What is the diagnosis? CASE STUDY no 1. What is the diagnosis? CASE STUDY no 1 USE OF THE LABORATORY WHEN MANAGING THE POISONED PATIENT

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1 USE OF THE LABORATORY WHEN MANAGING THE POISONED PATIENT USE OF THE LABORATORY WHEN Phil Routledge Dept Pharmacology, Therapeutics and Toxicology Wales College of Medicine Cardiff University WALES, UK Specific bioanalytical concentrations General bioanalytical screening CASE STUDY no 1 35 year-old male with history of alcoholism found at home in Anglesey, unconscious (Glasgow coma scale 4) with an empty bottle of diazepam (had contained 28-5mg tablets) and an empty bottle of windscreen wash near him. He is apyrexial and there are no focal neurological signs Biochemistry results are as follows. Urinalysis shows crystalluria, no ketones, protein or blood. Se. Na 147, K 4.4, Cl 13, Urea 1.5, Creatinine 91, Blood gases ph 6.73, po2 51.2, pco2 6.2, bicarb 6, glucose 16.9, Anion Gap 42, measured osmolality 47 mmol/l, Osmolal Gap 157 mmol What would you do first of all? CASE STUDY no 1 35 year-old male with history of alcoholism found at home unconscious (Glasgow coma scale 4) with an empty bottle of diazepam (had contained 28-5mg tablets) and an empty bottle of windscreen wash near him. He is apyrexial and there are no focal neurological signs Biochemistry results are as follows. Urinalysis shows crystalluria, no ketones, protein or blood. Se. Na 147, K 4.4, Cl 13, Urea 1.5, Creatinine 91, Blood gases: ph 6.73, po2 51.2, pco2 6.2, bicarb 6, glucose 16.9, Anion Gap 42, measured osmolality 47 mmol/l, Osmolar Gap 157 mmol What would you do first of all? 1. Benzodiazepine screen 2. CT head scan 3. Se. lactate concentration 4. Administer flumazenil 5. Administer ethanol 6. Administer fomepizole URINE Appearance Glucose/ketones Blood/ myoglobin crystals 1

2 BLOOD Arterial blood gases Hb FBC Urea/ creatinine/ HCO 3 / electrolytes Ca ++, Mg ++ Albumin Glucose/ ketones Creatine kinase International normalised ratio (INR) Liver function tests Anion Gap and Osmolality Ann Clin Biochem 22; 39: BLOOD Anion Gap Difference between sum of measured cations and anions. Normally represents negatively charged proteins (e.g. albumin), fatty acids and inorganic anions (phosphates and sulphates) ANION GAP = [ SODIUM + POTASSIUM] - [ BICARBONATE + CHLORIDE] All should be measured in mmol/l Usually mmol/l TOXBASE ANION GAP Raised in Ketoacidosis Lactic acidosis Salicylate poisoning Ethanol/ Methanol poisoning Ethylene glycol poisoning Iron poisoning Isoniazid poisoning Paraldehde poisoning Toluene poisoning Metformin poisoning Ann Clin Biochem 22; 39: BLOOD Osmolal Gap Method of assessing osmotically active constituents in serum (usually calcium, proteins and lipids). Based on difference between measured and calculated osmolality and is calculated using : OSMOLAL GAP = [MEASURED OSMOLALITY- CALCULATED OSMOLALITY] Calculated osmolality = 1.86 x [sodium] + [urea] + [glucose].93 (All should be measured in mmol/l) Normal osmolal gap about 1 mosm/kg H 2 A significant osmolal gap is > 1-15 mosm/kg H 2 TOXBASE OSMOLAL GAP Raised in Severe shock High lipids/protein Unmeasured osmoles Ethanol, Methanol, Ethylene glycol, Isopropanol, Mannitol, Glycine CASE 1 ANION GAP = [ SODIUM + POTASSIUM] - [ BICARBONATE + CHLORIDE] [ ] [ ] = 42.2 Calculated osmolality = 1.86 x [sodium] + [urea] + [glucose] x =

3 CASE 2 A 24 year-old male is found unconscious (Glasgow coma scale 3) in Llanfairpwllgwyngyllgogerychwyrndrobwllllantysiliogogogoch with empty bottles of aspirin and paracetamol (acetaminophen) next to him. His pulse is 75/min, respiratory rate 6 per minute and his pupils are small and unresponsive to light. He is apyrexial and there are no focal neurological signs What would you do first? CASE 2 A 24 year-old male is found unconscious (Glasgow coma scale 3) with empty botles of aspirin and paracetamol (acetaminophen) next to him. His pulse is 75/min, respiratory rate 6 per minute and his pupils are small and unresponsive to light. He is apyrexial and there are no focal neurological signs What would you do first? 1. Se. salicylate concentration 2. Se. paracetamol concentration 3. Administer flumazenil 4. General toxicology screen 5. Administer naloxone 6. Check blood gases SUTTON S LAW In attempting to diagnose a problem, one should first do the experiment that can confirm the most likely diagnosis. WILLIE SUTTON Robbed about 1 banks from the late 192s to his final arrest in 1952, with several prison terms in between Stole around $2 million Spent half his adult life in jail "Go where the money is... and go there often." Sutton W. Where the Money Was: The Memoirs of a Bank Robber (Viking Press, New York, 1976) Specific bioanalytical concs. (*within 2 h) Paracetamol (acetaminophen) Salicylates Ethanol Iron Lithium Carboxyhaemoglobin/ Methaemoglobin Digoxin Paraquat (qualitative) Theophlline Ann Clin Biochem 22; 39: Specific bioanalytical concs. (*urgently) Methanol Ethylene Glycol Phenytoin Carbamazepine Phenobarbitone (phenobarbital) Methotrexate Paraquat (quantitative) Acetylcholinesterase Heavy metals (As, Hg, Pb) Thyroxine (T 4 ) Ann Clin Biochem 22; 39:

4 Stat quantitative serum toxicology assays required to support an ED 1. TAT of 1 h or less. 2. More realistic TATs for these assays are 2 4 h. These tests are largely unnecessary in countries where these agents are not widely available Acetaminophen (paracetamol) Lithium Salicylate Co-oximetry for oxygen saturation, carboxyhemoglobin, and methemoglobin Theophylline Valproic acid Carbamazepine Digoxin Phenobarbital (if urine barbiturates are positive) Iron Transferrin (or UIBC assay if transferrin is not available) Ethyl alcohol (ethanol) Methyl alcohol (methanol) 2 Ethylene glycol 2 National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines: Recommendations for the Use of Laboratory Tests to Support Poisoned Patients Who Present to the Emergency Department General bioanalytical screening For determining previous ingestion illicit drugs In diagnosis of unexplained coma As aid in confirmation of brain death For forensic reasons Ann Clin Biochem 22; 39: Stat qualitative urine toxicology assays required to support an ED 1 Cocaine Opiates Barbiturates Amphetamines 2 Propoxyphene 2 PCP 2 TCAs 3 1 In general, urine toxicology screens such as these have a lower urgency and utility than do serum assays. They do not correlate well with clinical effects and suffer from problems with sensitivity and specificity, as discussed in the text. Although widely available, these assays (with the exception of that for the cocaine metabolite) require clinical interpretation 2 Need for these assays may be based on prevalence of drug use, which may vary from region to region. Regular review of drug usage is important 3 Recommended only if the clinical staff fully understands the specificity limitations of this assay, i.e., results are used in conjunction with the electrocardiograph to support a clinical suspicion of TCA toxicity, but not in cases where a positive urine drug test is the sole evidence for this suspicion National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines: Recommendations for the Use of Laboratory Tests to Support Poisoned Patients Who Present to the Emergency Department USE OF THE LABORATORY WHEN CASE 3 A 47 year-old female from Swansea presents to the Emergency Room with a history of having taken 3 paracetamol (5mg tablets), 1 diazepam (5 mg tablets) and 1 ibuprofen (2mg tablets) 9 hours earlier. She is fully conscious (Glasgow coma scale 14/15) and orientated, but is slightly unsteady on her feet. What would you do first of all? CASE 3 A 47 year-old female from Swansea presents to the Emergency Room with a history of having taken 3 paracetamol (acetaminophen 5 mg tablets), 1 diazepam (5 mg tablets) and 1 ibuprofen (2 mg tablets) 9 hours earlier. She is fully conscious (Glasgow coma scale 14/15) and orientated, but is slightly unsteady on her feet. What would you do first of all? 1. Se. ibuprofen conc. 2. Se. diazepam conc. 3. Urine benzodiazepine screen 4. Serum paracetamol (acetaminophen) conc. 5. Administer flumazenil 6. Administer acetylcysteine 4

5 PARKINSON S LAW OF DELAY If we suppose that a drowning man calls for help, evoking the reply "In due course," a judicious pause of five minutes may constitute for all practical purposes, a negative response. Delay is the deadliest form of denial Paracetamol conc mg/l) Time (h) Parker D et al. Safety of late acetylcysteine treatment in Paracetamol Poisoning. Hum Exper Toxicol 199; 9: Smith JAE et al. Paracetamol toxicity: is enzyme induction important? Human Toxicology 1986; 5: Plasma paracetamol (mg/l) A 14 Normal treatment line High risk treatment line.1 1 B Time (hours) Janes J M and Routledge P A. Recent developments in the management of paracetamol (acetaminophen) poisoning. Drug Safety 1992; 7: Plasma paracetamol (mmol/l) THE PRESCOTT NOMOGRAM Prescott LF et al. Intravenous N-acetylcysteine: the treatment of choice for paracetamol poisoning. Br Med j 1979; 2: THE RUMACK-MATTHEW NOMOGRAM Rumack BH, Matthew H: Acetaminophen poisoning and toxicity. Pediatrics 1975; 55: Evaluation of the validity of the Done nomogram in the management of acute salicylate intoxication Calculated predictive index for the nomogram.42, with highest predictive index (.79) in mild category Nomogram tends to over-predict severity of intoxication in moderate and severe categories. Nomogram had higher predictive index when used for concentrations drawn six to 12 hours after ingestion Decisions should be based on clinical presentation and good judgment as well as serum salicylate concentration Dugandzic RM et al. Ann Emerg Med. 1989; 18: SALICYLATE POISONING Haemodialysis is the treatment of choice for severe poisoning and should be seriously considered in patients with: renal failure, congestive cardiac failure, non-cardiogenic pulmonary oedema, coma, convulsions or CNS effects not resolved by correction of acidosis In the presence of symptoms suggestive of severe salicylate poisoning, haemodialysis should also be considered in patients with: severe metabolic acidosis (ph<7.2), persistently high salicylate concentrations unresponsive to urinary alkalinisation or plasma concentrations greater than 7 mg/l (5.1 mmol/l) Patients < 1 years or > 7 years have increased risk of salicylate toxicity and may require dialysis at an earlier stage. Children who require haemodialysis should be discussed with the local/regional paediatric intensive care unit TOXBASE IRON POISONING TOXBASE Serum iron taken at about 4 hours after ingestion the best laboratory measure of severity < 3 mg/l (55 micromol/l) mild toxicity 3-5 mg/l (55-9 micromol/l) moderate toxicity > 5 mg/l (9 micromol/l) severe toxicity Coma and shock indicate severe poisoning (URGENT TREATMENT IS REQUIRED) No single method of assessment is entirely satisfactory - clinical as well as laboratory features must be taken into account 5

6 PARAQUAT POISONING Unrestricted availability of plasma paracetamol (acetaminophn) assay service resulting in increased number of inappropriate requests Since May 1992, no restrictions on ordering paracetamol assay Requests considered appropriate if paracetamol ingestion suspected or unknown drugs ingested No. of patients having plasma paracetamol concentrations assayed increased from 51 in 1991 to 141 in 1993 (176%) Corresponding increase in the number of Chinese patients admitted to two of eight general wards with poisoning was estimated to be 93% Proportion of 'appropriate' plasma paracetamol measurements dropped from 55% in 1991 to 21% in 1993 Unrestricted availability of plasma paracetamol measurements resulted in an increase in the number of inappropriate requests Chan TY et al. Postgrad Med J Nov;71(841):678-8 USE OF THE LABORATORY WHEN Took 4 paracetamol (acetaminophen) tablets with 1 pints Guinness 6 hours earlier Vomiting & abdo. pain Plasma paracetamol concentration 24 mg/l at 6 hours & blood alcohol 69 mg/l Given N-acetylcysteine (NAC). Developed severe blistering rash at site of injection but received full dose 24 year-old male Se Creatinine (Umol/l) Day Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 When to contact a specialist liver centre in patients with acetaminopheninduced hepatotoxicity Progressive coagulopathy: PT in seconds greater than the number of hours since ingestion (or if the INR is >2 at 24 h, >4 at 48 h, and >6 at 72 h) Renal impairment (creatinine >2 mol/l) Hypoglycaemia Metabolic acidosis (ph <7.35) Hypotension despite fluid resuscitation Encephalopathy INR = International Normalized Ratio; PT = prothrombin time. Data from Bernal et al. Dargan PI & Jones AL. Acetaminophen poisoning: an update for the intensivist. Crit Care 22; 6: King's College Hospital criteria for liver transplantation in acetaminophen-induced acute liver failure Current criteria List for transplantation if: Arterial ph <7.3 after adequate fluid resuscitation List for transplantation if all three of the following occur within a 24-h period: Creatinine >3 μmol/l PT >1 s (INR >6.5) Grade III/IV encephalopathy Modified criteria Strongly consider listing for transplantation if: Arterial blood lactate concentration >3.5 mmol/l after early fluid resuscitation List for transplantation if: Arterial ph <7.3, or arterial blood lactate concentration >3. mmol/l after adequate fluid resuscitation List for transplantation if all three of the following occur within a 24-h period: Creatinine >3 μmol/l PT >1 s (INR >6.5) Grade III/IV encephalopathy Dargan PI & Jones AL. Acetaminophen poisoning: an update for the intensivist. Crit Care 22; 6:

7 USE OF THE LABORATORY WHEN LEVELS OF EVIDENCE (US Agency for Health Care Policy and Research) Ia: evidence from meta-analysis of randomised controlled trials Ib: evidence from at least one randomised controlled trial IIa: evidence from at least one controlled study without randomisation IIb: evidence from at least one other type of quasiexperimental study III: evidence from non-experimental descriptive studies, such as comparative studies, correlation studies and case-control studies IV: evidence from expert committee reports or opinions and/or clinical experience of respected authorities Data collection in clinical toxicology: are there too many variables? Whether that evidence base is derived from randomized controlled trials or observational studies, it is essential to collect data A clinical database provides accurate information in the areas of clinical practice, quality assurance (audit), and research In the area of research, an appropriately designed database can be both a source of hypotheses as well as a vehicle to test them It can also serve as a repository of research data in subsequent randomized controlled trials Whyte IM et al. J Toxicol Clin Toxicol. 22;4: ADMISSIONS TO THE CARDIFF POISONS TREATMENT UNIT All episodes Paracetamol Other Medicines Paracetamol Admission episodes in 1999 Beck P. et al. Increasing rate of deliberate self poisoning. BMJ 1994; 38:789 Bialas M et al. Changing patterns of self-poisoning in a UK health district. QJM 1996; 89: USE OF THE LABORATORY WHEN VENLAFAXINE Blood, liver, bile vitreous humor, urine and gastric contents were analyzed using high performance liquid chromatography with ultraviolet detection Blood concentrations of venlafaxine in the two overdose cases were 53 mg/l and 78 mg/l Comparison of venlafaxine concentrations in blood samples taken at different times after death revealed increases in concentrations over time, suggesting possible postmortem redistribution of venlafaxine. Jaffe PD et al. A study involving venlafaxine overdoses: comparison of fatal and therapeutic concentrations in postmortem specimens. J Forensic Sci. 1999; 44:

8 POST-MORTEM REDISTRIBUTION Post-mortem drug concentrations do not necessarily reflect concentrations at time of death Passive release from drug reservoirs such as the gastrointestinal tract, liver, lungs, and myocardium may occur immediately after death Later, cell autolysis and putrefactive process participate in redistribution Basic lipophilic drugs with large distribution volume particularly susceptible to PMR Nevertheless, this cannot explain the actual PMR of some non-basic, non-lipophilic drugs Persistence of drug metabolism immediately after death must be considered So analyse samples from different sampling sites to detect potential PMR and avoid misinterpretation results CRYMLYN BURROWS INCIDENT In October 1996, council workers sent to clean sewage chamber in Crymlyn, South Wales Vaccum equipment blocked One man climbed down into the chamber Work mate went in to help, third went to call for help but the other two men died Analysis revealed refrigerant Freon 11 (trichloromonofluoromethane) Pelissier-Alicot AL et al. Journal of Analytical Toxicology 23; 27: No ventilator equipment Vacuum equipment blocked Spillage (3 / 9.8 tonnes unaccounted for) HAZARD Fatal injuries while under the influence of psychoactive drugs (FIUI): a cross-sectional exploratory study in England Drugs implicated in intentional and unintentional FIUI Poor Communication Systems LOSS OF LIFE Poor communication systems No statutory requirement for confined space training Oyefeso A et al. BMC Public Health. 26; 6: 148 Fatal injuries while under the influence of psychoactive drugs (FIUI): a cross-sectional exploratory study in England Drugs implicated in FIUI by gender and age Oyefeso A et al. BMC Public Health. 26; 6: 148 USE OF THE LABORATORY WHEN MANAGING THE POISONED PATIENT CONCLUSIONS The laboratory can give valuable information to help answer the questions What is the management? What is the response to treatment? What can be learned for the future? What was the diagnosis? Such information is complementary to, but never a substitute for clinical assessment 8