We’ve done several columns on problems with methotrexate (see our What’s New in the Patient Safety World columns of July 2010 “Methotrexate Overdose Due to Prescribing Error” and July 2011 “More Problems With Methotrexate”). But most of the issues have focused on the erroneous prescription and administration of daily doses of methotrexate (as are used for oncological indications) instead of once weekly doses that are used for rheumatoid arthritis (RA) or other autoimmune diseases.
There are actually several other dangers associated with low-dose methotrexate, as outlined by a recent ISMP Canada Safety Bulletin (ISMP Canada 2015). They provide details of 3 incidents of methotrexate toxicity in patients with RA or other autoimmune diseases.
In the first incident a patient with RA and renal dysfunction and hypoalbuminemia doubled his weekly methotrexate dose (without his prescriber’s knowledge). This coincided with a course of amoxicillin and initiation of leflunomide therapy. The patient developed severe pancytopenia and died. The severe methotrexate toxicity was attributed to the doubled dose, the underlying risk factors (renal disease and hypoalbuminemia), and the drug interactions with amoxicillin and leflunomide.
In the second incident a patient on weekly methotrexate for RA was hospitalized with a fracture and was begun on diclofenac. Renal failure, pancytopenia, and death followed.
In the third incident a patient with an autoimmune disorder was prescribed a once weekly dose of methotrexate but the pharmacy dispensed a 3-month supply with instructions to take the medication daily. The patient developed severe harm necessitating prolonged hospitalization.
The ISMP Canada safety bulletin notes risk factors for methotrexate toxicity as renal dysfunction, hypoalbuminemia, and certain concomitant medications (like NSAID’s and proton pump inhibitors). They stress the importance of careful monitoring if one of these medications must be used. They also note that folate supplementation be considered to reduce GI and hepatic side effects.
The ISMP Canada article has several very practical recommendations for IT systems, prescribers, and pharmacists.
On the IT side, it recommends that CPOE and pharmacy IT systems should default to a weekly dose. If a daily dose is ordered there should be a hard stop requiring input of the indication and duration of treatment. It recommends provision of an alert about potential serious adverse effects of daily dosing, particularly in patients with some of the above risk factors or taking any of the interacting medications, with suggestions for monitoring. It also suggests linking lab results to order entry for methotrexate (eg. CBC, LFT’s, albumin, creatinine) so the prescriber and pharmacist can be reminded to check for risk factors and be reminded of parameters they may need to monitor.
It also recommends a robust drug-drug and drug-disease interaction module for methotrexate. That one is the most problematic. We already know that drug-drug and drug-disease and drug-food alerts are among the alerts most often ignored by prescribers. Many EHR’s and CPOE or e-prescribing systems allow for configuration of alerts to allow only certain more serious alerts to be shown. But some do not allow selective enabling of these alerts (i.e. allowing drug-drug or drug-disease alerts for just high alert medications as opposed to all medications).
On the prescriber side it recommends baseline values for parameters that may need to be monitored during therapy (eg. CBC, LFT’s, creatinine) and notes that a good order entry system could prompt the provider to order these at the time methotrexate is being ordered. It also has recommendations for frequency of monitoring these parameters, screening for hepatitis B and C and HIV prior to initiating therapy, and considering folate supplementation.
It has 2 excellent recommendations to avoid the error of patients getting daily methotrexate rather than intended once weekly methotrexate:
It also reminds the prescriber to ask the patient about specific prescription and any OTC medications they may be taking that could increase the likelihood of methotrexate toxicity.
On the pharmacist side it recommends a forcing function be developed to ensure that every prescription of methotrexate is reviewed with the patient (or caregiver). The patient should be counselled and given written information about methotrexate and stress the importance of adhering to the prescribed dose and monitoring. If folate supplementation has not been prescribed the pharmacist should contact the prescriber. The pharmacist should follow up on any drug interaction alerts that may appear and discuss with the prescriber and patient. Specific discussion about OTC medications or other medications known to interact with methotrexate should occur. And, again, the supply dispensed should only be for 4 weeks.
Most of the same recommendations appear in a recent article in the rheumatology literature (Blank 2015). This article has a couple more practical recommendations. It notes that use of a “dose pack” may help guide patients to take the proper weekly dose for non-oncologic indications. When reviewing the dosing schedule with patients it is important to explain that taking extra doses is dangerous and discuss that the medication is not to be used “as needed” for symptom control. Have the patient repeat back the instructions to validate that he or she understands the dosing schedule and toxicities of the medication if taken more frequently than prescribed.
In our July 2011 What's New in the Patient Safety World column “More Problems With Methotrexate” we noted that the patient in a long-term care facility may be especially vulnerable. In such cases, the original order for methotrexate is usually written by a specialist. The patient is then followed in the LTC facility typically by a primary care physician who may be less knowledgeable about the particular use of methotrexate for that condition. Also, the LTC patient may not be seen by a physician for periods as long as a month. And many LTC patients have cognitive impairments that might prevent them from understanding issues about their medications. So if a medication reconciliation error has occurred and a patient intended for once weekly dosing is now on daily dosing, the opportunity for toxicity is greatly increased. So LTC facilities should take steps to ensure that any of their residents taking methotrexate get the same level of supervision and protections that non-LTC patients would get.
Methotrexate can be a very effective drug for RA and other autoimmune diseases and is usually well tolerated. But, as the above examples demonstrate, even low-dose methotrexate can be associated with severe toxicity in certain circumstances. It is thus for good reasons that ISMP (US) includes methotrexate on its list of high alert medications. ISMP also provides a great consumer leaflet with safety tips for patients taking methotrexate.
ISMP Canada. Severe Harm and Deaths Associated with Incidents Involving Low-Dose Methotrexate. ISMP Canada Safety Bulletin 2015; 15(9): 1-5
Blank C. 10 Ways to Avoid Fatal Methotrexate Errors. Rheumatology Network 2015; December 2, 2015
ISMP (Institute for Safe Medication Practices). ISMP List of High-Alert Medications in Community/Ambulatory Healthcare.
ISMP (Institute for Safe Medication Practices). Consumer Leaflet with Safety Tips for Methotrexate. 2013
AORN (Association of periOperative Registered Nurses) has updated its guideline to prevent retained surgical items (Putnam 2015). The updated guideline stresses the importance of creating a culture and environment that promotes safety and communication. It highly recommends formal training programs, such as TeamSTEPPS™, that improve teamwork, promote respect and recognition of the role everyone in the OR plays, standardize communication, promote hearback, and break down hierarchical barriers so that all team members feel free to speak up at any time. The update also stresses the importance of limiting distractions to ensure accurate counting. Doing the initial count before the patient enters the OR is a start at avoiding distractions but it is important to create “no-interruption” zones when counts are being done, eliminating non-essential conversations and background noise and ensuring everyone’s attention is focused on the task at hand, akin to the “sterile cockpit” concept in aviation.
The guideline outlines best practices for counting using methods that are consistent and standardized. It recommends that the RN circulator and the scrub person perform the counts (with the same individuals performing the initial count and all subsequent counts). Both individuals should view the items (one separates and points out each item and counts audibly).
Counts should occur:
Putnam notes the scrub person should discard all surgical soft goods into a kick bucket immediately after use and the RN circulator should organize them in a pocketed sponge bag or similar system, which helps separate the items from one another and increase visibility for counting. Sponge pocketing systems are widely used now, with transparent units typically with 5 rows of 2 pockets so there is a total of 10 sponges per unit.
Count sheets and count boards should be used to avoid miscommunication and make sure all OR participants understand the status of the count(s). The sequence of the count should follow the order in which they are listed on the sheets and boards (standardization usually follows a proximal to distal sequence, e.g. first the surgical field, then Mayo stand, back table, and soft goods that have been discarded into a kick bucket).
Putnam also stresses the importance of perioperative personnel immediately inspecting on their removal from the surgical site all instruments and any attached labels for signs of damage or fragmentation. Small retained fragments from these may be particularly difficult to find because they often do not show up on X-rays.
Verna Gibbs, MD, one of the founders of the No Thing Left Behind campaign recently had some practical advice in Outpatient Surgery Magazine on preventing RSI’s (Gibbs 2015). In discussing the factors associated with RSI’s Gibbs, whose work we have highlighted in most of our previous columns on RSI’s listed below, categorizes 3 separate clinical scenarios:
The first type, Gibbs says, is most commonly seen in the obstetrical environment. She notes that perinatal birthing rooms often use gauze sponges that lack radiopaque markers and often do not have formal sponge management practices. That probably accounts for why the vagina is the second commonest site for RSI’s (after the abdomen). But she notes those same factors often occur in cardiac cath labs and sponges may be left behind after pacemaker implantations. This category accounts for about 10% of RSI cases. The second type (correct-count retention cases) accounts for about 70% of all retention cases. And the third type, incorrect-count retention cases, accounts for about 20% of cases.
One problem we’ve seen over and over occurs when there is a discrepant count and the sponge is later found. This gives rise to many surgeons complacently dismissing discrepant counts with statements like “The count was off in our last case and we found the sponge later”. We’ve seen near misses when that occurs and the staff speak up and insist an X-ray be performed, which finds the missing sponge in the patient.
Gibbs also points out one of what we’ll call an unintended consequence of teamwork: relegation of individual accountability to the team. She notes that “people often downplay the importance of their own roles when they know that more than one person has to slip up for a mistake to happen”. When we do team training and discuss the fact that an error cascade is usually necessary to breach the “swiss cheese” model of defenses, we stress that in most incidents with adverse outcomes avoiding any single one of the errors in the cascade could have prevented the ultimate adverse outcome. (Note that we see this same phenomenon in double checks, such as those used in medication safety, that are done incorrectly. We know that the error rate for someone supervising someone else’s work in any industry may approach 10% but there is probably also an increase in errors of the original work when someone thinks a second person will catch any errors they make. That is why double checks need to be done truly independently. See our October 16, 2012 Patient Safety Tip of the Week “What is the Evidence on Double Checks?”.)
Gibbs goes on to describe that the sponge accounting system needs to account for all sponges opened rather than sponges used. Transparent sponge holders, as noted above, typically with 5 rows of 2 pockets so there is a total of 10 sponges per unit. As sponges are used and thrown into a kick bucket they should be put into the sponge holder, one to a pocket, so they can easily be seen and counted. At the end of the case all sponges, including any unused ones, should be in the sponge holder. There should also be an erasable white board that everyone can see which keeps a count of the sponges. Before closing, surgeons must always do a methodical wound search (MWS) regardless of whether the count is correct or discrepant. And before leaving the OR the surgeon and circulating nurse must look at the sponge holder to make sure no pockets are empty. This is referred to as the “show me” step and can be included on your surgical safety checklist or your debriefing checklist. Gibbs advises that an “incorrect-count checklist” be posted in each OR so that everyone knows what to do when there is a discrepant count. If the sponge cannot be found, X-rays should be done and a radiologist (not just the surgeon) must call back the report before the patient is allowed to leave the OR.
While sponge accounting systems are at the top of everyone’s list because surgical sponges are far and away the most commonly retained surgical items, our previous columns warn you not to lose sight of the fact that all sorts of other RSI’s have been appearing more and more (blue towels, Kerlix, cautery tips, Glassman viscera container, KOH cup, instrument labeling tape, Jackson Pratt drain bulbs, Rainey clips, and others). Even the newest radiofrequency identification and tracking systems would miss most of those items.
An article in Anesthesiology News (Frei 2016) reviewed a poster presentation by Van Doren et al. at the 2015 annual meeting of the International Society for Pharmacoeconomics and Outcomes Research that pegged the cost of $6,412 per foreign object left behind during total joint arthroplasties. The poster authors also calculated that the rate of RSIs was one per 6,878 primary total hip arthroplasties and one per 11,961 primary total knee arthroplasties, for an overall rate was one per 11,948 procedures. The Frei article includes comments from Robert Cima, MD, who notes true costs are largely hidden and that this estimate significantly underestimates the cost of RSI’s, noting that indirect costs, litigation costs, meeting costs, etc. lead to a much higher financial toll. In our November 5, 2013 Patient Safety Tip of the Week “Joint Commission Sentinel Event Alert: Unintended Retained Foreign Objects” the Joint Commission sentinel event alert (TJC 2013) noted that 95% of the incidents result in additional care or extended hospital stay and additional costs (citing a Pennsylvania Patient Safety Authority estimate of $166,000 average cost for an RSI or “URFO” as the Joint Commission now apparently prefers to call them).
Whatever the financial cost of RSI’s might be, it pales in contrast to the human cost suffered by the patients affected and the reputation cost to the surgeons, teams and hospitals where such events occur.
Our prior columns on retained surgical items/retained foreign objects (RSI’s/RFO’s):
Putnam K. Guideline First Look. Guideline for prevention of retained surgical items. Periop Briefing 2015; 102(6): P11-P13
Gibbs V. A Better Way to Eliminate Retained Surgical Items. Accounting, not counting, will ensure no sponges are left behind. Outpatient Surgery Magazine 2015
Frei R. Cost Calculated for Each Retained Surgical Item in Total Knee, Hip Arthroplasty. Anesthesiology News 2016; January 1, 2016
Commenting on: Van Doren B, Odum S, et al. 2015 annual meeting of the International Society for Pharmacoeconomics and Outcomes Research (abstract PM58)
TJC (The Joint Commission). Sentinel Event Alert. Preventing unintended retained foreign objects. Issue 51 October 17, 2013
Several recent articles about contrast-induced nephropathy (CIN) prompted us to search our now nearly 1000 columns to see what we have written about CIN. Much to our surprise we only found one (see our June 2011 What's New in the Patient Safety World column “Reducing the Risk of Contrast-Related Damage from Imaging Studies”) and that one dealt as much with other contrast-related injuries as it did with CIN.
The study that attracted our attention was one that looked at long-term outcomes in patients who developed CIN (Mitchell 2015). They followed 633 emergency department patients undergoing contrast-enhanced CT, of whom 11% developed acute kidney injury consistent with contrast-induced nephropathy. Within one year 15% experienced at least 1 major adverse event (defined as the combined outcome of death of any cause, renal failure, myocardial infarction, and stroke or other arterial vascular events, in any anatomic territory, requiring invention), including 7% who died. After adjustment for a number of clinical variables the rate of these adverse events was almost 2 and a half times that of patients who did not develop CIN.
Our 2011 column noted many of the risk factors for CIN and mentioned a risk stratification nomogram for predicting CIN in patients undergoing contrast enhanced abdominal CT scans in the emergency room (Kim 2011). But another new study was a systematic review of predictive models that identified patients at risk of contrast induced nephropathy among adults undergoing a diagnostic or interventional procedure using conventional radiocontrast media (media used for computed tomography or angiography, and not gadolinium based contrast) (Silver 2015). Those authors found a total of 12 prediction models but found that ability to predict CIN was modest at best and really only relevant to patients receiving contrast for coronary angiography. The authors conclude that further research is needed to develop models that can better inform patient centered decision making, as well as improve the use of prevention strategies for contrast induced nephropathy.
Pertinent to management, a new study (Qian 2016) addressed prevention of CIN in a particularly high risk group – those patients with chronic kidney disease (CKD) and congestive heart failure (CHF). The incidence of CIN in this group of patients is more than 20%. So the Chinese investigators compared those patients managed with CVP-guided fluid administration vs. those without CVP monitoring in a randomized controlled trial. The incidence of CIN was 15.9% in the group managed with CVP-guided fluid administration vs. 29.5% in the group without CVP monitoring. The former group overall had a higher volume of fluid replacement and higher urinary output. The occurrence of acute heart failure did not differ between the two groups. Since hydration is the cornerstone for prevention of CIN, this study shows that our fears of precipitating acute heart failure or pulmonary edema may be keeping us from optimal fluid management in such patients receiving contrast. It demonstrates that use of CVP monitoring allows for more aggressive fluid management in this high risk group and helps avoid CIN.
While a CVP might allow for more aggressive fluid management, we’ll again note that a simple bedside maneuver may obviate the need for such catheters. Ever since our residency days we’d take great pride in showing our colleagues how a passive leg raise or equivalent can help with decisions about fluid/hemodynamic status in patients, avoiding the need for invasive monitoring.
The Royal College of Physicians also recently made available a toolkit on acute kidney injury and intravenous fluid therapy that includes advice on managing AKI and issues related to contrast (Royal College of Physicians 2015).
Mitchell AM, Kline JA, Jones AE, Tumlin JA. Major Adverse Events One Year after Acute Kidney Injury After Contrast-Enhanced Computed Tomography. Ann Emerg Med 2015; 66(3): p267-274.e4; Published online: May 21 2015
Kim KS, Kim K, Hwang SK, et al. Risk stratification nomogram for nephropathy after abdominal contrast-enhanced computed tomography. The American Journal of Emergency Medicine 2011; 29: 412-417
Silver SA, Shah PM, Chertow GM, et al. Risk prediction models for contrast induced nephropathy: systematic review. BMJ 2015; 351: h4395
Qian G, Fu Z, Guo J, et al. Prevention of Contrast-Induced Nephropathy by Central Venous Pressure–Guided Fluid Administration in Chronic Kidney Disease and Congestive Heart Failure Patients. J Am Coll Cardiol Intv 2016; 9(1): 89-96
Royal College of Physicians. Acute care toolkit 12: Acute kidney injury and intravenous fluid therapy. September 2015
The ACCP (American College of Chest Physicians) has issued its new antithrombotic guideline update for treatment of venous thromboembolism (VTE) (ACCP 2016). This is the 10th edition, updating the 9th edition that was published in 2012. Since the 9th edition the clinical trials of several novel oral anticoagulants (NOAC’s) have been completed and published and the new 10th addition acknowledges the place of these in the management of VTE.
According to the press release from the ACCP the key changes to recommendations in the 9th edition to the 10th edition include:
For VTE and no cancer, as long-term anticoagulant therapy, the new guideline suggests NOAC’s (dabigatran, rivaroxaban, apixaban, or edoxaban) over vitamin K antagonist (VKA) therapy and suggests VKA therapy over LMWH. However, for VTE and cancer it suggests LMWH over VKA or the NOAC’s.
Importantly, of 54 recommendations included in the total 30 statements, 20 were strong and none was based on high quality evidence. This highlights the need for further research.
The full guideline is available in CHEST (Kearon 2016).
ACCP (American College of Chest Physicians). CHEST issues new antithrombotic guideline update for treatment of VTE disease. Press release January 7, 2016
Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline. Chest 2016; January 2016
Print “PDF version”