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SALICYLATES

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					                                   SALICYLATES
INTRODUCTION
   Asparin, oil of wintergreen (methyl salicylate) is an extremely toxic form
   Over 2000 OTCs contain salcylates
   One of the most common co-ingestants
   Draw ASA levels in every overdose
   Chronic ASA toxicity is commonly missed in elderly
   Various types of salicylates have same presentation
   Various skin creams have ASA: aspercreme, Ben-Gay -----> common cause of chronic
     ASA toxicity in elderly
   Peptobismal has enough ASA to lead to toxicity
   Oil of Wintergreen
                   Methylsalicylate
                   35% weight/volume is common (35gm/100ml)
                   Aspirin converting factor is 1.39 thus equivalent to even more ASA
                   Oil of wintergreen: 1 tsp = 7gm
                   Skin oil
                   A535 contains methylsalicylate



                          OIL OF WINTERGREEN = DEATH TO KIDS




PHARMOKINETICS AND TOXICOKINETICS
   Rapid absorption: ½ hr, peak levels at 2-4hrs
   ECASA: delayed absorption (8-9hrs), absorbed in small intestine
   Recommended maximum dose: 3900 mg in 24hrs
   Pylorospasm thus collection in stomach: tablet mass (may be reason to lavage)
   Acetylsalicyclic acid is converted to salicylic acid which is bound to albumin
   Salicyclic acid enters tissues/cells and is toxic metabolite
   [salicylate] in CNS has direct correlation with mortality
   Aspirin Conversion Factor (ACF) and Aspirin Equivalent Dose (AED): see chart
   Therapeutic levels: 1.1-2.2 mmol/L at 2-4hrs
   Toxicity
                    < 150 mg/kg: non-toxic (note: same as APAP)
                    150-300 mg/kg: mild to moderate toxicity
                    300-500 mg/kg: severe toxicity
                    > 500 mg/kg: lethal
   Elimination
                    Low dose: 1st order kinetics (elimination increases as [drug] increases)
                    Higher doses: zero order kinetics (elimination is constant despite incr
                      [drug])
                    Toxic doses: saturation of enzymes and durg basically only excreted in
                      urine thus t1/2 goes up to 15-30 hours
PATHOPHYSIOLOGY
   GI Effects
                  Gastritis from local effects (can get UGI bleed)
                  Vomiting from gastritis, stimulation of cerebral chemo receptor, decreased
                    gastric mobility and pylorospasm
   Metabolic effects of ASA
                  Enters mitochondrion and uncouples oxidative phosphorylation
                    (similar to CO, Fe, CN, H2S)
                  Actually inhibits the phosphorylation phase (not oxidation)
                  Essential prevent production of ATP by aerobic metabolism (oxygen is the
                    final common substrate to produce ATP which is the energy molecule of
                    the cell)
                  Metabolism shift to anerobic metabolism thus lactate is produces
                  CATABOLIC STATE because anerobic metabolism is inhibitis
                    -        Lipolysis ----------> ketonuria
                    -        Protein lysis --------> amino acids
                    -        Glycogenolysis and gluconeogeneis ---------> hyperglycemia
   ACID-BASE disturbances
                  Variable A-B status
                  Common result is a metabolic acidosis + respiratory alkalosis (seen as
                    acidemia with C02 lower than expected for compensation: ie; > 1:1 drop in
                    the C02 for each drop in the HC03)
                  Respiratory alkalosis occurs b/c of direct stimulation of respiratory centers
                  Respiratory acidosis more common in chronic overdoses due to
                    suppression
                  Note that co-ingestant can prevent the respiratory alkalosis (TCA,BZD,etc)
                  Reasons for metabolic acidosis
                             -       Acetylsalicylic acid
                             -       Salicylic acid
                             -       Lactic acid
                             -       Free fatty acids
                             -       Amino acids
   Hypokalemia
                  Vomiting thus K+ loss
                  Direct increase in K+ excretion from renal tubules
                  Shift into cell after bicarb treatment
   Ion Trapping
                  pKa of salicyclic acid is 3(pH at which ½ is ionized)
                  Acidic environment: HA form crosses cell membranes easily
                  Basic environment: H+A- form doesn’t cross cell membranes easily
                  Thus essentially 100% is in ionized form at pH 7.4
                  Ion trapping in serum (doesn’t want to enter tissues)
                  Ion trapping in urine (decreased re-absorption)
                  Changes in volume of distribution make serum levels difficult to interpret
   Hearing/Tinnitus
                  Tinitis occurs before hearing loss
                  Metabolic changes in endolymph
                  Electrophysiologic changes in inner ear and CN VIII
   Pyrexia
                  Catabolic state b/c of uncoupling of oxidatitive phosphorylaton
                 Leads to heat production
   Glucose Alteration
                 Hyperglycemia early
                 Hypoglycemia late, more common: increased energy requirements due to
                   uncoupling of oxidative phosphorylation
                 Paradoxical CNS hypoglycemia
                           -       Low CNS glucose in setting of normal or high serum
                                   glucose
                           -       Due to increased cerebral glycolysis
                           -       Fluid hydrate with glucose containing solution
                           -       Bicarb drip will have glucose (D5W + bicarb)
                           -       Use D5NS if not using bicarb drip
   Pulmonary Edema/ARDS
                 Non-cardiogenic mechanism but exact mechanism unknown
                 Prospective series of ASA level > 2.2: 35% developed ARDS
                 Adult risk factors: > 30yo, smoker, chronic toxicity, metabolicacidosis, ASA
                   > 2.9
                 Peds risk factors: low K, low C02, large anion gap
                 Mx: intubate, ventilate, dialysis (indication for dialysis)
   Neurotoxicity
                 Cerebral edema, seizures, altered LOC
                 CNS depression common in chronic ingestion
                 Seizures treated w/ BZDs and phenobarb
                 Continued deterioration in LOC is an ominous sign and is an immediate
                   indication for dialysis
   Other
                 Coagulopathy: salicylic acid inhibits production of factors V, VII, X
                 Seizures: CNS toxicity, hypoglycemia, hypo/hypernatremia, hypocalcemia
                 Reye’s syndrome: N/V, hepatitis, coma following viral illness thought to be
                   associated with ASA use but never proven
                 ARF: direct effect
                 Hepatitis
                 Rhabdomyolysis
                 Ventricular arrythmias
SUMMARY OF ACUTE INGESTION CLINICAL FEATURES
  General
                 Think GI ------> Metabolic --------> CNS --------> Renal and respiratory
  Correlation with increasing levels
                 Asymptomatic
                 \Tinitis
                 Nausea, vomiting, fever, diaphoresis
                 Hyperventilation, metabolic acidosis
                 Dehydration, electrolyte abnormalities
                 Confusion, delirium, visual hallucinations, lethargy
                 Coma, seizures
                 Renal and respiratory failure


CHRONIC SALICYLATE POISONING
  Most commonly occurs in elderly who are using ASA for osteoarthritis, headaches, etc
  THINK of ASA toxicity in an elderly person on ASA
  GI: hearing loss, tinnitis, N/V
  Resp: SOB and pulmonary edema
  Neurologic: confusion, agitation, lethargy, hallucinations, seizures, coma, slurred speech
  Commonly misdiagnosed
                 Check ASA level in any elderly patient taking ASA
                 Misdiagnosed as CHF, delirium NYD, dementia, sepsis



INVESTIGATIONS
   Ferric - Chloride Test
                   Add a few drops of 10% FeCl3 to 1ml of urine
                   Purple = salicylic acid, acetoacietic acid, or phenylpyruvic acid
                   Very sensitive to small levels of salicylates
                   Qualitative (not quantitative)
                   -ve rules out salicylates
   Trinder - Spot Test
                   Premixed reagent added to 1ml of urine
                   Urine will turn purple in present of salicylates
   Salicylate Levels
                   Draw in essentially every overdose (debatable)
                   Toxicity correlates POORLY with serum levels
                   CSF salicylate levels correlate better with toxicity but impractical to
                     measure
                   Initial levels can be acceptible in patients that will become toxic
                   Level toxic at 2hrs: start treatment as it will continue to rise
                   Repeat levels q2-4hrs
                   Seriously ill patients need q2hr levels
                   Less ill patients need at least one level after peak is reached to show
                     decrease
                   Salicylate levels need to be interpreted in conjunction with arterial pH
                   NOTE: Decreasing salicylate levels + ....
                               -      Decreasing pH: drug being distributed into the tissues and
                                   the patient is deteriorating
                            -      Increasing pH: drug being eliminated and patient improving
   Done Nomogram
               Developed from pediatric studies
               Intended to be applied only > 6hrs from overdose
               Acute, single ingestion, non-enteric coated preparation
               Patient’s blood pH must be 7.4 or greater (ya, like that is the case!)
               Many retrospective reviews show POOR predictive value of nomogram
   Other
               CXR for ARDS
               Consider ddx: acute iron poisoning, Reye’s syndrome, theophyline,
                 caffeine
               Medical workup for sepsis, meningitis, etc
               Phenistix = urine dipstick detects mod - large amounts of salicylates in
                 urine


MANAGEMENT
  General
                 Vitamin K for inc PT
                 Antacids for gastritis
                 Close monitoring essential
                 Check urine pH q1hr
                 Check K+ q2hr
                 Decreased LOC: try one amp DW50 before assuming cerebral edema
                   (even if serum glucose normal)
   Gastric Lavage
                 NO specific trials with ASA and GL
                 Should be considered because: potentially lethal, pylorospasm, gastric
                   concretions, antidotes not 100% effective,
   Activated Charcoal
                 Very effective binding to ASA
                 Decreases absorption by 50-80%
                 The sooner the administration the better
                 Ideal is 10:1 charcoal to ingested dose
                 Effective for SR preparations as well
                 Benefit of sorbitol has been demonstrated in one study
                 Multi-Dose Activated Charcoal (MDAC)
                              -       Role for decontamination in SR preparation
                              -       Thought to enhance elimination but this is controversial
                              -       AACT position statement: evidence is currently insufficient
                                      to recommend MDAC for routine saliclate poisoning
   Whole Bowel Irrigation
                 WBI has been shown to be better than AC in decreasing peak serum ASA
                   levels in a study of volunteers
                 Consider for SR preparations
   Fluid Replacement
                 Universal hypovolemia: vomiting, tachypnea, fever, hypermetabolic state,
                   perspiration, solute loass by kidneys
                 Forced diuresis: theoretical benefit to increase renal excretion but has
                   little clinical effect because MAIN determinant of urine excretion is urine
                   pH; carries risk of fluid overload
                 All pts w/ CNS depression or seizures should be assumed to be
                   hypoglycemic and given DW50 if chemstrip not immediately available



   Alkalinization and Alkine Diuresis
                   Goals: arterial pH > 7.4 and urine pH of 8
                   Traps ASA in serum and urine and keeps out of brain, etc
                   Alkalinization of the urine logrithmically increases salicylate excretion
                   Hyperventilation alone should not be relied on
                   Acetazolamide is not used: carbonic anyhdrase inhibitor, results in the
                     formatio of a bicarbonate rich urine, BUT also causes a systemic acidosis
                   Bicarbonate (iv) therapy is treatment of choice
                   Don’t use oral bicarbonate
                   When to stop? clinical resolution and level < 2.5
                   Indication to alkalinize
                             -       Salicylate level > 2.2
                             -       Clinical signs of toxicity regardless of level
                   How to achieve alkalinization?
                             -       Bolus 1-2 mEq/kg of NaHCO3
                             -       Bicarb infusion: D5W 850 ml + 150 Nabicarb and run at 2X
                                     maintenance. NOTE: add 40 mEq Kcl/L if peeing
                             -       Check ABG: goal pH > 7.4
                             -       Check urine pH: goal pH 8.0
   Hypokalemia
                   MOST common error
                   MOST common reason for failure of urine alkalinization
                   Kidney will excrete H+ instead of K+ if hypokalemic
                   Replace oral and iv aggressively (use caution in renal failure)
   Dialysis
                   Hemodialysis is the treatment of choice b/c of drug clearance and
                     Acid/Base + electrolyte correction that are not correctable by
                     hemoperfusion alone
                   Peritoneal dialysis is not recommended
                   Hemoperfusion may be used if HD not available or a co-ingestant exists
                     that would lead to hemodialysis being preferred
                   Alkalinization should continue during dialysis
                   Indications
                             -       Renal Failure
                             -       Pulmonary Edema/ARDS/fluid overload
                             -       Cerebral Edema/comatose/encephalopathic
                             -       Clinical deterioration despite alkalinization
                             -       Rising ASA levels despite alkalinzation
                             -       Cardiac arrythmias
                             -       Hepatic dysfunction with coagulopathy
                             -       Acute ingestion level > 7.2 mmol/L
                             -       Chronic ingestion level > 4.3 mmol/L
   Mortality
                   Retrospective review of pure ASA ingestions leading to mortality
                   25% didn’t receive ASA level
     None got dialysis
     90% didn’t get charcoal




 ASA TREATMENT BOX
ABCDEs
ACTIVATED CHARCOAL
CONSIDER WBI OR MDAC (SR PREPS)
BOLUS 1-2 Meq/kg NaHC03
BICARB INFUSION + 40 Meq Kcl/L 2-3xs
MAINTENANCE
MUST REPLACE K+
MONITOR URINE pH q1hr
MONITOR K+ q2hr
GLUCOSE FOR CNS HYPOGLYCEMIA
DIALYSIS
    Clinical toxicity
    Acute level > 7
    Chronic level > 4