“Careless Arithmetic Nullifies Careful Compounding”1, a paper published in the Journal of the American Pharmaceutical Association in 1951, was assigned in my first pharmacy compounding lab class in fall 1964 at the University of Florida. When graduating three years later, I knew the paper title was too forgiving and should have been titled, "Careless Arithmetic Is Careless Compounding."
Among several harmful examples over ensuing years, the most poignant incident was Martha Alice Covert’s death at Charlotte Memorial Hospital in June 1988 from pharmacist-compounded hydrochloric acid (HCl) intravenous (IV) infusion. She died from "high potassium levels as a result of infusion of highly acid fluid."2 In brief, pharmacist(s) had stuck a handwritten note that said 1 Normal (N) over the manufacturer’s bottle label that was printed 36.5% w/w (= 43.1% w/v and 11.8 N HCl). Instead of 0.15 N or 0.55% w/v HCl as the doctor ordered, and Martha received 1.8 N or about 6.6% w/v; in other words, 12 times too strong a concentration!
I have memorialized her preventable death as an assignment in my parenteral therapy elective course the past 18 years, a raison d’être for strict ingredient purity and strength requirements when leading creation of U.S. Pharmacopeia (USP) Chapter 797 and as the first citation in my 1989-2013 timeline history of USP797.3
Twenty-seven years ago, pharmacists would have had better pre-pharmacy and in-pharmacy chemistry education than graduates of the PharmD-only era;4 thus, the Charlotte Memorial error is particularly troubling. Since circa 1970, compounding has seen the introduction and/or growth of:
Hospital IV drug and nutrition therapy
Guidance documents from the American Society of Health-System Pharmacists (ASHP)
Specialty community pharmacies and certification, supply, and training businesses
Enforceable and informational USP chapters
Regulatory guidance documents from the FDA
The International Journal of Pharmaceutical Compounding (IJPC)
Casualties and lawsuits predominantly from what should-have-been sterile preparations.
By circa 1990, pre-pharmacy students began learning less chemistry and math, and pharmacy students less compounding. Why? Please see the appendix below for selected pre-pharmacy school factors. While once in pharmacy school some of those reasons persist, the following causes are exclusive:
The Accreditation Council for Pharmacy Education's (ACPE) requirement to increase active learning, which I’ve witnessed to be as much or more entertaining – and frustrating - than educational. Why has passive learning begun to fail in just the past 10 or so years, after having well-served pharmacy and all of humanity for the past several hundred? The following are four “quick and dirty” checks I learned actively in lab and passively in lecture from freshman college chemistry. Any of them could have readily differentiated 36.5% w/w from 1N HCl, i.e., could have spared Martha Alice Covert from HCl overdose. If you polled beginning pharmacy students since 1995, a majority may know one of these; a minority, two; a smaller minority, three; none of these students would know all four:
A drop of 36.5% rapidly chars or burns a hole in paper; 1 N does not.
Each mL of 36.5% weighs about 0.16 g more than 1 N, so weigh the same volume of each.
Fumes evolve from 36.5% and cause instant eye-nose irritation when the bottle is too close and not (properly) in an exhaust hood, those events do not occur with 1N.
36.5% added to an equal to two times volume of water in a small glass container rapidly becomes very hot; 1N does not.
ACPE's increasing requirement for vocational training credits (“experiential education” is ACPE’s euphemism), which decreases time and respect for the pharmaceutical sciences and compounding.4-6 The 5-year BS in Pharmacy included 0-15% experiential learning in its three professional years credits over its 1964-2003 accreditation lifespan. Experiential learning now commands 30% or more of professional credits in current PharmD curricula. Furthermore, BS education merited at least 10-12 compounding credits; the four professional years of the 6-year PharmD may have fewer than 3.
The experiential surge, ironically, has reduced a prime active learning source, namely hands-on compounding and pharmaceutical sciences labs. Schools, when faced with a choice between these two high expense endeavors (in money, people and time), mostly give up their labs. Consequently, pharmacists acquire less chemical, physical and organoleptic drug knowledge, which historically has been paramount among healthcare professionals. Drug expertise is increasingly narrowed to drugs in the body (clinical therapeutics) while the knowledge disappears for drugs in the bag, bottle, pump, reservoir, syringe, tubing and vial before entering the body.
Long before ACPE emerged in 1932, pharmacists in practice had been "cutting corners" off their formal education and training. This readily observable, but seldom acknowledged; experiential shortcoming can be costly, harmful, and deadly − especially when the practice is sterile compounding. About 100 years ago, the insufficiencies and inefficiencies of apprenticeship to become a pharmacist and internship to become a physician were superseded by science-based curricula. Is pharmacy education coming full circle?
My 51 years since meeting "Careless Arithmetic Nullifies Careful Compounding" have included hospital total parenteral nutrition and other sterile compounding in the 1970s and 1980s, serving on USP compounding advisory panels and expert committees since 1993, being a consultant on cases of patient deaths and risks from sterile compounding since 1996, authoring and presenting scores of papers and talks on compounding, and spending the past 39 years teaching pharmaceutical calculations, pharmaceutics, pharmacokinetics, and parenteral therapy.
In reflection thereof, I offer the following replacement title: “Careless Compounding by a Few Pharmacists Cheats, Hurts and Kills Patients; Impugns Competent Pharmacists; and Nullifies Their Own Education and Reputation.”
Suppose that at the New England Compounding Center (NECC) in 2012 the converse effect of the 1988 Charlotte Memorial error had occurred. If NECC had made a big careless arithmetic mistake in the strength of their methylprednisolone acetate (MPA) injectable suspension, but made it sterile (i.e., careful compounding) then the largest quantity of dead and injured patients in U.S. history from a single product from a single compounding pharmacy3,7 would have been nullified. Why so? Unlike HCl, MPA is a wide therapeutic range drug, and its effectiveness and safety by epidural injection have not been adequately evidenced to earn FDA approval since it premiered as Depo-Medrol® in 1959. NECC wasn’t the first, but to date is the foremost proof that careful arithmetic does not nullify careless compounding.
A perfect storm of grade 1 through pre-pharmacy college factors that synergistically decrease ability and desire to learn math and science, and; thus, underlie poorer math, science and compounding competence by post-1990 pharmacy students and graduates.*
*Please insert "some" anywhere it is deemed appropriate.
Students and parents faulting teachers for making students feel bad by assigning justly earned “C” and lower math and science grades where "A" and "B" for effort do not nullify inaccurate, wrong and deficient answers and explanations.
Teachers forgiving and forgetting students’ grammar, spelling, math, and science errors to avoid low evaluations and administrative reprimands or worse, resulting in grade inflation, lessened learning achievement and appetite, and student appeasement.
Students being academically rewarded to memorize short-term for school and standardized tests instead of comprehending for the next education level and life.
Students being distracted and preoccupied with entertainment and social media on their portable electronic digital devices.
If you doubt or reject these, then please cogently explain otherwise:
The paradox of unprecedented large quantities of American pre-college “honor students” concurrent with mediocre international standing on math, reading and science achievement tests.
1. Goldstein SW, Mattocks AM. Careless Arithmetic Nullifies Careful Compounding. J Am Pharm Assoc. 1951;XII:485-487.
2. Garloch K. Hospital Error Involved a Few Decimal Points. The Charlotte Observer. 1989, April 8:1A,4A.
3. Newton DW. United States Pharmacopeia Chapter <797> Timeline: 1989-2013. IJPC. 2013;17:283-288.
4. Newton DW. The ps in Therapeutics. IJPC. 2012; 16:58-61.
In 1990 the American Council for Pharmaceutical Education, ACPE, announced a minimum 6-academic year Doctor of Pharmacy as the professional entry degree accredited for students entering in and after year 2000. In 2003 ACPE was renamed Accreditation Council for Pharmacy Education when it ended accreditation of 5-year B.S. in Pharmacy graduates since 1964.
5. Newton DW. Science-based Pharmacy Education. Am J Pharm Educ. 2007; 71(2) Article 38 (http://www.ajpe.org/view.asp?art=aj710238&pdf=yes), accessed July 16, 2015.
6. Newton DW. Compounding Paradox: Taught Less and Practiced More. Am J Pharm Educ. 2003; 67(1) Article 5 (http://www.ajpe.org/view.asp?art=aj670105&pdf=yes), accessed July 19, 2015. Reprinted with permission in IJPC. 2003; 7:399-400.
7. Centers for Disease Control and Prevention. Multistate Outbreak of Fungal Meningitis and Other Infections. October 23, 2013 (http://www.cdc.gov/hai/outbreaks/meningitis.html), accessed July 15, 2015.