studies, there was equivocal evidence of carcinogenic activity of sodium fluoride in male F344/N rats, based on the occurrence of a small number of osteosarcomas in dosed animals. "Equivocal evidence" is a category for uncertain findings defined as studies that are interpreted as showing a marginal increase of neoplasms that may be related to chemical administration. There was no evidence of carcinogenic activity in female F344/N rats receiving sodium fluoride at concentrations of 25, 100, or 175 ppm (11, 45, or 79 ppm fluoride) in drinking water for 2 years. There was no evidence of carcinogenic activity of sodium fluoride in male or female mice receiving sodium fluoride at concentrations of 25, 100, or 175 ppm in drinking water for 2 years. Dosed rats had lesions typical of fluorosis of the teeth and female rats receiving drinking water containing 175 ppm sodium fluoride had increased osteosclerosis of long bones^ref. Early geographical studies of cancer in areas that have naturally-occurring fluoride at different levels gave no indication of an effect on cancer rates associated with higher intakes of fluoride. Following widespread fluoridation to improve dental health in the United States and Britain, non-epidemiologists presented analyses of cancer data which they claimed demonstrated such an effect. However, subsequent large-scale comparisons of cancer rates in fluoridated and non-fluoridated areas for successive periods following fluoridation have not indicated any increase, either for all cancer or for malignancies across the range of individual sites. Studies undertaken specifically to examine the claims of the non-epidemiologists have, time-and-again, shown that, with the use of accurate data and correct statistical methods, the purported effects cease to be apparent. Details of the earlier evidence and claims are given in the 'Report of a Working Party on the Fluoridation of Water and Cancer' by Professor George Knox (1985) and of more recent analyses in Hoover et al. (1991a; 1991b; unpublished internal US PHS Memo, 1993^{ref1, ref2,}