Month: May 2017

I recently had the opportunity of recording a podcast episode for the Virtual Critical Care Rounds (VCCR) of the Society of Critical Care Medicine (SCCM) with Sean Kane, PharmD, BCPS (@ClinCalc). We discussed the nuances of acetaminophen toxicity and practical application of the Rumack-Matthew nomogram in the clinical setting.

You can find the link to the podcast episode here (as well as other episodes of the SCCM VCCR).

Some suggested references for the episode are below for review and further reading:

#FOAMed references:

Lin M. Paucis Verbis: Acetaminophen Toxicity. Academic Life in Emergency Medicine (ALiEM). Available at: https://www.aliem.com/2011/11/paucis-verbis-acetaminophen-toxicity/

Sarchi A, Carroll S. Acetaminophen Overdose. EM Basic. Available at: http://embasic.org/acetaminophen-overdose/ 

Hayes BD. Utility of Pre-4-Hour Acetaminophen Level in Acute Overdose. ALiEM. Available at: https://www.aliem.com/2015/08/utility-of-pre-4-hour-acetaminophen-levels-in-overdoses/

Hayes BD. Are Acetaminophen Levels Necessary in All Overdose Patients? ALiEM. Available at: https://www.aliem.com/2013/09/are-acetaminophen-levels-necessary-in-all-overdose-patients/

Non-FOAMed references:

Rumack BH. Acetaminophen hepatotoxicity: the first 35 years. J Toxicol Clin Toxicol 2002; 40(1):3-20.

Hodgman MJ, Garrard AR. A review of acetaminophen poisoning. Crit Care Clin 2012; 28(4):499-516.

Dougherty PP, Klein-Schwartz W. Unexpected late rise in plasma acetaminophen concentrations with change in risk stratification in acute acetaminophen overdoses. J Emerg Med 2012; 43(1):58-63.

Kirschner RI, Rozier CM, Smith LM, Jacobitz KL. Nomogram line crossing after acetaminophen combination product overdose. Clin Toxicol 2016; 54(1):40-6.

ACMT Position Statement: Duration of Intravenous Acetylcysteine Therapy Following Acetaminophen Overdose. J Med Toxicol 2017; 13(1):126-127.

Gosselin S, Juurlink DN, Kielstein JT, et al. Extrip Workgroup. Extracorporeal treatment for acetaminophen poisoning: recommendations from the EXTRIP workgroup. Clin Toxicol 2014; 52(8):856-867.

• 6,165 patients in their first trimester were included of which 1,233 were exposed to ondansetron. First trimester exposure represent the highest risk for cardiac malformations as the heart is formed during this time.
• Both groups had a 2.9% occurrence of any major birth defect (adjusted prevalence OR = 1.12, CI 0.69-1.82).
• This study accounted for a wide range of maternal co-morbidities to reduce confounding factors.
• Cleft palates were not observed in children born to women exposed to ondansetron.

• Andersen et al. conducted a similar study to Pasternak et al., using the same registries.(5)
• They added 7 years of data to the Pasternak et al. study but only added 15 women who were exposed to ondansetron.
• This study is often cited for finding a higher incidence of cardiac malformations in infants whose mothers were exposed to ondansetron during the first trimester (OR = 2.0, CI 1.3-3.1)
• This study was only published as an abstract, never in a peer-reviewed journal.
• The abstract lacks critical information needed to determine its validity.
• This study cannot be used to make a decision in any data driven way.

• Danielsson et al. conducted a retrospective study using the Swedish Medical Birth Register, Birth Defect Register based on diagnosis at hospital discharge. (6)
• 43,658 infants with malformations were included, of which 1,349 were exposed to ondansetron during the first trimester. 435 exposures were reported by the mother while 914 were identified by the prescription register.
• No statistically significant difference in major malformations was found (OR 0.95, 95% CI 0.72-1.26).
• However, after accounting for some confounding factors the investigators found an increased risk of cardiovascular defects (OR 1.62, 95% CI 1.04-2.14), primarily septal in nature.
• In comparison to the Pasternak et al. study this investigation adjusted for fewer confounders, performed fewer sensitivity analysis and used simpler methods.

• The association of ondansetron exposure during the first trimester and cleft palate originates from Anderka et al., where a 20% prevalence was observed in infants with mother exposed to ondansetron in the first trimester (n = 55) vs 11% in those who were not exposed (n = 4,479). (9)
• This number is relatively high, especially taking into consideration other much larger studies including Pasternak et al. and Danielsson et al. with 1,233 and 1,349 maternal exposures to ondansetron during the first trimester of pregnancy respectively, with no demonstrated increased risk of cleft palates.
• Exposure to ondansetron was based on maternal recall, introducing a  risk for recall bias. Mothers of infants with birth defects are more likely to report exposures than mothers of infants without birth defects.
• The suboptimal methods, strikingly high prevalence and relatively small number of ondansetron exposures (n = 55) make it difficult to associate ondansetron exposure during the first trimester to cleft palates.

• In October of 2015 the FDA denied a petition to do the following. (3)
• Reclassify the drug ondansetron (Zofran) from pregnancy risk category B to category C, D, or X after evaluation of “new safety information”.
• Notify obstetricians and gynecologists (OB /GYNs) that there is insufficient scientifically acceptable evidence that ondansetron is associated with improved treatment outcomes and may lead to adverse maternal and fetal events or outcomes.
• Notify OB/GYNs that promotion of continuous subcutaneous ondansetron pump for the treatment of nausea and vomiting of pregnancy (NVP) is a violation of FDA regulations.

• Dehydration, electrolyte abnormalities, ketosis, nutritional deficiencies and weight loss can also cause fetal malformations. (10)
• Fejzo et al. reported that mothers who took ondansetron reported less miscarriages and higher rates of live births. (11)

1. O’Brien B, Zhou Q. Variables related to nausea and vomiting during pregnancy. Birth. 1995;22:93–100.
2. Ondansetron. In: In Depth Answers [database on the Internet]. Ann Arbor (MI): Truven Health Analytics; 2016 [cited 22 April 2017]
3. https://www.reedsmith.com/files/uploads/DrugDeviceLawBlog/FDA_2013-P-0048.pdf
4. Pasternak B, Svanström H, Hviid A. Ondansetron in pregnancy and risk of adverse fetal outcomes. N Engl J Med 2013; 368:814–23.
5. Andersen JR, Jimenez-Solem E, Andersen NL, Poulsen HE. Ondansetron use in early pregnancy and the risk of congenital malformations—a registry based nationwide cohort study. Pharmacoepidemiol Drug Saf 2013;22:13–4.
6. Danielsson B, Wikner BN, Källén B. Use of ondansetron during pregnancy and congenital malformations in the infant. Reprod Toxicol 2014;50:134–7. 
7. Colvin L, Gill AW, Slack-Smith, et al. Off-label use of ondansetron in pregnancy in Western Australia. Biomed Res Int 2013; 2013:909860.
8. Carstairs SD. Ondansetron use in pregnancy and birth defects: A systematic review. Obstet Gynecol 2016; 127 (5):878-883. 
9. Anderka M, Mitchell AA, Louik C, Werler MM, Hernández-Diaz S, Rasmussen SA; National Birth Defects Prevention Study. Medications used to treat nausea and vomiting of pregnancy and the risk of selected birth defects. Birth Defects Res A Clin Mol Teratol 2012;94:22–30
10. Lee NM, Saha S; Nausea and vomiting of pregnancy. Gastroenterol Clin North Am. 2011 Jun;40(2):309-34.
11. Fejzo MS, MacGibbon KW, Mullin PM. Ondansetron in pregnancy and risk of adverse fetal outcomes in the United States. Reprod Toxicol. 2016 Jul;62:87-91.

Why this is important is several fold. The number of patients taking ACEi is increasing as a result of increasing role in therapy for hypertension, diabetes and heart failure. As this knowledge translation takes place, we are in fact seeing an increase in ACEi usage and AAE. In a retrospective observational study of patients presenting to the ED for angioedema saw a significant increase in the occurrence of angioedema cases over the study’s 5 year period; from ~5.8 per 10,000 presentations to 11.3 per 10,000. (5)

By no means is this any reason to not use ACEi or commentary that we are using too many. In fact, we are likely not prescribing these drugs enough. But as we do, we must be cautious of both ADRs and drug interactions that unnecessarily  increase this risk. This is particularly important given the multitude of new drugs that are, and have come to market that may play a role in the pathophysiology of AAE. These drugs, namely NEP inhibitors and DPP-IV inhibitors, are going unrecognized in their risk in increasing the risk of AAE.

Sacubitril is the latest addition in the drug therapy cache for addressing the neurohormonal imbalance in our current understanding of heart failure (HF) pathophysiology. This drug is by no means hot off the press, since the PARADIGM-HF trial was published back in 2014, it is picking up steam and starting to show up on medication profiles of HF folks in the ED.(6) With the high hopes of improved mortality, reduced hospitalization of this drug (which is co-formulated with valsartan) compared to a non-optimized dose of enalapril, this drug has an ugly side in terms of cost and drug interactions.

Sacubitril’s active metabolite inhibits neprilysin (aka neutral endopeptidase, NEP) allowing for prolonged exposure natriuretic peptides. It’s co-formulated with an ARB (valsartan) rather than an ACE-inhibitor because of whopping increase in the risk of angioedema.

The ill fated predecessor of sacubitril, omapatrilat (a NEP and ACE inhibitor) demonstrated a 2.17% incidence of angioedema compared to 0.68% with ACE-inh (enalapril) alone. This should be of no surprise after reviewing the proposed mechanisms of ACE-inh angioedema.

Briefly, accumulation of bradykinin, causing increased vascular permeability from interaction with the bradykinin-2 receptor and substance P mediated edema, both as a result of ACEi.  Since not all patients receiving ACEi develop angioedema, it is theorized that those who are affected also have deficiencies/abnormalities related to the other enzymes that metabolized bradykinin, namely aminopepdidase P (APP), NEP, DPP-IV, carboxypeptidase N. (7-9)

Looking further into NEP, it is a plasma membrane-bound zinc metalloprotease that catalyzes the metabolism of endothelin 1 (ET-1) and angiotensin II (AngII), as well as the metabolism of other peptides, including bradykinin, ANP, brain and C-type natriuretic peptides (BNP and CNP, respectively), and substance P. NEP is also involved in the enzymatic conversion of big ET-1 to its active form, ET-1. Therefore, the balance of effects of NEP inhibition on vascular tone will depend on whether the predominant substrate degraded by NEP are vasodilators or vasoconstrictors and on the extent of NEP involvement in the processing of big ET-1.(10) Furthermore, when combined with ARB, Ang-II receptor unopposed, thus more vasodilation. However, knocking out two of these pathways with ACE-inh and NEP, increases the risk of angioedema, as demonstrated as a trend in the OVERTURE study and a positive relationship in the OCTAVE study. (11, 12) There is also concern that NEP inhibition itself can potentiate angioedema. In fact, more patients in the treatment arm developed angioedema than did in the enalapril arm of the PARADIGM-HF trial (0.5% versus 0.2%. (6)

Practically speaking, there is a listed drug interaction with ACE-inh and sacubitril to avoid combination therapy and to wait 36 hours from discontinuation of any ACE-inh before initiating sacubitril. (13) However, this interaction has slowly made its way to the third party provided alert software and may not alert providers who are trying to initiate enalaprilat in the ED for patients with acute HF on sacubitril. That is, if they alert isn’t lost among the countless other alerts and “best practice advisories.”

The dipeptidyl peptidase IV (DPPIV) inhibitors are a group of medications used in the management of type 2 diabetes. Inhibition of dipeptidyl peptidase IV (DPP-IV) results in prolonged active incretin levels. Incretin hormones (eg, glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]) regulate glucose homeostasis by increasing insulin synthesis and release from pancreatic beta cells and decreasing glucagon secretion from pancreatic alpha cells. (14) Under normal physiologic circumstances, incretin hormones are released by the intestine throughout the day and levels are increased in response to a meal. These hormones are kept in balance by rapid inactivation by DPP-IV.

Sitagliptin, saxagliptin, and linagliptin are available in the United States and often used in combination with ACE inhibitor and ARB therapy. However, the incidence and prevalence of DPPIV inhibitor associated angioedema is unknown. Never-the-less, healthcare providers should be aware that angioedema has been associated with DPP-IV inhibitors, either alone or when used concomitantly with certain classes of medications, including ACE inhibitors and ARBs.(15-17) In one analysis of vildagliptin (not available in US) with an ACEi compared to an ACEi alone, there was a significant increase in the risk of angioedema to the tune of a 4.57 odds ratio (95% CI 1.57 to 13.28). (18)

If AAE does occur and is as a result of one of these interactions, the treatment options are varied. Depending on the clinical scenario, early intubation may be required to secure the airway, but other strategies are hardly ‘reversal’ strategies, but rather aim to sway the pendulum back to a balanced state by either preventing the production of bradykinin (C1-INH, FFP), enhance breakdown (FFP) or block its activity (Icatibant).  Ultimately, we hope these mechanism would translate into the prevention of airway compromise (which occurs in roughly 4% of Angio cases) or reduction in hospital LOS (which is about 4.8 days).(5)  However, the perceptions of the efficacy in terms of patient-oriented outcomes are often poorly formed as a result of a paucity of high quality evidence. This causes these drugs to be veiled in myth and legend.

Despite the available observational studies, the literature is heavily influenced by publication bias of case reports where these interventions have been linked to positive outcomes. With purified C1-inhibitor concentrate, this story holds true in that they have been effective in case reports (19-23).  This agent appears to be more popular in Europe, with inclusion in the French guidelines for management of ACEI-AAG (24).  Currently there is an ongoing phase III study of C1-inhibitor concentrate so this may change (NCT01843530).

The evidence supporting FFP appears more plentiful, but still subject to publication bias.(25-29). The most common proposed alternative to C1INH or icatibant is FFP. FFP has several advantages that make it a reasonable option; it contains ACE (to breakdown bradykinin) as well as other enzymes (AAP, NEP, etc), additional plasma proteins, relatively inexpensive vs alternatives, and readily available in most hospitals. Unfortunately, FFP does also contain kallikrein, bradykinin itself which can potentially worsen angioedema, the volume required to be administered can be significant to patients with underlying cardiac disease (TACO), requires type/screen, and infusion reactions (TRALI).  Furthermore, there are no controlled trials evaluating the safety and efficacy of FFP in this scenario.

Ecallantide (an expensive recombinant protein that inhibits Kallikrein) has been investigated for management of AAG. One phase 2, double blind dose ranging study of ecallantide in patients with ACEi-AE was stopped early due to futility.(30) While a similarly designed, phase 2, blinded study comparing ecallantide to placebo showed a 10% increase in ability to discharge patients earlier from the emergency department which did not meet the predetermined expected reduction of 50%.(31)  For the price of a pretty decent car the clinical results with Ecallantide have been unimpressive.

Icatibant (FIRAZYR) is a very small peptide which blocks bradykinin-receptors.  Until now, Icatibant was supported by case reports and one uncontrolled study.  Icatibant has some potential advantages over FFP because it is formulated in a lower amount of volume and does not risk viral transmission.  However, it is extremely expensive.

Recently Bas et al. published a prospective RCT in the New England Journal of Medicine comparing Icatibant to antihistamine plus 500 mg of prednisolone plus clemastine 2 mg for management of ACEI-AAG.(32)  All patients were eligible to receive an open label dose of icatibant plus prednisolone if there were no reduction in symptoms by 6 hours after initial treatment.  The primary endpoint was the time to complete resolution of edema as evaluated on the basis of investigator-assessed and patient-assessed symptom scores and investigator’s assessment of the severity of angioedema based on physical exam.  Although the study only included 27 patients in its analysis, it did meet power and was able to demonstrate a significant reduction in the duration of edema in patients who received icatibant compared to standard therapy (8.0 hrs IQR(3.0-16.0) vs 27.1 hrs (20.3-48.0); p=0.002). While hospital admission, LOS and disposition data was not reported, 3 patients in the standard therapy arm required rescue therapy with open label drug administration and one of these patients underwent tracheotomy. By comparing Icatibant to steroid/antihistamine, this trial is effectively comparing Icatibant to a placebo.  Unfortunately, by failing to compare Icatibant to FFP, this study is not very helpful for most clinicians.  Icatibant is enormously expensive and is not widely available.  A study evaluating the utility of FFP would be much more useful to most clinicians throughout the world, especially in less affluent regions.

What is absent from the literature entirely is the utility of these agents in patients with AAE that persists after intubation. In these patients it is not known whether preventing the production of bradykinin (C1-INH, FFP), enhance breakdown (FFP) or block its activity (Icatibant) will shorten the duration of MV and thereby the associated risks to the patient (infection, thrombosis, delirium, etc) as well as the significant cost. A return on investment analysis should take place when considering these drugs in this setting at the hospital administration level. Here at CTMFHC, we took a similar approach with sugammadex, another drug that appears to shorten certain parameters but does not impact patient oriented outcomes (LOS, morbidity or mortality).

1. Cicardi M, et al. Classification, diagnosis, and approach to treatment for angioedema: consensus report from the Hereditary Angioedema International Working Group. Allergy. 2014 May;69(5):602-16
2. Zuraw BL, et al. A focused parameter update: hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor-associated angioedema. J Allergy Clin Immunol. 2013 Jun;131(6):1491-3
3. Lang DM, et al. International consensus on hereditary and acquired angioedema. Ann Allergy Asthma Immunol. 2012 Dec;109(6):395-402
4. Campo P, et al. Angioedema induced by angiotensin-converting enzyme inhibitors. Curr Opin Allergy Clin Immunol. 2013 Aug;13(4):337-44
5. Bluestein HM, et al. Angiotensin-Converting Enzyme Inhibitor-Induced Angioedema in a Community Hospital Emergency Department. Ann allerg asthma immunol 2009;103:502-07
6. McMurray JJV, et al. Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure. N Engl J Med 2014; 371:993-1004
7. Dussaule JC, Stefanski A, Bea ML, Ronco P, Ardaillou R. Characterization of neutral endopeptidase in vascular smooth muscle cells of rabbit renal cortex. Am J Physiol 1993;264(1 Pt 2):F45–F52
8. Stephenson SL, Kenny AJ. Metabolism of neuropeptides. Hydrolysis of the angiotensins, bradykinin, substance P and oxytocin by pig kidney microvillar membranes. Biochem J 1987;241:237–247
9. Vijayaraghavan J, Scicli AG, Carretero OA, Slaughter C, Moomaw C, Hersh LB. The hydrolysis of endothelins by neutral endopeptidase 24.11 (enkephalinase). J Biol Chem 1990;265:14150–5.
10. Ferro CJ, et al. Inhibition of Neutral Endopeptidase Causes Vasoconstriction of Human Resistance Vessels In Vivo. Circulation 1998;97:2323-2330
11. Packer M, Califf RM, Konstam MA, Krum H, McMurray JJ, Rouleau JL, Swedberg K. Comparison of omapatrilat and enalapril in patients with chronic heart failure: the Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE). Circulation 2002;106:920–926.
12. Kostis JB, Packer M, Black HR, Schmieder R, Henry D, Levy E. Omapatrilat and enalapril in patients with hypertension: the Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial. Am J Hypertens 2004;17:103–111
13. Entresto (sacubitril and valsartan) [prescribing information]. East Hanover, NJ: Novartis; August 2015
14. Powers AC, D’Alessio D. Endocrine Pancreas and Pharmacotherapy of Diabetes Mellitus and Hypoglycemia. In: Brunton LL, Chabner BA, Knollmann BC. eds. Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 12e New York, NY: McGraw-Hill; . http://accesspharmacy.mhmedical.com/content.aspx?bookid=1613&sectionid=102162253. Accessed April 27, 2017
15. Brown NJ, et al. Dipeptidyl Peptidase-IV Inhibitor Use Associated With Increased Risk of ACE Inhibitor-Associated Angioedema. Hypertension. 2009;54:516-523
16. Lefebvre J, et al. Dipeptidyl Peptidase IV Activity in Patients With ACE-Inhibitor-Associated Angioedema. Hypertension. 2002;39:460-464
17. Gosmanov AR. Sitagliptin-Associated Angioedema. Diabetes Care Aug 2012, 35 (8) e60
18. Byrd JB, et al. Dipeptidyl Peptidase IV in angiotensin-converting enzyme inhibitor-associated angioedema. Hypertension 2008 Jan;51(1):141-7
19. Nielsen EW, Gramstad S. Angioedema from angiotensin-converting enzyme (ACE) inhibitor treated with complement 1 (C1) inhibitor concentrate. Acta Anaesthesiol Scand. 2006 Jan;50(1):120-2
20. Hermanrud T, Duus N, Bygum A, Rasmussen ER. The Use of Plasma-Derived Complement C1-Esterase Inhibitor Concentrate (Berinert®) in the Treatment of Angiotensin Converting Enzyme-Inhibitor Related Angioedema. Case Rep Emerg Med. 2016;2016:3930923
21. Urnoski E, Grillo A, Rosini JM.Use of C1 Inhibitor for Angiotensin-Converting Enzyme (ACE) Inhibitor-Induced Angioedema Decreases Mechanical Ventilation Time.J Emerg Med. 2015 Dec;49(6):e173-5
22. Lipski SM, Casimir G, Vanlommel M, Jeanmaire M, Dolhen P. Angiotensin-converting enzyme inhibitors-induced angioedema treated by C1 esterase inhibitor concentrate (Berinert®): about one case and review of the therapeutic arsenal. Clin Case Rep. 2015 Feb;3(2):126-30
23. Rasmussen ER, Bygum A.ACE-inhibitor induced angio-oedema treated with complement C1-inhibitor concentrate. BMJ Case Rep. 2013 Oct 4;2013
24. Nosbaum A1, Bouillet L, Floccard B, Javaud N, Launay D, Boccon-Gibod I, Fain O; Groupe d’experts du CREAK; French National Center for Angioedema. [Management of angiotensin-converting enzyme inhibitor-related angioedema: recommendations from the French National Center for Angioedema]. Rev Med Interne. 2013 Apr;34(4):209-13. doi: 10.1016/j.revmed.2012.12.017. Epub 2013 Feb 4. [Article in French]
25. Karim MY, Masood A. Fresh-frozen plasma as a treatment for life-threatening ACE-inhibitor angioedema. J Allergy Clin Immunol. 2002 Feb;109(2):370-1
26. Warrier MR1, Copilevitz CA, Dykewicz MS, Slavin RG. Fresh frozen plasma in the treatment of resistant angiotensin-converting enzyme inhibitor angioedema. Ann Allergy Asthma Immunol. 2004 May;92(5):573-5
27. Stewart M, McGlone R. Fresh frozen plasma in the treatment of ACE inhibitor-induced angioedema. BMJ Case Rep. 2012 Aug 24;2012. pii: bcr2012006849
28. Bolton MR, Dooley-Hash SL. Angiotensin-converting enzyme inhibitor angioedema. J Emerg Med. 2012 Oct;43(4):e261-2
29. Hassen GW, Kalantari H, Parraga M, Chirurgi R, Meletiche C, Chan C, Ciarlo J, Gazi F, Lobaito C, Tadayon S, Yemane S, Velez C. Fresh frozen plasma for progressive and refractory angiotensin-converting enzyme inhibitor-induced angioedema. J Emerg Med. 2013 Apr;44(4):764-72
30. Lewis LM, Graffeo C, Crosley P, Klausner HA, Clark CL, Frank A, Miner J, Iarrobino R, Chyung Y. Ecallantide for the acute treatment of angiotensin-converting enzyme inhibitor-induced angioedema: a multicenter, randomized, controlled trial. Ann Emerg Med. 2015 Feb;65(2):204-13
31. Bernstein JA, Moellman JJ, Collins SP, Hart KW, Lindsell CJ. Effectiveness of ecallantide in treating angiotensin-converting enzyme inhibitor-induced angioedema in the emergency department. Ann Allergy Asthma Immunol. 2015 Mar;114(3):245-9
32. Bas M, et al. A Randomized Trial of Icatibant in ACE-Inhibitor–Induced Angioedema. N Engl J Med 2015; 372:418-425