Antidote Policy and treatment of specific
poisonings
Florian Eyer Toxikologische Abteilung Klinikum rechts der Isar
Technische Universität München [email protected]
!
Klinikum rechts der Isar
!
Technische Universität München !
Antidote policy in Clinical Toxicology in Germany (Munich)
Pragmatic classification of antidotes
• supportive antidotes - “nice to have - but usually not life-saving” - should be available in hospitals
• life-saving antidotes - should be available both in the preclinical (e.g. paramedics) and clinical setting (ED, ICU)
Antidotes available in the preclinical German emergency physician system
• Atropin 1% (OP poisoning - cholinergic crisis)
• Obidoxim (Toxogonin®) 250 mg Amp. (OP poisoning - reactivation of AChE)
• 4-DMAP 250 mg Amp. (Cyanide poisoning)
• Sodium-thiosulfate 10% Inf. (Cyanide poisoning)
• Biperiden (Akineton®) 5 mg Amp. (Anticholinergic agent to treat extrapyramidal tardive dyskinesia)
• Flumacenil (Anexate®) 0.5 mg Amp. (BZD-Antagonist)
• Naloxon (Narcanti®) 0.4 mg Amp. (Opioide-Antagonist)
• Physostigmine (Anticholium®) 2 mg Amp. (CAS-Syndrome)
• Diazepam (Valium®) 10 mg Amp. (e.g. Cocaine-intoxication)
Life-saving antidotes
Poison Antidote Trading name Dose
Chloroquine Diazepam Valium® 1-2 mg/kg
Ethylenglycol Ethanol / 4-MP Ethanol 0.6 g/kg
Insulin / Sulfonylurea Glucose 25 g
CO Oxygen 100 %
Met-Hb-building agents Toloniumchloride Toluidinblau® 2-4 mg/kg
Organophosphates Atropin /Obidoxime 1% Atropin 1-20 mg bzw. 250mg/750 mg/24h
Tricyclic AD Sodium bicarbonate NaBic 8.4% 1-2 mval/kg
Cyanide 4-DMAP or Hydroxocobalamin
4-DMAP Zyanokit®
250 mg 5-10 g
Supportive Antidotes
Poison Antidote Trading name DoseAnticholinergic agents
Antihistamines Physostigmine Anticholium® 2-4 mg i.v.
Benzodiazepines Flumazenil Anexate® 0.5-1 mg Neuroleptic overdose Biperiden Akineton® 2.5-5 mg Organophosphates Obidoxime Toxogonin® 250 mg / 750 mg
Opiates Naloxon Narcanti® 0.4 mg Irritant gas (chlorine,
phosgene, NOx) Corticosteroides Junik® Ventolair® 250 mg i.v.
Cyanides Sodium thiosulfate S-Hydril® 7 g
Life-saving antidotes - Hospital
Poison Antidote Trading name Dose
Digitalis glycosides Digitalis- Antitoxin
Digi-Fab® Digi-Bind® 40-80 mg bolus dose
Iron poisoning Desferoxamin Desferal® 15 mg/kg/h
Paracetamol N-Acetylcysteine Fluimucil®150 mg / 1 h 50 mg / 4 h
100 mg / 16 h
Heavy metals Dimercaptopropansulfonate Dimercaptosuccinic acid
Dimaval® Succimer® 250 mg alle 3 h
Supportive antidotes - Hospital
Poison Antidote Trading name Doseß-blocking agents Glucagon Glucagon® 7 mg Hydrofluoric acid Calciumgluconate Ca-Braun 10%® 1-2 g i.a. / s.c.
Heparin Protamine Protamin® 10 mg für 1000 IEIsoniacid Pyridoxine Pyridoxal® 5 g
Amatoxines Silibinin Legalon-Silibinin® 20 mg/kgOAK (Cumarines) Phytomenadion Konakion® 25 mg / d oral
Thallium Prussian blue Antidotum Thalli-Heyl® 3 g oral
Organophosphate poisoning in the developed world - a single centre
experience from here to the millennium
Florian Eyer Toxikologische Abteilung Klinikum rechts der Isar
Technische Universität München [email protected]
!
Klinikum rechts der Isar
!
Technische Universität München !
Background
• OP poisoning is still associated with high morbidity and mortality, both in resource-poor settings and in developed countries
• Despite large-sized studies with sufficient statistical power, individual details of OP-poisoned patients are rarely reported
• We therefore conducted a retrospective study on patients with OP poisoning admitted to our ICU
• Aim: To describe clinical features, complications and differences between Dimethyl- or Diethyl-OP compounds as well as differences between survivors and fatalities
• Reactivation by oximes, influence on RBC-AChE and NMF were beyond the scope of this study
Methods• Retrospective single centre study on OP poisoned patients admitted
between January 2000 - December 2012
• Tertiary university hospital (1100 beds)
• Computerized search of an electronic database (Oracle) using the search code „organophosphate“ or the ICD-10 code T60.0, respectively
• Inclusion criteria:
• Acute ingestion of OPs requiring admission to ICU (e.g. coma, seizures, need for mandatory ventilation, or cardiovascular support)
• Signs of cholinergic syndrome calling for treatment with atropine and/or obidoxime, respectively
• Exclusion criteria:
• Patients under the age of 18
• Carbamate ingestion
Number of included patients during the study period (n=33)
0
2
4
6
8
10
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
11
0
11
22
1
3
44
6
7
*11/33 patients treated between Jan. 2000 - Dec. 2001 were included in a small prospective multicenter study Eyer et al., Clinical Toxicol 2009; Thiermann et al., Clinical Toxicol 2009
Data extraction• Patient charts were reviewed to obtain data on
• type and alleged volume of ingested OP
• demographics, laboratory data, ABG, hemodynamics
• Severity: GCS, APACHE II, SOFA, PSS-score
• ECG: HR, Arrhythmia, QT- and corrected QTc-intervals (Bazett), QT-interval nomogram
• Treatment: Gastric lavage, AC, treatment with atropine and oximes, LOS in hospital/ICU and length of MV
• Complications: Pneumonia, seizures, sepsis, arrhythmia, cardiovascular failure, outcome
Chan A et al., QJM 2007; Isbister G et al., Int Clin Psychopharmacol 2009
Subgroups & Statistics• Dimethyl- versus Diethyl-OP´s
• Survivors versus fatalities
• Survivors
• full recovery and those with
• (neurologic) residual symptoms
• Data given as medians [min-max], differences between groups were calculated using the Fisher exact test for categorical variables and the Mann-Whitney U-test for quantitative, not normally distributed variables
Results: Clinical characteristics of the total cohort
• 33 patients, age 56 [19-84], 75% male
• 28/33 (85%) survived, 5/33 (15%) died
• 32 patients ingested the OP in a suicidal attempt, only 1 case was accidentally
• Alleged ingested volume: 100 mL [10-750]
Ingested OPs
• n=19: Dimethyl-OP (oxydemeton-methyl n=14)
• n=8: Diethyl-OP (parathion n=7)
• n=6: „Others*“
★ mixture of oxydemeton-methyl and parathion n=2
★ Diamide insecticides n=4
✴ Methamidophos n=3
✴ Triamiphos n=1
*not included in statistic calculations
PChE in the course (n=179 and n=64 single determinations in Dimethyl- and Diethyl-OPs)
PChE 353 U/L
PChE 149 U/Lp=0.09 {
Treatment• ICU-LOS: 264h [1-1245 h]
• LOS in hospital: 382 h [1-1296]
• 32/33 ITN and mechanical ventilation 168 h [0-1058]
• Gastric lavage: 20/33 (61%), AC 30/33 (91%)
• Atropin (n=33): 136 mg [7-844]
• Obidoxime (n=27): 1.5 g [0.5-8.3] for 45 h [3-276]
• Dimethyl-OPs: 44 h
• Diethyl-OPs: 102 h ⧽p=0.12
Complications• (Aspiration)-pneumonia predominated in 27/33 patients
• Extubation failure in 12/33, tracheotomy in 2 patients; IMS twice
• Renal insufficiency 17/33 patients, 6 required RRT
• cerebral seizures 5/33
• multiorgan failure 5/33, sepsis 4/33
• Hypoxic brain damage 3/33, stroke 2/33, myocardial infarction 1/33, perforated ulcus duodeni 1/33 (fatal outcome)
Folidol®-Oil (250 mL) aspiration with ARDS (day 16)
Survivors versus fatalities
All Patients (n=33)
Survivors* (n=28)
Fatalities* (n=5)
p-Value*
Age (y) 56 [19-84] 53 [19-75] 69 [48-84] 0.2 Sex (male) 25 (76%) 20 (71%) 5 (100%) 0.3 Poison ingested
Dimethyl–OP 19 (58%) 17 (61%) 2 (40%) 0.63 Diethyl–OP 8 (24%) 5 (18%) 3 (60%) 0.08 Others 6 (18%) 6 (21%) 0 0.56
Ingested amount (mL) 100 [10-750; n=25] 80 [10-750; n=20] 100 [20-750; n=5] 0.36 Time to admission (h) 2 [1-17.5; n=29] 2 [1-17.5; n=24] 1 [1-4.5; n=5] 0.35 Severity of poisoning PSS
3 [1-4]
3 [1-3]
4 [4-4]
0.0001
APACHE II 19 [2-34] 19 [2-33] 24 [17-34] 0.07 SOFA 7 [1-19] 7 [1-13] 10 [7-19] 0.02 GCS at adm. 9.5 [3-15] 3 [3-15] 3 [3-15] 0.290 Hemodynamics at adm. RR systolic (mmHg)
125 [0-175]
134 [70-175]
110 [0-138]
0.05
RR diastolic (mmHg) 75 [0-110] 75 [45-110] 73 [0-89] 0.16 HR (bpm) 90 [0-155] 90 [40-155] 87 [0-139] 0.5 Cholinergic syndrome Number of patients (n)
30 (91%)
25 (89%)
5 (100%)
1.0
Maximum (h after adm.) 1 [-0.5-88; n=21] 1 1 [-0.5-88; n=16] 2 [-0.5-5; n=5] 0.73
Survivors versus fatalities
All Patients (n=33)
Survivors* (n=28)
Fatalities* (n=5)
p-Value*
ECG parameters QTc-time (msec.) 2
438 [322-535]
428 [333-535]
497 [440-520]
0.03
Intermediate/High-Risk3 3 (10%) 2 (8%) 1 (25%) 0.4 Arrhythmia in the course AVB° ≥ IIb
4 (12%)
4 (14%)
0
1.0
Multiple VES 4 (12%) 4 (14%) 0 1.0 TdP 4 (12%) 3 (11%) 1 (20%) 0.5 VF 3 (9%) 2 (7%) 1 (20%) 0.40
Asystolia 9 (27%) 5 (18%) 4 (80%) 0.01 ∑Severe arrhythmia4 18 (55%) 13 (46%) 5 (100%) 0.05 Laboratory at adm. pH 7.35 [6.8-7.5] 7.37 [7.1-7.5] 7.27 [6.8-7.3] 0.004 pCO2 (mmHg) 36 [5-70] 36 [5-68] 44 [30-70] 0.16 pO2 (mmHg) 156 [26-431] 159 [27-431] 123 [88-170] 0.45 BE -4.2 [-20-4.1] -3.9 [-15-4.1] -6.4 [-20--3.7] 0.02 PChE (U/L) 200 [100-12292] 190 [100-12292] 300 [100-350] 0.87
Dimethyl- versus Diethyl-OP
All patients
(n=33) Dimethyl-OP*
(n=19) Diethyl-OP*
(n=8) Others
(n=6) p-
Value* Decontamination Gastric lavage 20 (61%) 12 (63%) 4 (50%) 4 (67%) 0.68 Activated charcoal 30 (91%) 19 (100%) 5 (63%) 6 (100%) 0.02 Basic life support CPR before/at adm. 3 (9%) 1 (5%) 2 (25%) 0 0.2 CPR in the course 4 (13%) 3 (16%) 1 (14%) 0 1.0 Intubation Preclinical
19 (58%)
7 (37%)
7 (88%)
5 (83%)
0.03
At admission 10 (30%) 9 (47%) 1 (13%) 0 0.19 In the course 3 (9%) 2 (11%) 0 1 (17%) 1.0 Antidotal therapy Atropin dose (mg) 136 [7–844] 115 [23-644] 200 [7-410] 199 [27-844] 0.9 Oximtherapy (n,%) 27 (82%) 16 (84%) 6 (75%) 5 (83%) 0.62
Duration (h) 45 [3-276] 44 [15-94] 102 [23-276] 44 [3-177] 0.12 Dose (g) 1.5 [0.5-8.3] 1.4 [0.5-3.4] 3.4 [0.9-8.2] 1.6 [0.5-3.7] 0.11
Dimethyl- versus Diethyl-OP
All patients
(n=33) Dimethyl-OP*
(n=19) Diethyl-OP*
(n=8) Others
(n=6) p-
Value* Length of treatment MV (h) 168 [0-1058] 161 [0-1058] 152 [2-551] 257 [67-528] 0.93 ICU (h) 264 [1-1245] 278 [18-1245] 209 [1-552] 367 [122-692] 0.46 In hospital (h) 382 [1-1296] 381 [18-1296] 382 [1-552] 552 [144-840] 0.29 Outcome Full recovery 20 (61%) 13 (68%) 3 (38%) 4 (67%) 0.20 Residual symptoms 8 (24%) 4 (21%) 2 (25%) 2 (33%) 1.0 Fatal 5 (15%) 2 (11%) 3 (38%) 0 0.14 Complications Pneumonia 27 (82%) 17 (89%) 6 (75%) 4 (67%) 0.56 Reintubation 12 (36%) 8 (42%) 2 (25%) 2 (33%) 0.67 IMS 2 (6%) 2 (11%) 0 0 1.0 Sepsis 4 (12%) 3 (16%) 1 (13%) 0 1.0 ARF1 6 (18%) 3 (16%) 2 (25%) 1 (17%) 0.62 Seizure 5 (15%) 2 (11%) 1 (13%) 2 (33%) 0.57 MOV 5 (15%) 2 (11%) 3 (38%) 0 0.14
Outcome of survivors
• 8/28 suffered from neurological disabilities; 20/28 recovered fully
• Patients with residual symptoms vs. full recovery:
• Age: 65 versus 50 (p=0.39)
• GCS on admission: 4.5 vs. 14 (p=0.08)
• LOS hospital: 718 vs. 312 h (p=0.02)
• LOS ICU: 552 h vs. 208 h (p=0.003)
• Duration of MV: 444 vs. 152 h (p=0.005)
• Severe Arrhythmia: 75% vs. 35% (p=0.10)
• Resuscitation: 25% vs. 0% (p=0.07)
• no difference in the administered dose of atropine or obidoxime
Conclusion• The fatality rate of OP poisoning in a well-staffed and
equipped ICU of a developed country was quite similarly high compared to the rate observed in developing countries (but: Class I-OPs predominated in our cohort!)
• Death occurred rather late when obvious signs of cholinergic crisis were mostly no longer present; death was therefore frequently related to non-poison specific complications
• We did not detect significant differences in outcome (despite probably clinical relevant) between dimethyl- and diethyl-OPs; however, some obvious differences might become significant in larger patient cohorts
• Special attention to arrhythmia and QT-interval prolongation in OP-poisoned patients seems mandatory
Salicylate poisoning
!
Klinikum rechts der Isar
!
Technische Universität München !
Clinical features of Salicylate poisoning
• Mild poisoning: nausea, vomiting, tinnitus, dizziness or lethargy may occur
• Moderate poisoning: above plus tachypnoea, hyperpyrexia, sweating, dehydration, restlessness
• Severe poisoning: above plus hallucinations, stupor, coma, convulsions, cerebra edema, renal failure, cardiovascular failure and metabolic acidosis
• Often misdiagnosed as sepsis, myocardial infarction or psychiatrically ill patients
1. Preventing absorption
• Large doses may induce gastric pylorospasm or lead to Bezoar-formation
• Gastric lavage is of unpredictable efficacy
• Activated charcoal (given within 1 hour p.i.) may prevent absorption of salicylates and has a favorable risk/benefit relationship - should be administered when felt safe to do so
• Study in adult volunteers taking 1.9 g aspirin: AC 50 g, three times, four hourly resulted in significantly decreased absorption when comparing to SDAC
• Give MDAC until salicylate level peaks
Barone JA et al., 1988; Kirshenbaum LA et al., 1990
2. Increasing elimination
• Urinary alkalization traps dissociated acetyl-salicylate (pK 3.5) and salicylate (pK 3.0) and promotes urinary excretion
• Alkalization of serum pH promotes movement of salicylate from tissues (CNS) into serum and diminishes toxicity.
• urine alkalization: increasing urine pH from 5 to 8 increases renal salicylate clearance 10-20-fold
• start alkalization of serum and urine on presentation at hospital and replace potassium, as potassium depletion may increase reabsorption of bicarbonate with difficulty achieving an alkaline urine
• continue alkalization until plasma salicylate decreases and/or cessation of patient´s symptoms
• forced diuresis is of no additional value and may be harmful (pulmonary edema, hypernatremia, hypokalemia)
Urine-pH and salicylate clearance
Proudfoot A et al., Toxicol Rev. 2003; 22(3)
Diagnosis of salicylate poisoning (1)
• Salicylate measurement: in those with a positive history of ingestion of salicylates or reduced level of consciousness along with clinical features of salicylate poisoning
• Determine serum salicylate level (4 h p.i.) and repeat measurement making sure that continued absorption does not occur
• Routine use of salicylate nomograms (e.g. Done-nomogram) is not suggested (little correlation!)
• Caveat: different values of salicylate reported (mg/dL or mg/L)
• SR-preparations: salicylate levels may not peak before 12 hrs p.i.
• roughly estimation of toxicity (along with pH)
• 30 - 50 mg/dL: mild toxicity
• 50 - 70 mg/dL: moderate toxicity
• >750 mg/dL: severe toxicity
Wood DM et al. 2005; Todd PJ et al., 1981; Proudfoot A et al.; 1983; Done AK et al., 1960
• Under acidic serum conditions salicylate is protonated in the serum into its nonionized, lipid-soluble form passing passively blood-brain-barrier
• It is thus inappropriately to rely on serum salicylate levels to make treatment decisions
• It should be viewed in the context of the pH
• As blood pH falls, Vd of salicylate rises (diffuses out of the serum into tissues, mainly CNS, heart and lung)
• Falling concentrations can than be a harbinger of decompensation and should be only interpreted as sign of therapeutic success in the context of improvement of patient´s condition
• Serum salicylate levels are therefore at best an adjunct to the assessment of severity of poisoning.
Salicylate diagnosis (2)
Metabolic changes
• Anion gap shows unmeasured anions including a mixture of lactate, salicylate + metabolites, and ketoacids
• Caveat*: Normal anion gap caused by interference (high salicylate levels may cause false increase in chloride in some analyzers)
• Uncoupling oxidative phosphorylation -> oxygen consumption↑ and CO2-production↑ -> further stimulates medulla oblongata
• anaerobic metabolism less effective for ATP production -> Energy releasing during glucose metabolism in the electron transport chain is released as heat -> hyperthermia
• Acidaemia occurs due to the inability to buffer hydrogen ions (less pyruvate, more lactate) as well as kidneys excrete HCO
-3
• The presence of salicylic acid or acetylsalicylic acid per se contributes less to acidosis
Yip L et al., 1994; *Jacob J et al., 2011; Ann Emerg Med
Salicylate PK
• Aspirin is readily absorbed from the GI as both aspirin and salicylate
• peak serum concentrations within 1 h (therapeutic doses).
• Enteric coated achieve peaks 4-6 h post ingestion but the onset of toxicity may be delayed up to 8-12 h p.i.
• Serum half life 2-4 h at low doses and prolonged to 10-50 h following overdosage
• About 2-30% of salicylate is excreted unchanged in the urine (less in acidic urine or impaired renal function)
• Distribution related to the serum pH: the lower the pH the more nonionized salicylate is able to cross membranes
• Most elimination routes can be saturated with respect to their kinetics leading to zero-order-kinetics with prolonged elimination rates
Chyka P et al., 2007
ABG-Changes in salicylate poisoning
• Initially pure respiratory alkalosis due to salicylate´s direct stimulation of the respiratory drive in the Medulla oblongata.
• Mixed acid-base disturbances: after absorption, increases in lactate occur and oxidative phosphorylation is disturbed
• Hyperventilation becomes now a compensatory mechanism; it decreases paCO2 and decreases HCO-
3; pH normal or diminished, depending on the ability of the patient to fully compensate respiratory or to retain bicarbonate in the kidney.
• Metabolic Acidosis: compensatory mechanisms fail; pH drops; lactate accumulates and serum HCO-
3 is consumed.
• Patients with a pH below 7.4, low paCO2 and low HCO-3 are
dangerously unstable, likely to decompensate hemodynamically and will demonstrate other signs of end-organ damage.
Haemodialysis (1)
• HD reduced mortality and morbidity
• Should be considered in severe poisoning
• i.e. plasma salicylate >80 mg/dL in adults or >70 mg/dL in children or the elderly
• or patients with systemic metabolic acidosis, young or very old patients, CNS features (seizures, significant CNS-depression), acute renal failure or pulmonary edema
• continue urine alkalization during HD?: prevent acidaemia and promote forced salicylate elimination
• prompt HD should be at least coincident with the need of ITN
Yip L et al., 1994; Holubek W et al., 2008; Tyagi P et al., 2008
Haemodialysis (2)• Only half of the TESS-reported salicylate fatalities (2004) had salicylate
levels above 100 mg/dl (range 50-70 mg/dl)
• HD effectively removes also lactate and possible byproducts of mitochondrial poisoning
• Most of fatalities did not receive HD in an appropriate time frame.
• Although patients with salicylate levels above 100 mg/dL may clearly warrant empiric HD regardless of their immediate clinical condition, many patients with lower values who are symptomatic do as well.
• Dialysis should be performed in the case of CNS symptoms (drowsiness, delirium, lethargy, seizures, coma), severe hyper-ventilation, renal failure, pulmonary edema, or severe acid-base disturbance.
• HD should be prompted early not waiting for failure to appropriately alkalize the patients serum and urine nor for returning salicylate levels. HD-machine has to be prepared and vascular access has to be installed – both manoeuvres can result in the loss of valuable time.
Haemodialysis (3)• ECR of salicylates is efficient: MW 138 Da (aspirin; acetylsalicylate 180);
apparent Vd 0.2 L/kg; Pb at therapeutic doses up to 90%; at toxic salicylate conc. free salicylate increases as protein binding becomes saturated
• Even though AC-HP results in better salicylate clearance, it es expensive, has side effects and is rarely available -> HD treatment of choice.
• Proven protocols do not exist but excellent clearance should be achieved with a blood flow of 350-400 ml/min for a least 3.5-4 hours
• Use biocompatible haemodialysis membranes with larger surface areas
• Reassessment of salicylate levels and the patients clinical condition indicates whether a second HD treatment is indicated.
• CVVHD: is relatively slower and may not be prompt enough in its efficacy for severe cases but may be an alternative for patients suffering from hemodynamic instability or when HD is not available.
Goodman JW et al., Semin Dial. 2006
What are classic pitfalls?
• When interpreting the respiratory rate one should account for the depth of breathing – hyperpnea frequently occurs instead of tachypnea and is missed unless specific attention is paid.
• This results in large tidal volumes and is a pivotal compensatory mechanism
• Intubation is a classic point where these patients rapidly deteriorate – especially in the case of paralyzing and RSI
• This results in sudden loss of respiratory compensation leading to a precipitous fall in the pH
• Increasing nonionized salicylate crossing the blood brain barrier -> central nervous systemic acidosis -> cerebral edema and seizures.
• Seizing further lowers the pH leading to a rapid decline and – eventually death
• Tidal volumes should be adequate to achieve an alkalaemic pH
Salicylate poisoning - Take home• make the diagnosis early
• reduce absorption and increase elimination
• do not rely on serum salicylate level
• do not fail to recognize potential for clinical deterioration despite decreasing serum conc.
• treat sufficiently vigorous, maintain euvolaemia and keep blood pH alkaline
• Focus on both, urine AND blood alkalization (usually requires sodium bicarbonate AND potassium supplementation)
• do not allow arterial pH to decrease using sedatives or ITN with inadequate respiratory settings
• institute hemodialysis at the onset of neurotoxicity
Thank you for your kind attention!
