Showing posts with label drug safety. Show all posts
Showing posts with label drug safety. Show all posts

Wednesday, August 1, 2018

The Problem With Checklists.....





I have critiqued the checklist approach to psychiatry in many posts on this blog.  Several like-mind psychiatrists have also added many comments in this area. I had recent experience with surgical checklists that leave a lot to be desired.  So much so that if I was not an MD - I might not be sitting here and typing this post right now.  For now, I will just post the bare bones sequence of events for illustrative purposes.  On April 14, I had an operative procedure that required antibiotic prophylaxis that consisted of a single intravenous dose of antibiotics given right before surgery. On July 31, I had a second operative procedure to address complications of the first procedure. Both procedures were done under general anesthesia (fentanyl and midazolam or Versed).  A laryngeal mask airway (LMA) was used instead of intubation.  The general sequence of events went like this.

1.  Preop physical exam - good for 1 month prior to surgery.  The exam is done by a primary care MD.  The surgery will not occur without it.  The goal is to identify and complicating or potentially contraindicating conditions.  Specific instructions are given to the surgeon and anesthesiologist based on this assessment.  Specific instructions are given to the patient about if they need to change up their medications at all prior to the surgery.  For example, it is common advice to hold aspirin and other anti-inflammatory medications (NSAIDs), and certain vitamin supplements for 1-2 weeks prior to the surgery.

2.  Hospital intake - over the hour or two before surgery there are intense meetings with a number of disciplines:

Pre-Op RN:  Reviews the medication list and confirms that all of the recommended medications and pre-op instructions were followed.  Assesses functional capacity as well as presence of eyeglasses, hearing aids, implants, pacemakers, CPAP mcahines and artificial joints.

Pharmacist:  Reviews the detailed list of medications and looks for potential drug-drug interactions as well as drug-anesthesia interactions.

Anesthesiologist:  Reviews the detailed list of medications and rationale.  Takes a detailed cardiovascular history. Examines heart and lungs.  Asks detailed family history and personal history for anesthesia interactions particularly malignant hyperthermia. In both cases this hospital trained nurse anesthetists who asked the same questions and administered the pre-op midazolam before leaving the pre-op area.

 OR Nurse:  Also interviews patient about concerns over the surgery and assures that all intravenous lines and devices that will be in the operating room (OR) are present and working.

That is the overall sequence of events.  Each of these team members has specific jobs and checklists that were entered into an EHR.  The primary care physician handed me a copy of my pre-op exam to take with me in case the faxed version was lost.  It was printed out from a well known enterprise wide EHR.

I have a condition called lone atrial fibrillation that is commonly seen in middle-aged (and now old) men who exercise too much.  It was originally thought to be associated with high levels of dynamic exercise like cycling and running, but epidemiological studies suggest it may also be associated with jobs that require a lot of heavy lifting - like furniture and piano moving.  I have also talked to power lifters in the gym who developed it when they continued the lifting into their 50s and 60s.  I take flecainide and it keeps me in a steady sinus rhythm and that has worked well for the past 8 years.  The problem with flecainide is that it is a fairly toxic medication if you have the wrong biological substrate or if you mix it with the wrong medications. A trial of flecainide in ventricular tachycardia was halted because of increased fatalities in the treatment group compared to placebo.  The last electrophysiologist I talked with suggested that I needed to get an exercise stress test done every year to make sure that the QRS interval was not widening due to the drug.  For the purpose of these surgeries my primary concern was not getting a medication that would interact with flecainide and result in a fatal arrhythmia.  I knew that this surgical specialty used fluoroquinolones preoperatively and if you search that interaction in any database this is a typical result.           

"Moderate risk - can cause QTc prolongation and should be avoided when possible. Increased risk for torsades de pointes and other significant ventricular arrhythmias.  Other factors (old age, female sex, bradycardia, hypokalemia, hypomagnesemia, and higher concentrations of the interacting drugs can increase risk for potential life-threatening arrhythmias."

I naturally wanted to avoid the fatal arrhythmia.

At every step in the above chain, I explained this drug interaction and advised the team members that I can safely take cephalosporins.  And here is what happened.

In both cases I had the same primary care MD doing the pre-op physical exam.  He was very focused on the pre-op checklist and in fact the rooming medical assistance reviewed the med list, vital signs, and review of systems that was entered into the EHR checklist before I saw the physician.  When he was done he asked me if I had any concern and I told him "Any antibiotic or anesthesia agent that interacts with flecainide - I do not want to take. I know that I can take fentanyl and Versed for general anesthesia so those are the preferred agents if they can use them for this surgery."  The first time he pulled up the interaction in the EHR, agreed and said - "I will flag this in my assessment so they see it."  The second time he said the same thing but reviewing the H & P he handed me it was not present.  It is possible it was transmitted on another form.

And so it went with every members of the preop team.  They all seemed surprised every time I brought it up.  They thought I was talking about an allergy as opposed to a drug-drug interaction. One of the pharmacists looked it up on her Smartphone app and confirmed.  There was a lot of confusion about the preop antibiotic right up until the time of administration.  Was there another drug that could be used? Would the doctor change the standard orders to administer another drug?  For the past surgery - I had to tell them to look up the April record and confirm that I was given 2 grams of IV cefazolin and not levofloxacin.

When it was finally clarified, it took two nurses to figure out how the levofloxacin could be discontinued from the standard order in the EHR so that the cefazolin could be given.  I was finally given the cefazolin, operated on and so far (barring another complication) things are going well.

The lessons:

1.  Almost everything you hear about the EHR and checklists increasing safety is a myth -  

In this case all of the professionals were using state of the art (and extremely expensive) EHRs containing checklists and forms that were dutifully completely and the ultimate check here was the patient who happened to be a physician who compulsively studies drug interactions and cardiac complications.  That is not a level of safety that I want to see for any of my family members or patients who are undergoing surgery.

2.  Patients or competent family members are the best safeguards for safety at this point -     

I have worked with very bright and insightful nurses who told me that they have a rule that they accompany hospitalized colleagues and check everything that is going to happen to them as well as what medications are administered to them.  On the other hand I have asked patients what medications they take and been told: "You tell me doc.  I just put them in a pill container.  I don't know the names, doses or what they do."

There is a lot of talk about patient empowerment, but it has to be built on a solid foundation of patient literacy.  I certainly realize that a lot of people do not want to know, but I have also talked with many people having less than a high school education who could tell me every drug they took during a complicated course of cancer treatment that included a bone marrow transplant.  Reading and understanding the pharmacy printout given with a medication is a basic prerequisite for the literacy I am talking about. 

3.  This is a systems problem and not a personnel problem -  

Let's face it - all of the personnel in the system are highly competent licensed professionals. They are all focused on their tasks and they do a good job of it.  The problem is that all of these very competent individual assessments are not synthesized into a useful safety plan.  Experts have been writing about the importance of checklists in industry (like the airline and automotive industries) for decades but medical information is individualized complex, and not redundant.  Any adverse outcome of the sequence of events that I described is likely to be something like this:

"Well Dr./Nurse X - did you fail to read all of the narratives in the chart and the patient stating that he had concerns about drug interactions with flecainide?"

Any response to the effect that the EHR is difficult to read and in some cases incoherent and should have flagged this concern automatically is likely to be met with:

"Well that's our EHR and we have to live with it. Our focus groups with the nurses and the manufacturer have been working on fixes for the past 5 years."

Translation:  somebody has to take the blame and it won't be the EHR.



4.  Why doesn't the EHR/checklist approach work? 

It failed miserably - not just once but twice in my case and I was advocating at every level to flag flecainide and not give me any interacting drug.  Having worked with EHRs now for nearly 20 years I can speculate on a few things.  First, there is very little intelligence built into EHRs.  In this case the EHR will do a comprehensive drug interaction search on the current list.  But there is probably not an automatic search on the standard preop antibiotic.  If there is - physicians are numbed to dismissing so many false positive drug interactions that could have happened as well. Second, any discussion of the patients concern or doctors advice is buried in documentation that is prioritized for billing, rarely read, and not translated into any rational action. An intelligent EHR would convert the concern about flecainide interactions into what is called a hard stop. That means the potentially offending drug could not be ordered until some further action was taken - like a discussion between the physician, pharmacist, and patient.  In this case, my discussion with 10 people was not beneficial and the only reason I did not get levofloxacin was that I was in a hospital bed about 6 feet away from where the nurse was working and I was a physician who has worked for years to prevent these kinds of problems.

It is hard to believe that such extremely expensive and heavily lobbied systems can't provide a basic level of safety.  I was not surprised to read that having the same primary care physician for years is probably a better assurance of longevity.

For the non-medical person reading this - know your medications, what they do, and what the potential safety concerns are when you are in a situation where those medications are being changed. Ask your pharmacist and physician to do a drug interaction search to make sure these transitions can be safely made. Refuse any medication unless a sound rationale can be provided to you about why you are taking the drug and how safe it is to take with your current prescriptions.


George Dawson, MD, DFAPA

     
Graphics Credit - the graphic at the top is from Shutterstock per their standard licensing agreement.








Wednesday, May 31, 2017

Minnesota Street Drug Bulletin - Designer Benzodiazepines


Benzodiazepine structures clonazepam (upper left) and alprazolam (lower left) are both prescription benzodiazepines.  Clonazolam (upper right) and etizolam (lower right) are not. 



Designer benzodiazepines are benzodiazepine class drugs that are not approved for therapeutic use in any country.  They are analogues that were synthesized by drug companies, and in some cases went to clinical trials and published results but never made to to market.  The name makes is seem like there are chemists out there synthesizing these drugs for a purpose, but there are not.  They are all part of the original research for benzodiazepine class medications that has not really seen any innovation in decades.  These drug are a current problem because there are online sources allow people to purchase them in tablet, capsule, powder, and blotter form.  There are several online venues where users talk about their experience and which drug creates the "best" high.  Medical staff need to realize that many of these drugs are undetectable as molecules.  They show up as "false positives" in standard toxicology testing largely due to a lack of reference material.  Drug users are often told that the drug is undetectable in standard toxicology assessments and that the drugs are also not listed as a standard prohibited substance and therefore it is a "legal" high.  That is a fairly weak argument when users are overtly intoxicated and sustain all of the consequences of intoxication.

Just as a check I looked at a list of 13 designer benzodiazepines (1) (clonazolam, deschloroetizolam, diclazepam, estazolam, etizolam, flubromazepam, flubromazolam, flutazolam, 3-hydroxyphenazepam, meclonazepam, nifoxipam, phenazepam, and pyrazolam) and compared them to the most recent posted list of Controlled Substances from the DEA.  Only one of those compounds (estazolam) is listed on the most current list dated 05-May-17.  It is listed as a Schedule IV drug.  I have no way of knowing which compounds are being considered for the list.  Just being on the list does not deter the illegal sale of controlled substances, but the designer designation generally means that there is far less known about the drug in terms of safety.  In some cases the toxicology lags behind exposures because the physicians treating intoxication, withdrawal, and overdoses with these compounds are uncertain about what they are treating.  The patient or collateral contacts of the patient may not know what the drug is and that lag time creates additional danger for the patient.     

The first time I searched for clonazolam on Medline, I was impressed with the fact that there were only 5 references in the medical literature including the analysis reference that listed 13 designer benzodiazepines.  In fact, they all had to do with analysis but also described the complications of intoxicated driving (2) while taking them and the complications of life threatening intoxication (3).  The minimal online information available suggests that it has very high potency.  There are doses suggested in the range of high potency benzodiazepines but there are no clinical applications.  As a result, there are no FDA package inserts or even reliable data from other agencies.  It is not listed in the British National Formulary (bnf.org).  Despite this lack of clinical information and application, it is immediately obvious that large quantities are available for purchase online.  On these sites it is described as a research chemical with no clinical applications.  It is also described as not for human consumption - a label I am familiar with from synthetic cannabinoids.  The current problem is that as long as this chemical or its precursors are not listed as controlled substances anyone can purchase it for any purpose.  The suggested prices quoted for this drug are far below the street price of diverted prescription benzodiazepines.  That makes these compounds ideal for illegal trafficking.

Searching etizolam on Medline resulted in 96 references and 13 clinical trials.  Some of the trials were as recent as 2009.  The trials were for anxiety disorders and based on the abstracts the results sound equivocal ranging from improvement over 4 weeks to (4) to no improvement (5).  The striking feature of the trials is the dose of etizolam being 0.5 mg BID indicating that it is a high potency benzodiazepine.  The fact that several studies were done and the drug was never approved suggests either the lack of sufficiently powered studies or some side effect that was obvious only to the pharmaceutical company or regulators.  In some cases the drug is also too difficult to use clinically.  There are several examples of benzodiazepine class medications that were determined to be problematic after use and either banned at that point or an additional warning was issued.      

One of the more disturbing trends recently in the number of benzodiazepine compounds that are involved in polypharmacy overdoses.  In the most recent analysis of overdoses by the CDC -  2 of the top 10 compounds were alprazolam and diazepam - both prescription benzodiazepines. In both cases 95% of these overdoses involved concomitant drugs.  In the US, 30% of fatal opioid overdoses involve benzodiazepines. Due to the current problems with analysis, it is highly likely that designer benzodiazepines involved in overdose deaths are not detected. This is a compelling reason to not use designer benzodiazepines.  

Reading through some of the web sites that promote the use of these compounds, it is ironic that there are messages out that that these drugs can be used safely with adequate research by the user on the Internet.  Prescription medications are understood to have qualified safety when they are approved by the FDA and prescribed by a qualified physician.  There are still completely unanticipated reactions and these approved medications are not generally tested with other addictive compounds.  There are reactions that can only be detected by pharmacosurveillance of a much larger database.  In the case of these designer benzodiazepines, they are not approved, not prescribed, and highly potent drugs being sold by sources with no responsibility to the user.

Anyone seeking to get high in that context should be questioning the value of getting high.


George Dawson, MD, DFAPA



References:

1:   Pettersson Bergstrand M, Helander A, Hansson T, Beck O. Detectability of designer benzodiazepines in CEDIA, EMIT II Plus, HEIA, and KIMS II immunochemical screening assays. Drug Test Anal. 2017 Apr;9(4):640-645. doi: 10.1002/dta.2003. Epub 2016 Jul 1. PubMed PMID: 27366870.

2:  Høiseth G, Tuv SS, Karinen R. Blood concentrations of new designer benzodiazepines in forensic cases. Forensic Sci Int. 2016 Nov;268:35-38. doi: 10.1016/j.forsciint.2016.09.006. Epub 2016 Sep 16. PubMed PMID: 27685473.

3: Łukasik-Głębocka M, Sommerfeld K, Teżyk A, Zielińska-Psuja B, Panieński P,Żaba C. Flubromazolam--A new life-threatening designer benzodiazepine. Clin Toxicol (Phila). 2016;54(1):66-8. doi: 10.3109/15563650.2015.1112907. Epub 2015 Nov 20. PubMed PMID: 26585557.

4: Savoldi F, Somenzini G, Ecari U. Etizolam versus placebo in the treatment ofpanic disorder with agoraphobia: a double-blind study. Curr Med Res Opin. 1990;12(3):185-90. PubMed PMID: 2272192..

5: De Candia MP, Di Sciascio G, Durbano F, Mencacci C, Rubiera M, Aguglia E, Garavini A, Bersani G, Di Sotto A, Placidi G, Cesana BM. Effects of treatment with etizolam 0.5 mg BID on cognitive performance: a 3-week, multicenter, randomized, double-blind, placebo-controlled, two-treatment, three-period, noninferiority crossover study in patients with anxiety disorder. Clin Ther. 2009 Dec;31(12):2851-9. doi: 10.1016/j.clinthera.2009.12.010. PubMed PMID: 20110024.