Anaphylaxis to Drugs

Transcription

1 Anaphylaxis to Drugs Prof Ian Whyte FRACP, FRCP(Edin), FACMT, FAACT, FEAPCCT

2 Nomenclature Hypersensitivity describes objectively reproducible symptoms or signs initiated by exposure to a defined stimulus at a dose tolerated by normal persons Allergy is a hypersensitivity reaction initiated by specific immunological mechanisms Allergy can be antibody-mediated or cellmediated

3 Nomenclature When other mechanisms can be proven, as in hypersensitivity to aspirin, the term nonallergic hypersensitivity is used Anaphylaxis is a severe, life-threatening generalised or systemic hypersensitivity reaction Allergic (immune-mediated) Nonallergic (non-immune mechanism)

4 Johansson SG, Bieber T, Dahl R, Friedmann PS, Lanier BQ, Lockey RF, Motala C, Ortega Martell JA, Platts-Mills TA, Ring J, Thien F, Van Cauwenberge P, Williams HC. Revised nomenclature for allergy for global use: Report of the Nomenclature Review Committee of the World Allergy Organization, October J Allergy Clin Immunol May;113(5):832-6.

5 Drug hypersensitivity Immediate allergic (IgE-mediated) Penicillins Delayed allergic (usually T-cell mediated) Serum sickness-like reaction (cefaclor) SCAR (severe cutaneous adverse reactions) DRESS: Drug rash with eosinophilia and systemic symptoms Anticonvulsants SJS/TEN: Stevens-Johnson syndrome/toxic epidermal necrolysis Allopurinol Nonallergic drug hypersensitivity Vancomycin

6 Case presentation IB, 66 year old male Presenting illness /2/2016 Ambulance called; sudden onset of shortness of breath 2244 PR 110 bpm (irregular); BP 174/110 mmhg; RR 34/min; T 37.2 C; SpO 2 79% RA; widespread crackles Given O 2 15 L/min; GTN 0.3 mg subling

7 Emergency Department /2/2016 Triage Previous admission for acute pulmonary oedema on 16/2/ presentations to ED in last 12 months Increasing SOB for several days with productive cough and sweats Widespread crackles Moved to resuscitation area BiPAP (18/8 mmhg) Nitroglycerin infusion

8 History Medical/Surgical Chronic obstructive pulmonary disease Aortic and mitral valve replacements Atrial fibrillation Moderate global systolic dysfunction Type 2 diabetes on insulin Allergy to Tazocin?reaction Medications Warfarin Aspirin Ramipril Bisoprolol Digoxin Metformin Insulin, glargine Pantoprazole Fluticasone/salmeterol Tiotropium

9 Haematology Investigations Hb 129 g/l WCC 26.2 x 10 9 /L; Neutrophils 17.5 INR 1.8 Biochemistry Na mmol/l K mmol/l Cl 109 mmol/l HCO 3 18 mmol/l Urea 5.3 mmol/l Creatinine 111 micromol/l Troponin I 19 ng/l Blood sugar 11.2 mmol/l

10 /2/2016 Progress Given antibiotic (doxycycline 200 mg) 0330 Intravenous nitrates and BiPAP ceased 0600 CXR APO?elements of infection/pneumonia

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13 Report: Chest X-ray Compared to the previous examination of The CTR at today s examination is 17.3:31.4 The pulmonary vasculature is prominent consistent with a degree of failure There is loss of volume in the left base consistent with superimposed infection

14 23/2/ /2/2016

15 Treatment (23/2/2016) Lantus 16 Units 0800 (BSL 6.4) Doxycycline 200 mg oral 0109 then Doxycycline 100 mg oral daily 0800 Salbutamol 5 mg neb 0335 & 0615 then Salbutamol 5 mg neb every 6 hours Amiodarone 200 mg mane 0800 Nicotine patch 21 mg top daily 0800

16 Progress /2/2016 Settled, awaiting ward bed Regress 1102 Sudden onset of funny taste; hypersalivation; difficulty breathing, flushing feeling and rash 1103 Patient unresponsive, no pulse 1105 Advanced life support commenced 1105 Adrenaline 0.5 mg Adrenaline 4 mg 1116 Son in attendance 1117 Bedside echo 1118 ALS ceased No cardiac activity; no palpable pulse; no shockable rhythm

17 Treatment (23/2/2016) Benzylpenicillin 1.2 G IV every 6 hours First dose given at 1100

18 Discussion

19 Risk factors Older age, especially with co-morbidity Cardiovascular disease and/or Chronic obstructive pulmonary disease Risk factor for severe anaphylaxis Hospitalisation Prolonged hospital stay Fatality

20 Risk factors Beta-blockers and ACE inhibitors Higher risk of severe anaphylaxis Patients taking a beta-blocker AND an ACE inhibitor concurrently IB 66 years old Severe CVD and COPD On bisoprolol and ramipril

21 /2/2016 Prescriber Presentation with respiratory distress and symptoms of chest infection Left basal crackles and chest X-ray consistent with pneumonia Allergies discussed with patient and son IB reported allergy to Tazocin (piperacillin/tazobactam) but not penicillins in general Had had penicillin before without problems Confirmed from medical record

22 Penicillin [2/12/2011 Alerts from ipm (via CAP) Adverse Drug Reaction Including Drug Allergies] 1/2015 Benzylpenicillin [IV] for 5 days without issue 14/1/2016 [39 days before] Flucloxacillin [IV (one dose) followed by ceftriaxone IM daily for 4 days] without reaction /2/2016 Benzylpenicillin (1.2 G) administered IB complained of flushing then rapidly became unresponsive ALS commenced Consensus decision (including son) to cease Death due to anaphylaxis to penicillin

23 Timeline 2/12/2011 Drug allergy 2/11/2015 Anaphylaxis to Tazocin /2/2016 Benzylpenicillin 1/2015 Benzylpenicillin without issue 12/1/2016 Flucloxacillin without reaction /2/2016 Death

24 Tazocin /11/2015 (92 days before death) Three day history Intermittent, right upper quadrant, abdominal pain with nausea and vomiting Right upper quadrant tenderness 37 C; WCC 17.4; Neutrophils 12.8 Gamma GT 176 (12 64) Units/L ALP 129 (30 110) Units/L INR 1.9

25 0828 2/11/2015 Cholecystitis 1020 Surgical review IV Tazocin G every 8 hours IV heparin for prosthetic valves Sliding scale insulin Abdominal CT with IV contrast 70 ml Omnipaque 300

26 1500 2/11/2015 Procedure Laparoscopic cholecystectomy and intraoperative cholangiogram 1745 Chronic cholecystitis HDU for postoperative care (well)

27 HDU /11/2015 Tazocin 4.5 G IV infusion started [first dose] 1900 Sudden onset dizziness BP 45/28 mmhg arterial line Previously 120/60 Flushed red all over Sodium chloride 0.9% 1000 ml IV Metaraminol 3 mg IV Hydrocortisone 100 mg IV 1930 BP 99/60

28 2010 2/11/2015 Medical review BP 110/60 Widespread, erythematous, blanching rash Previous steroid dependence noted Continue IV hydrocortisone 100 mg IV every 6 hours Likely anaphylactoid reaction 2035 Cease IV Tazocin No further IV antibiotics Much improved; rash fading ECG and troponin normal

29 Discharge summary He developed dizziness and pre-syncopal symptoms post Tazocin dose for which he was given IV hydrocortisone and Tazocin ceased Known Allergies/Adverse Reactions: Substance: Tazocin, Reaction Type: Allergy, Reaction Description: Anaphylatic [sic] Reaction, Effective Date: 05/11/2015, Category: Drug

30 Ward pharmacist Medication plan Piperacillin/tazobactam anaphylaxis Next admission 6/1/2016 Known Allergies/Adverse Reactions: Substance: tazocin, Reaction Type: Toxicity, Reaction Description: unknown, Effective Date: 08/01/2016, Category: Drug, Severity: Unknown

31 MedChart

32 Discussion

33 Autopsy report Direct cause of death Anaphylaxis RCA Antecedent cause of death Benzylpenicillin administration No evidence of pneumonia Request for a clinical pharmacologist to review the record and provide an opinion Any other medications given at the same time?

34 1900 2/11/2015 Review of Tazocin Attended patient for R/V prior to starting heparin Had just received heparin IV heparin infusion was charted and signed for on Variable Dose Medication section of NIMC Subsequent note indicates not given secondary to anaphylaxis to Tazocin

35 Review of benzylpenicillin 23/2/2016 INR /2 CLEXANE subcut 60 mg BD Subtherapeutic INR A. Doctor A. Doctor 23/2 Benzyl penicillin IV 1.2g QID AN 1100 AN A. Doctor A. Doctor

36 Review of flucloxacillin 14/1/2016 (53 days after anaphylaxis to piperacillin/tazobactam) Chest tightness and shortness of breath worsening throughout day Ambulance to Hospital Tachycardic Tachypnoeic CXR consolidation Inflammatory markers raised Intravenous flucloxacillin

37 Post-flucloxacillin Increasing respiratory distress Required BiPAP to maintain O 2 saturation Transferred to ICU Changed to ceftriaxone and azithromycin Respiratory symptoms improved On room air within 4 days IV antibiotics ceased after 5 days Discharged

38 Anaphylaxis On both occasions of anaphylaxis Penicillin Piperacillin (reaction started 30 minutes into infusion) Benzylpenicillin (< 5 min) Heparin Unfractionated heparin (< 5 min) Enoxaparin (< 5 min) Between these two occasions had received flucloxacillin IV without anaphylaxis No interval heparin

39 Heparin Unfractionated heparin (UFH) is a heterogenous mixture of glycosaminoglycans (anionic polysaccharides) MW ~5 30 kilo Dalton (kda) Low-molecular-weight heparins (LMWHs) derived from UFH by chemical or enzymatic depolymerisation MW ~2 15 kda

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41 Delayed hypersensitivity Cell-mediated Common (up to 7.5%) Pruritic, erythematous plaques at the injection sites At least 7 10 days but more often weeks to months DRESS (very rare) Drug Reaction with Eosinophilia and Systemic Symptoms

42 HIT Heparin-induced thrombocytopenia Antibody-mediated hypersensitivity reaction Multi-molecular complexes on the platelet surface Platelet factor 4 Heparin IgG antibodies Bind to the FcγIIa (IgG) receptors of platelets Platelet activation Thrombocytopenia Thrombosis (HITT)

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44 Immediate hypersensitivity Rare (< 0.1%) but well-reported IgE-mediated Pruritus/urticaria Palmoplantar Generalised Conjunctivitis, rhinitis, asthma Anaphylaxis IgG-mediated Re-exposure within 90 days of HIT (5% anaphylaxis) Cross-reactivity very high Within LMWHs (92.9%) Between UFH and LMWH (67.1%)

45 Timeline /11/2015 Tazocin /11/2015 Anaphylaxis /2/2016 Benzylpenicillin AND enoxaparin /11/2015 Heparin 12/1/2016 Flucloxacillin without anaphylaxis /2/2016 Death

46 Clinical pharmacology opinion Unusual for immune-mediated anaphylaxis to present 30 minutes into a continuous intravenous infusion of a causative agent Evidence of intravenous heparin administration immediately before onset of first episode of anaphylaxis Subsequently tolerated intravenous flucloxacillin with, at worst, increasing respiratory distress but no anaphylaxis

47 Clinical pharmacology opinion Enoxaparin given at the same time as the benzylpenicillin (immediately before onset of anaphylaxis) Immune-mediated hypersensitivity to heparins including anaphylaxis, although rare, is well documented Cross-reactivity between unfractionated heparin and LMWHs is very high Raises the possibility of death due to anaphylaxis to heparin

48 In summary On the balance of probabilities it appears that death was due to anaphylaxis to heparin rather than anaphylaxis to penicillin Suggested immunologist opinion

49 Discussion

50 RCA Initial anaphylactic reaction in 2015 occurred while the patient was under the care of a surgical team and there was no evidence of subsequent immunology review Allergy was clearly documented in the medication plan prepared by the Pharmacist however no follow up was documented The reaction was only documented in the text of the discharge and the allergy section and not listed as a significant diagnosis

51 RCA Inconsistent and inaccurate recording of allergies and adverse drug reactions in the patient s medical record over several admissions between November 2015 and the final admission Allergy is recorded by the brand name Tazocin rather than the generic name piperacillin/tazobactam

52 RCA A significant contraindication for prescribing benzylpenicillin A clearly documented history of hypersensitivity to a beta-lactam antibiotic No subsequent evidence of definite tolerance to penicillin

53 RCA Found that the patient was prescribed benzylpenicillin which led to an immediate anaphylaxis and cardiac arrest, from which the patient was unable to be resuscitated