A lady with repeated vomitingA lady with repeated vomiting

20/9/200620/9/2006Drs. SF Chan and PN WongDrs. SF Chan and PN Wong

KWHKWH

Case HistoryCase History

42/F42/FGood past healthGood past healthNonNon--smoker, nonsmoker, non--drinkerdrinkerMarried and live with husbandMarried and live with husbandPrimigravidaPrimigravida with elective caesarean with elective caesarean section delivery on 3/5/2006section delivery on 3/5/2006

Case HistoryCase History

Admitted to KWH on 26/7/2006 ( postAdmitted to KWH on 26/7/2006 ( post--partum 12 weeks )partum 12 weeks )Complained of repeated vomiting > 8 Complained of repeated vomiting > 8 times at home with undigested foodtimes at home with undigested foodBrought to the A&E department by Brought to the A&E department by husbandhusbandNo family history of renal diseasesNo family history of renal diseases

Physical examinationPhysical examination

AfebrileAfebrileGCS 15/15, alert and conscious but slow in GCS 15/15, alert and conscious but slow in responseresponseBP 80/42mmHg, pulse 90/minBP 80/42mmHg, pulse 90/minSaOSaO22 98% RA, 98% RA, tachypnoeatachypnoea 28 28 bpmbpmCVP set: first reading 0 cmHCVP set: first reading 0 cmH22OOCVS/abdomen/chest: NADCVS/abdomen/chest: NAD

InvestigationsInvestigationsWBCWBC 13.3 X1013.3 X1099/L/L Total Total

proteinprotein70 g/L70 g/L pHpH 7.437.43

HbHb 13.2 13.2 g/dLg/dL AlbuminAlbumin 38 g/L38 g/L pCO2pCO2

pO2pO2

HCO3HCO3

Total CO2Total CO2

Base Base excessexcess

O2 sat.O2 sat.

ChlorideChloride

PlateletPlatelet 410 X10410 X1099/L/L GlobulinGlobulin 32 g/L32 g/L

2.9 2.9 kPakPa(4.7(4.7--6.0)6.0)

16.7 16.7 kPakPa

13.9 13.9 mmolmmol/L/L(22(22--26)26)

15.8 15.8 mmolmmol/L/L

--7.9 7.9 mmolmmol/L/L

97%97%

NaNa 143 143 mmolmmol/L/L TBTB 10 10 umolumol/L/L

KK 3.2 3.2 mmolmmol/L/L ALP ALP 27 IU/L27 IU/L

UreaUrea 4.4 4.4 mmolmmol/L/L ASTAST 27 IU/L27 IU/L

CreatinineCreatinine 80 80 umolumol/L/L ALTALT 30 IU/L30 IU/L

CalciumCalcium 2.26 2.26 mmolmmol/L/L PO4PO4 1.1 1.1 mmolmmol/L/L 105 105 mmolmmol/L/L

Differential diagnosis??Differential diagnosis??

Differential diagnosis??Differential diagnosis??

Respiratory alkalosisRespiratory alkalosispH normal 7.43pH normal 7.43LowishLowish pCO2pCO2

Metabolic compensationMetabolic compensationFor every 10mmHg decrease in pCO2 ( 1.333 For every 10mmHg decrease in pCO2 ( 1.333 kPakPa ); ); the body buffers will reduce the HCO3the body buffers will reduce the HCO3-- by 2mmol/Lby 2mmol/LExpected drop in HCO3: Expected drop in HCO3:

( 4.7( 4.7--2.9 )/1.333 X 2 =2.72.9 )/1.333 X 2 =2.7Expected compensated HCO3 level: 19.3mmol/LExpected compensated HCO3 level: 19.3mmol/L

Combined metabolic acidosis and respiratory Combined metabolic acidosis and respiratory alkalosisalkalosis

Differential diagnosis??Differential diagnosis??

Anion gapAnion gapAnion Gap:143 Anion Gap:143 -- 15.8 15.8 -- 105 = 22.2 (10+/105 = 22.2 (10+/-- 4)4)

High anion gap metabolic acidosisHigh anion gap metabolic acidosisKetoneKetone acidosisacidosisLactic acidosisLactic acidosisRenal failure: sulfate, phosphate, Renal failure: sulfate, phosphate, urateurate, , hippuratehippurateingestion: ingestion: salicylatesalicylate, methanol, ethylene glycol, , methanol, ethylene glycol, paraldehyleparaldehyle , toluene, sulfur, toluene, sulfurMassive Massive rhabdomyolysisrhabdomyolysis

Further investigationsFurther investigations

Serum Serum ketoneketone: trace positive: trace positiveRandom glucose: 6.8 Random glucose: 6.8 mmolmmol/L/LSerum lactate: 0.73 Serum lactate: 0.73 mmolmmol/L ( normal )/L ( normal )Serum Serum SalicylateSalicylate level: 6.4 level: 6.4 mmolmmol/L ( 0.7/L ( 0.7--2.2 2.2 mmolmmol/L; /L; toxic > 2.9 toxic > 2.9 mmolmmol/L )/L )Detailed History: Detailed History:

Suspected postSuspected post--partum depressionpartum depressionLow mood with poor sleepLow mood with poor sleepAdmit suicidal attemptAdmit suicidal attemptTaken 50Taken 50--75 tablets of aspirin ( total 1575 tablets of aspirin ( total 15--22.5g ) about 6 hours 22.5g ) about 6 hours before admissionbefore admissionFatherFather--inin--law has law has ischaemicischaemic heart diseaseheart disease

ManagementManagement

Gastric Gastric lavagelavage X 1X 1Massive fluid resuscitation with normal salineMassive fluid resuscitation with normal saline

>5000ml of fluid to reach CVP > 5cmH2O>5000ml of fluid to reach CVP > 5cmH2O

Urinary Urinary alkalinizationalkalinizationBaseline urinary pH 5Baseline urinary pH 5--66100ml 8.4% NaHCO3 infused over 1 hour100ml 8.4% NaHCO3 infused over 1 hour80ml 8.4% NaHCO3 + 420ml D5 + 10mmol 80ml 8.4% NaHCO3 + 420ml D5 + 10mmol KClKClinfusion at 500ml/hourinfusion at 500ml/hourUntil urinary pH > 8Until urinary pH > 8

ManagementManagement

HaemodialysisHaemodialysisSevere Severe salicylatesalicylate intoxicationintoxicationThrough right neck double lumen catheter Through right neck double lumen catheter ( from old CVP line )( from old CVP line )Duration 3 hoursDuration 3 hoursNa 140, HCO3 36, normal CaNa 140, HCO3 36, normal Cano no ultrafiltrationultrafiltration

ProgressProgress

SalicylateSalicylate level 6.4 level 6.4 →→ 4.64.6 →→ 3.8 ( just 3.8 ( just before HD, ~20 hours postbefore HD, ~20 hours post--poisoning )poisoning )Further dropped to 0.7 after Further dropped to 0.7 after haemodialysishaemodialysis1 day afterwards: 1 day afterwards: salicylatesalicylate level not level not detectabledetectable

ProgressProgress

Psychiatrist assessment:Psychiatrist assessment:PostPost--natal depressionnatal depressionPatient refused KCH for observationPatient refused KCH for observationStarted on Started on FluoxetineFluoxetine and Valiumand ValiumFit for discharge and refer to psychiatric OPD Fit for discharge and refer to psychiatric OPD for early FUfor early FU

SummarySummary

Lady with postLady with post--natal depressionnatal depressionSuicidal attempt with toxic dose of aspirinSuicidal attempt with toxic dose of aspirinWith combined metabolic acidosis and With combined metabolic acidosis and respiratory alkalosisrespiratory alkalosisTreated with urinary Treated with urinary alkalinizationalkalinization and and haemodialysishaemodialysis onceonce

Extracorporeal techniques in Extracorporeal techniques in the treatment of poisoningthe treatment of poisoning

20/9/200620/9/2006Drs. SF Chan and PN WongDrs. SF Chan and PN Wong

KWHKWH

Treatment of PoisoningTreatment of Poisoning

1.1. Removal of offending agentsRemoval of offending agents2.2. Administration of Administration of antidoseantidose3.3. Use of supportive nonspecific therapyUse of supportive nonspecific therapy

Elimination of toxinsElimination of toxins

1.1. From the gastrointestinal tractFrom the gastrointestinal tractMultipleMultiple--dose activated charcoaldose activated charcoalGastric Gastric lavagelavage

2.2. From the blood/target organFrom the blood/target organUrinary Urinary alkalinizationalkalinization/acidification/acidificationExtracorporeal techniquesExtracorporeal techniques

Haemodialysis/haemofiltration/haemoperfusionHaemodialysis/haemofiltration/haemoperfusionPlasmaphoresisPlasmaphoresis/exchange transfusion/exchange transfusionPeritoneal dialysisPeritoneal dialysis

History History

HaemoperfusionHaemoperfusionUse of anionic exchange resins for removal of Use of anionic exchange resins for removal of uraemicuraemic toxins in 1948toxins in 1948For extraction of exogenous poisons in 1958For extraction of exogenous poisons in 1958Side effects: Side effects: haemolysishaemolysis, , thrombocytopaeniathrombocytopaenia, , pyogenicpyogenic reaction, etcreaction, etcActivated charcoal was first introduced in 1964Activated charcoal was first introduced in 1964Technique of Technique of microencapsulationmicroencapsulation developed in 1969developed in 1969

HistoryHistory

HaemodialysisHaemodialysisIntroduced in 1951 by Dr. Introduced in 1951 by Dr. DoolanDoolan ( JAMA ) ( JAMA ) and later by Dr. Schreiner in 1955 ( NEJM ) in and later by Dr. Schreiner in 1955 ( NEJM ) in the use of the use of salicylatesalicylate overdoseoverdoseWide acceptance in 1960sWide acceptance in 1960s

Technical aspectsTechnical aspects

HaemodialysisHaemodialysisToxins in the blood diffuse through the Toxins in the blood diffuse through the semipermeablesemipermeable membrane into the membrane into the dialysatedialysate along a along a steep concentration gradientsteep concentration gradient

HaemoperfusionHaemoperfusionCartridges containing activated charcoal covered with Cartridges containing activated charcoal covered with an an ultrathinultrathin porous coatingporous coating““activatedactivated””: exposed to steam, CO: exposed to steam, CO22 or Zinc oxide or Zinc oxide 100g of activated charcoal = several thousand m100g of activated charcoal = several thousand m22

Technical aspectsTechnical aspects

HaemoperfusionHaemoperfusionExtraction ratio of the drug Extraction ratio of the drug

(A(A--V)/AV)/AA: inlet concentration; V: outlet concentrationA: inlet concentration; V: outlet concentration

Examples: Examples: salicylatesalicylate 0.5, 0.5, digoxindigoxin 0.30.3--0.6, 0.6, theophylinetheophyline 0.70.7

Clearance rate = flow rate X extraction ratioClearance rate = flow rate X extraction ratio

Technical aspectsTechnical aspects

HaemofiltrationHaemofiltrationLarge volume of replacement fluid is infused Large volume of replacement fluid is infused into the blood line for dilutioninto the blood line for dilutionThe replacement fluid + excess fluid is The replacement fluid + excess fluid is ultrafilteredultrafiltered across the hollow across the hollow fibresfibres or flat or flat sheet membranesheet membraneGenerating convective transport of solutes by Generating convective transport of solutes by the the arteriovenousarteriovenous pressure differencepressure difference

Technical aspectsTechnical aspects

Vascular assessVascular assessUsually through the femoral veinUsually through the femoral vein

More rapidly and safely insertedMore rapidly and safely insertedNot necessitate radiological confirmationNot necessitate radiological confirmation

AnticoagulationAnticoagulationheparinheparin

Kinetics of extracorporeal Kinetics of extracorporeal eliminationelimination

Molecular mass of the toxinMolecular mass of the toxinSolubilitySolubilityProtein bindingProtein bindingVolume of distributionVolume of distributionRate of redistributionRate of redistributionEndogenous clearanceEndogenous clearance

HaemodialysisHaemodialysis haemoperfusionhaemoperfusion haemofiltrationhaemofiltration

Molecular massMolecular mass < 500< 500daltonsdaltons

< 500< 500daltonsdaltons

< 40,000< 40,000daltonsdaltons

SolubilitySolubility waterwater water & lipidwater & lipid waterwater

Poorly bound to proteinPoorly bound to protein

Small volume of distribution < 1L/kgSmall volume of distribution < 1L/kg

Single compartment kinetics ( rate of redistribution )Single compartment kinetics ( rate of redistribution )

Low endogenous clearance < 4 ml/min/kgLow endogenous clearance < 4 ml/min/kg

ComplicationsComplications

ExpensiveExpensive44--8 hours of HD/HP/HF with the dialysis pump 8 hours of HD/HP/HF with the dialysis pump compared to spending a day in the ICUcompared to spending a day in the ICU

Medical Journal of Australia 1991Medical Journal of Australia 1991

Catheter related: infection, Catheter related: infection, haemorrhagehaemorrhage, air , air embolismembolismHypotensionHypotensionMetabolic disequilibriaMetabolic disequilibria

HypophosphatemiaHypophosphatemiaAlkalemiaAlkalemia, etc, etc

ComplicationsComplications

HaemoperfusionHaemoperfusionCharcoal Charcoal embolisationembolisationHypocalcaemiaHypocalcaemiaThrombocytopaeniaThrombocytopaenia

Platelet count decreases by 30Platelet count decreases by 30--50% for each 450% for each 4--8 8 hours hours haemoperfusionhaemoperfusion

LeukopeniaLeukopenia ( 10% )( 10% )

heparinisationheparinisation

IndicationsIndications

No controlled clinical studies to determine if No controlled clinical studies to determine if haemoperfusionhaemoperfusion reduces morbidity or mortality reduces morbidity or mortality as compared to supportive measuresas compared to supportive measures

Prognosis largely determined by the time interval of Prognosis largely determined by the time interval of presentation to hospitalpresentation to hospital

Correlation between kinetics and clinical resultsCorrelation between kinetics and clinical resultsHaemoperfusionHaemoperfusion > > HaemodialysisHaemodialysis > > haemofiltrationhaemofiltrationFavourableFavourable pharmacokinetic data, animal studies, pharmacokinetic data, animal studies, case reports/series and uncontrolled retrospective case reports/series and uncontrolled retrospective studiesstudies

IndicationsIndications

1.1. Progressive deterioration despite full Progressive deterioration despite full supportive therapysupportive therapy

2.2. Sever intoxicationSever intoxication3.3. Development of complicationsDevelopment of complications4.4. Impairment of normal drug excretory functionImpairment of normal drug excretory function5.5. Poisoning with severe metabolic and delayed Poisoning with severe metabolic and delayed

effectseffects6.6. Extractable drug with clearance rate > Extractable drug with clearance rate >

endogenous eliminationendogenous elimination

IndicationsIndications

Special considerations:Special considerations:Isopropanol,methanolIsopropanol,methanol and ethylene glycol: and ethylene glycol:

haemodialysishaemodialysis is effective to remove the parent is effective to remove the parent drugs and its noxious metabolic productsdrugs and its noxious metabolic productsrepair the acidrepair the acid--base abnormalitiesbase abnormalitiesAdjunctive measure to the administration of Adjunctive measure to the administration of ethanolethanol

SalicylateSalicylate::In severe case especially in renal impairment, In severe case especially in renal impairment, metabolic acidosis and fluid overloadmetabolic acidosis and fluid overload

IndicationsIndications

IndicationsIndications

PlasmapheresisPlasmapheresis/Exchange /Exchange transfusiontransfusion

Removal of a quantity of plasma/blood from a Removal of a quantity of plasma/blood from a poisoned patient with replacement with an poisoned patient with replacement with an identical quantity of whole bloodidentical quantity of whole bloodRarely indicated exceptRarely indicated except

PlasmaphoresisPlasmaphoresis in in thyroxinethyroxine intoxicationintoxicationEndocrEndocr Rev 1989 May;10(2):113Rev 1989 May;10(2):113--2424

Massive Massive haemolysishaemolysis in arsine or sodium chlorate in arsine or sodium chlorate poisoningpoisoningMethemoglobinemiaMethemoglobinemiaSulfhemoglobinemiaSulfhemoglobinemia in hydrogen sulfate exposurein hydrogen sulfate exposure

Complications: transfusion reaction, hypothermia, Complications: transfusion reaction, hypothermia, hypocalcaemia etchypocalcaemia etc

Peritoneal dialysisPeritoneal dialysis

Little application because of limited and Little application because of limited and slow clearanceslow clearance1/8 to 1/4 as efficient as 1/8 to 1/4 as efficient as haemodialysishaemodialysis

SalicylateSalicylate overdoseoverdose

IntroductionIntroduction

Aspirin ( acetylsalicylic acid ) is rapidly Aspirin ( acetylsalicylic acid ) is rapidly converted to salicylic acid in the bodyconverted to salicylic acid in the bodyFatal intoxication occurs after 10Fatal intoxication occurs after 10--30g by 30g by adultsadultsTherapeutic range 0.7 Therapeutic range 0.7 –– 2.2 2.2 mmolmmol/L/LSigns of intoxication if > 2.9 Signs of intoxication if > 2.9 mmolmmol/L/LMethlysalicylateMethlysalicylate( analgesic balm ): one ( analgesic balm ): one teaspoon 5ml contains ~ 7g of teaspoon 5ml contains ~ 7g of salicylatesalicylate

Mechanism of actionMechanism of action

Inhibition of Inhibition of cyclooxygenasecyclooxygenase: : ↓↓prostaglandins, prostaglandins, prostacyclinprostacyclin, , thromboxanesthromboxanesStimulate chemoreceptor trigger zone in Stimulate chemoreceptor trigger zone in medulla: nausea and vomitingmedulla: nausea and vomitingActivate respiratory center of medulla: Activate respiratory center of medulla: respiratory alkalosisrespiratory alkalosisInterfere with cellular metabolism: Interfere with cellular metabolism: metabolic acidosismetabolic acidosis

PharmacokineticsPharmacokinetics

Molecular mass: 180 Molecular mass: 180 daltonsdaltonsRapidly absorbed in stomachRapidly absorbed in stomachPeak blood level in 1 hourPeak blood level in 1 hour90% protein bound ( in therapeutic level )90% protein bound ( in therapeutic level )Limited to the vascular spaceLimited to the vascular spaceVolume of distribution: 0.15 L/kgVolume of distribution: 0.15 L/kgMetabolized in liverMetabolized in liverHalfHalf--life: 2life: 2--4 hours4 hours

PharmacokineticsPharmacokinetics

During overdoseDuring overdosePeak blood level after 6 hours or more: Peak blood level after 6 hours or more: pylorospasmpylorospasm, , bezoarbezoar formation, use of formation, use of entericenteric--coated formulacoated formulaProtein bound Protein bound ↓↓50%50%Hepatic detoxification saturated and mainly Hepatic detoxification saturated and mainly depends on slow renal excretion: halfdepends on slow renal excretion: half--life life ↑↑up to 30 hoursup to 30 hours

Clinical featuresClinical featuresTachypneaTachypnea, hyperventilation, fever, hyperventilation, feverTinnitusTinnitusNausea and vomitingNausea and vomitingAlteration of mental state: cerebral edema, Alteration of mental state: cerebral edema, neuroglycopenianeuroglycopenia ( despite normal serum ( despite normal serum glucose level ) glucose level ) indication for indication for haemodialysishaemodialysis

NoncardiogenicNoncardiogenic pulmonary edema pulmonary edema indication for indication for haemodialysishaemodialysis

Biochemical considerationBiochemical consideration

AcidAcid--base determinationbase determinationSalicylateSalicylate is a weak acid that exists in charged is a weak acid that exists in charged and uncharged formand uncharged form

HH ++ + Sal+ Sal-- < < –– > HS> HSUncharged molecules HS can easily cross the Uncharged molecules HS can easily cross the cellular barrier e.g. bloodcellular barrier e.g. blood--brain barrier, renal brain barrier, renal tubulestubulesKeeping the charged form Keeping the charged form SalSal-- can result in can result in ““trappingtrapping”” effecteffect

Biochemical considerationBiochemical consideration

Serum Serum salicylatesalicylate level: > 7.2 level: > 7.2 mmolmmol/L are /L are associated with profound morbidity and associated with profound morbidity and mortality mortality indication for indication for haemodialysishaemodialysis

Serum Serum creatininecreatinine: should be normal; : should be normal; renal renal failure is an Indication for failure is an Indication for haemodialysishaemodialysis

K level: K level: hypokalemiahypokalemia promotes K promotes K reabsorptionreabsorption in the distal tubule via the Kin the distal tubule via the K--H exchange H exchange pumppump→→excretionexcretion of protons of protons decrease the effort of urinary decrease the effort of urinary alkalinizationalkalinization

ManagementManagement

Assessment and stabilizationAssessment and stabilizationAirway: in case of Airway: in case of intubationintubation, ensure high , ensure high minute volume to maintain minute volume to maintain alkalemiaalkalemia with pH with pH 7.5 7.5 –– 7.597.59Circulation: Circulation: hypotensivehypotensive secondary to secondary to systemic systemic vasodilationvasodilation, dehydration, dehydration

Gastrointestinal decontaminationGastrointestinal decontaminationMDAC: loading 1g/kg MDAC: loading 1g/kg popo; then 0.5; then 0.5--1g/kg Q21g/kg Q2--4H X 3 more 4H X 3 more

ManagementManagement

AlkalinizationAlkalinization of plasma and urineof plasma and urineIncreasing pH 7.2 to 7.5 will decrease the fractional Increasing pH 7.2 to 7.5 will decrease the fractional concentration HS from 0.006% to 0.003%concentration HS from 0.006% to 0.003%Significant reduction in tissue levelSignificant reduction in tissue levelUse of NaHCO3 to keep serum pH 7.5 Use of NaHCO3 to keep serum pH 7.5 –– 7.59 and 7.59 and urinary pH > 7.5urinary pH > 7.5

IV bolus 1IV bolus 1--2mmol/kg 8.4% NaHCO3, then continuous 2mmol/kg 8.4% NaHCO3, then continuous infusion 40infusion 40--80mmol/hour in D5 with 80mmol/hour in D5 with KClKCl supplementsupplement

ManagementManagement

HaemodialysisHaemodialysis indicated inindicated inSevere poisoningSevere poisoningAltered mental stateAltered mental statePulmonary or cerebral edemaPulmonary or cerebral edemaRenal impairmentRenal impairmentFluid overloadFluid overloadClinical deterioration despite full supportive Clinical deterioration despite full supportive carecare

SummarySummary

Mainstay of treatment for poisoning is Mainstay of treatment for poisoning is decontamination decontamination MDAC, plasma and urinary MDAC, plasma and urinary alkalinizationalkalinization are the are the mainstay of treatment for mainstay of treatment for salicylatesalicylate overdoseoverdoseUse of extracorporeal treatments for poisoning Use of extracorporeal treatments for poisoning are limited to certain conditionsare limited to certain conditionsno RCT to support their efficacy in reducing no RCT to support their efficacy in reducing morbidity or mortalitymorbidity or mortality

ReferencesReferences““Clinical physiology of acidClinical physiology of acid--base and electrolyte disordersbase and electrolyte disorders”” by Dr. by Dr. Burton David Rose and Dr. Theodore W. PostBurton David Rose and Dr. Theodore W. Post

““Extracorporeal techniques in the treatment of exogenous Extracorporeal techniques in the treatment of exogenous intoxicationsintoxications”” by Dr. by Dr. SerafinoSerafino GarellaGarella; ; Kidney International 1988Kidney International 1988““Extracorporeal techniques in the treatment of poisoned patients Extracorporeal techniques in the treatment of poisoned patients ( review )( review )”” by Dr. SM Pond; by Dr. SM Pond; Medical Journal of Australia 1991Medical Journal of Australia 1991““HaemoperfusionHaemoperfusion with activated carbon in the treatment of with activated carbon in the treatment of exogenous acute poisoningexogenous acute poisoning”” by DR. by DR. SantamariaSantamaria; ; Minerva Minerva AnestesiologicaAnestesiologica 19811981““Handbook of DialysisHandbook of Dialysis”” by Dr. John T. by Dr. John T. DaugirdasDaugirdas et alet al

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