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October 25, 2016
Desmopressin Back in the Spotlight
It’s been almost a decade since our March 18, 2008 Patient Safety Tip of the Week “Is Desmopressin on Your List of Hi Alert Medications?” outlined our multiple concerns about the safety of desmopressin. Last week an FDA Advisory Panel recommended approval of a desmopressin nasal spray for treatment of nocturia (Bankhead 2016). The FDA has not yet ruled on approval but usually follows the recommendations of the advisory panels.
Several desmopressin formulations, including a nasal spray formulation, are already FDA-approved. But they are approved for conditions other than the treatment of nocturia. Approved indications are the treatment of central diabetes insipidus, primary nocturnal enuresis in children, and to maintain hemostasis in patients with von Willebrand’s Disease and Hemophilia A during surgery. There are no current FDA-approved drugs indicated for the treatment of nocturia.
But, in reality, we know that desmopressin is already being used off-label for the treatment of nocturia. A meta-analysis of use of desmopressin for nocturia in 2012 found five studies involving a total of 619 participants and 8 additional randomized controlled trials in a systematic review (Zong 2012). The authors concluded that “desmopressin might significantly decrease the frequency of nocturnal voids, nocturnal urine volume and nocturnal diuresis, potentially resulting in an extended duration of the first sleep period and improved sleep quality. The adverse effects of desmopressin were similar to those observed in the placebo group.” Based upon those studies, some clinicians have been using desmopressin for treatment of nocturia already.
But we are very concerned about the potential adverse consequences of its use for nocturia, particularly in view of the seeming limited clinical significance of its efficacy in clinical trials. Most of the safety concerns in our March 18, 2008 Patient Safety Tip of the Week “Is Desmopressin on Your List of Hi Alert Medications?” have not changed.
The applicant to the FDA is seeking a rather broad approval of the desmopressin nasal spray for “nocturia”. Remember: nocturia is a symptom of a variety of underlying conditions. Given the wide range of conditions giving rise to nocturia we can anticipate that some patients will be more prone than others to adverse consequences of this treatment.
The FDA briefing document (FDA 2016) presented to the FDA Bone, Reproductive and Urologic Drugs Advisory Committee (BRUDAC) summarized the clinical trials used to support the request for FDA approval. Patients recruited into the clinical trials were all age 50 or older and there were multiple exclusionary criteria. One wonders how many patients with those exclusionary conditions might ultimately be treated with the drug if it gets approved for broad use for nocturia.
First, the efficacy evidence. Enrolled patients had at least a six-month history of at least two nocturic episodes per night, on average. All received placebo during a 2-week lead-in period and then were randomized to receive either 0.75 mcg, 1.0 mcg, or 1.5 mcg of desmopressin nasal spray or placebo nightly (the second trial just randomized patients to 0.75 mcg or 1.5 mcg of desmopressin nasal spray or placebo nightly) for a 12-week treatment period. Co-primary efficacy endpoints were (1) change from baseline in the mean number of nocturic episodes per night and (2) percentage of patients with ≥50% reduction in mean number of nocturic voids per night. One of the two trials also included the Impact of Nighttime Urination (INTU) Questionnaire as a secondary endpoint. It appears that neither clinical trial included fluid intake restriction.
The FDA briefing document includes a discussion on the use of an ITT (intention-to-treat) analysis vs. a mITT (modified intention-to-treat) analysis but we won’t bore you with the details. Only the 1.5 mcg dose of desmopressin was statistically superior to placebo on both co-primary efficacy endpoints. Regarding the first endpoint, there was a mean reduction of 0.3-0.4 episodes per night (from a baseline of about three nightly nocturia episodes on average) with the 1.5 mcg dose compared to placebo. Though statistically significant, the FDA briefing document questions the clinical significance of this finding. In both trials, those that achieved at least 50% reduction in mean number of nocturic voids per night compared to placebo did so only with the 1.5 mcg dose (52% vs. 33% in one trial and 46% vs. 29% in the other). The 1.5 mcg desmopressin dose decreased the INTU Overall Impact score by 2.6 points more than placebo. That point difference was statistically significant but, again, of unclear clinical significance.
On the safety side, the incidence of subjects with at least one adverse event was slightly greater in those who received active drug compared to placebo. The common adverse events occurring at a greater incidence in those treated with active drug were nasopharyngitis, urinary tract infection, hypertension/blood pressure increased, sneezing, nasal congestion, back pain, dizziness, and hyponatremia. But the incidence of serious adverse events was similar to the incidence in the placebo group. All 5 deaths occurred in those receiving active drug but it was felt that the drug did not likely contribute in at least 3 of those and was questionable in the others. Four of the 5 deaths occurred in patients age 75 and older. The incidence of subjects discontinuing due to an adverse event was slightly greater in active drug group than the placebo group. The most common adverse events leading to discontinuation in those on active drug were nasal discomfort and hyponatremia. Hyponatremia occurred with incidences of 1.1%, 0%, and 0.2% respective in the 1.5 μg, 0.75 μg, and placebo treatment groups. The incidence of hyponatremia with active drug appears lower among subjects younger than 65 years of age compared to those over 65 years of age.
Prior studies have looked at adverse events in patients receiving intransal desmopressin. In a report on adverse events during the use of intranasal desmopressin acetate for patients with haemophilia A or von Willebrand disease, Dunn and colleagues noted 27/40 patients experienced some clinical signs of symptoms related to the drug (Dunn 2000). Most were mild but several reported moderate-to-severe side effects, including one patient who required medical intervention for symptomatic hyponatremia. The authors suggest that side-effects may be minimized if patients adhere to instructions regarding fluid intake and composition while using intranasal desmopressin. Lose and colleagues looked at the effects of long-term (10-12 months) desmopressin use for nocturia (Lose 2004). Desmopressin was well tolerated with few males (14%) or females (10%) withdrawing due to adverse events. Most adverse events were mild (44%) or moderate (44%) in severity. Four males experienced serious drug related adverse events, (dizziness, cardiac failure, headache and vomiting, chest pain and hypertension) and one female experienced 4 serious drug related adverse events (hyponatremia, headache, nausea and vertigo). Two patients had clinically significant hyponatremia.
On the basis of the clinical trial data, you’d probably conclude that this is a drug that has a marginal clinical value (though it may be more valuable to some patients) but appears to be relatively safe. The FDA Bone, Reproductive and Urologic Drugs Advisory voted 14-4 margin that benefits of the treatment outweighed potential risks.
But we have 2 major concerns. First is that the drug would undoubtedly get used in patient populations other than those enrolled in the clinical trials. Second is that the drug is likely to be prescribed by or managed by healthcare personnel who are relatively unfamiliar with it.
The exclusion criteria in the clinical trials were diabetes insipidus, uncontrolled diabetes mellitus, congestive heart failure (New York Heart Association Class IIIV), polydipsia, uncontrolled hypertension, nephrotic syndrome, peripheral edema (>2+ pretibial edema on physical exam), history of urinary retention, neurogenic detrusor overactivity, obstructive sleep apnea, loop diuretics, glucocorticoids, and severe lower urinary tract symptoms due to benign prostatic hypertrophy, overactive bladder, or severe stress urinary incontinence. Yet the application is for approval of the desmopressin formulation for any adult with nocturia. Undoubtedly it would get used in some patient populations in whom it has not been studied.
Hyponatremia is probably the most feared potential complication of desmopressin therapy. Keep in mind that in the clinical trials, fasted serum sodium concentration was assessed on Days 1 (baseline), 15, 29, 43, 57, 71, 85, and 99 of the studies. In the real world it is not likely that there will be such frequent monitoring of serum sodium levels. And it is particularly when intercurrent events occur (such as infections) that further perturbations of serum sodium might occur in patients on desmopressin therapy.
Perhaps our most serious concern involves the patient receiving desmopressin therapy who now gets hospitalized for either an intercurrent condition or an elective procedure. The healthcare personnel dealing with such patients on an inpatient basis are quite likely to have limited experience with and knowledge about the use of desmopressin.
We did our March 18, 2008 Patient Safety Tip of the Week “Is Desmopressin on Your List of Hi Alert Medications?” because of several reports of adverse events related to desmopressin over a short period of time. The FDA issued an alert in December 2007 (FDA 2007) about the dangers of severe hyponatremia and seizures related to desmopressin. This alert was based on their review of 61 post-marketing cases of hyponatremic seizures associated with desmopressin use, including two fatal cases. Children with primary nocturnal eneuresis (PNE) taking intranasal formulations of desmopressin are particularly susceptible to these complications so the FDA alert cautioned that the intranasal formulation was no longer indicated for treatment of PNE. It also cautioned that treatment of PNE with desmopressin tablets should be interrupted during acute illnesses that may lead to fluid/electrolyte disturbances. And it cautioned that all desmopressin formulations should be used with caution in patients at risk for water intoxication with hyponatremia or in patients taking medications that may cause them to drink more fluids, such as tricyclic antidepressants or SSRI’s. The FDA has subsequently archived that safety alert. Labelling changes were made in 2007 and a safety review in 2010 revealed no further deaths or serious adverse events.
ISMP Canada issued an alert (ISMP Canada 2008) shortly thereafter about the need for monitoring protocols in patients taking desmopressin. This followed a report of a patient who developed diabetes insipidus following neurosurgical removal of a nonmalignant brain tumor. The patient was treated with desmopressin and had numerous problems with fluid/electrolyte management and had a positive fluid balance of several liters, resulting in death presumably from water intoxication and cerebral edema. Even minor increases in electrolyte-free water have been associated with disproportionately high increases in intracranial pressure. Contributing factors in this case were continued administration of hypotonic fluids and desmopressin after the serum sodium had normalized and the rapidity of the shift from a hypernatremic state to a hyponatremic state.
And a case study in an AHRQ WebM&M (AHRQ 2008) dealt with an adverse outcome related to desmopressin. Though the WebM&M focused on the issue of “hold” orders, the case again pointed out the dangers associated with desmopressin.
Those cases point out two important reasons to identify desmopressin as a hi-alert medication. First, it is a drug that may be associated with serious, even fatal, complications. Second, it’s a drug that many physicians, nurses, and pharmacists have limited experience with. Many patients now end up being admitted for an unrelated reason and staff unfamiliar with desmopressin are saddled with managing it during a hospitalization. That is exactly the circumstance where having available strict protocols and monitoring programs is a smart addition to your medication safety program.
The ISMP Canada alert recommends development and use of standardized order sets (preprinted orders or electronic order sets), including monitoring parameters, for postoperative management of postoperative neurosurgical patients to facilitate early diagnosis and management of central diabetes insipidus. They also discuss the need for discussion of such potential complications to be a part of all hand-offs. They stress the importance of standardized order sets for monitoring patients treated with desmopressin, including the frequency with which the parameters should be monitored. Urine output, by itself, should not be used to determine whether subsequent doses of desmopressin are given. The trend in the monitored parameters may be as important as the actual numbers. The choice and rate of IV fluids and the need for desmopressin should be determined by the results of those parameters. The patients should be carefully monitored for signs or symptoms of hyponatremia or water intoxication. Besides seizures, headache, nausea, vomiting and obtundation are common symptoms of water intoxication. In addition to the standardized order sets, everyone caring for the patient should have ready access to information and protocols about the drug and the monitoring. Families, too, should be engaged in monitoring because they may pick up subtle changes in the patient before professional staff would. And it is critical that the laboratory test results be available on a prompt basis.
Though the ISMP Canada alert was aimed at neurosurgical patients, the advice is wise and most of it is also applicable to other types of patients being treated with desmopressin. Perhaps the most important initial question to ask is whether continued use of desmopressin is even indicated during the acute hospitalization. For many of it uses, particularly the bladder-related ones, there may be no reason to use desmopressin at all during the hospital stay. If it is determined that desmopressin should be continued, then the type of standardized order sets and monitoring protocols similar to those in the ISMP Canada alert should be used.
Most hospitals have included in their hi-alert medication safety programs categories of more frequently used drugs that have a narrow therapeutic index or possible severe adverse side effects and then looked at drugs within those categories that may be particularly likely to be unfamiliar to clinical staff. For example, most hospitals include anticoagulants in their hi-alert medication safety program and typically focus on coumadin, heparin, LMWH’s, and antiplatelet agents. However, some have recognized that drugs like argotroban may need to be used under rare circumstances and that few practitioners have extensive experience with that drug. Therefore, they have made special attempts to make appropriate information on the less familiar drug available to practitioners and have developed standardized order sets for dealing with such drugs. The same sort of logic should apply to desmopressin and it should be addressed in your hi-alert medication safety program.
One additional concern is the potential risk that an order for desmopressin might erroneously be interpreted as an intravenous medication rather than intranasal one, potentially leading to very serious complications. One such incident where it was mistakenly given intravenously was reported by ISMP (ISMP 2009). The example given included the use of the abbreviation “IN” (for intranasally), an abbreviation that ISMP would put on a “do not use” list. ISMP notes that, in addition to being mistaken for “IV”, the abbreviation “IN” can also be mistaken for “IM”. ISMP suggests writing out “intranasal” or “nasally” or using “NAS” instead.
We would hope that the FDA ultimately limits the scope of the population for which intranasal desmopressin is approved. Some have stated that “nocturnal polyuria”, implying the need to urinate multiple times at night, may be a more appropriate indication for use of intranasal desmopressin. But in anticipation that it will approve its use for nocturia in some capacity and knowing that some clinicians have already been using it for that purpose, we think that all hospitals should be doing certain things:
And for the clinician, use of desmopressin for nocturia should only be considered when other non-pharmacologic measures have been taken and when the nocturia truly impairs quality of life. Nocturia may contribute to cumulative sleep deprivation and may also increase the risk of falls in the elderly (see our June 9, 2015 Patient Safety Tip of the Week “Add This to Your Fall Risk Assessment” and our many columns on fall risk and prevention). First and foremost, remember that nocturia is a symptom and has a variety of causes. Treating the underlying cause is most important. For example, nocturia may be a manifestation of congestive heart failure. So treatment of the CHF should be primary. In a review of management of nocturia in the elderly, Osman and Chapple note that lifestyle interventions, though not widely studied on a population basis, are often used based upon both logical and anecdotal evidence (Osman 2013). Lifestyle measures included reducing caffeine and alcohol, limiting evening fluid intake, leg elevation and interventions aimed at improving sleep (e.g., exercise, and warm temperature). And when desmopressin might be considered, good communications are required, not only between physician and patient but also between physicians. Most likely it may be a urologist who recommends desmopressin but the primary care physician is usually in a better position to understand potential interactions with other medications and comorbidities. The young and the elderly are two populations that are more prone to develop hyponatremia during desmopressin treatment. Desmopressin also has a relatively long and variable duration of action. Issues of unusually long half-life or bioactivity have been implicated in some cases of adverse events related to desmopressin (Dehoorne 2006). In some cases, hyponatremia due to desmopressin may have been made more likely by a second drug, such as ibuprofen (Garcia 2003).
Desmopressin is a valuable drug for many conditions. Though it may be effective and relatively safe for treating nocturia in a relatively narrow population, expansion of its use to other patient populations may well result in unintended consequences.
Bankhead C. FDA Panel Backs Nasal Spray for Nocturnal Polyuria - Support for intransal desmopressin despite reservations. MedPage Today October 19, 2016
Zong H, Yang C, Peng X, Zhang Y. Efficacy and safety of desmopressin for treatment of nocturia: a systematic review and meta-analysis of double-blinded trials. International Urology and Nephrology 2012; 44(2): 377-384
FDA (US Food and Drug Administration). FDA Briefing Document. Bone, Reproductive and Urologic Drugs Advisory Committee (BRUDAC). October 19, 2016
Dunn AL, et al. Adverse events during use of intranasal desmopressin acetate for haemophilia A and von Willebrand disease: a case report and review of 40 patients. Hemophila 2000; 6(1): 11-14 January 2000
Lose G, Mattiason A, Walter S, et al. Clinical Experiences with Desmopressin for Long-Term Treatment of Nocturia. The Journal of Urology 2004; 172(3): 1021-1025
FDA (US Food and Drug Administration). Information for Healthcare Professionals: Desmopressin Acetate (marketed as DDAVP Nasal Spray, DDAVP Rhinal Tube, DDAVP, DDVP, Minirin, and Stimate Nasal Spray). FDA Safety Alert 12/4/2007. Now archived and unavailable. http://www.fda.gov/cder/drug/InfoSheets/HCP/desmopressinHCP.htm
ISMP Canada Alert March 3, 2008. Desmopressin Incidents Identify a Need to Evaluate Monitoring Protocols. http://www.ismp-canada.org/download/ISMPCSB2008-01DDAVP.pdf
AHRQ WebM&M. Hold That Order. March 2008 http://www.webmm.ahrq.gov/case.aspx?caseID=171
ISMP (Institute for Safe Medication Practices). On the “do not use” list. ISMP Medication Safety Alert! Nurse Advise –ERR Edition 2009; 7(1): 3 January 2009
Osman NI, Chapple CR. Focus on Nocturia in the Elderly. Aging Health 2013; 9(4): 389-402
Dehoorne JL, Raes AM, van Laecke, E, Hoebeke EP, Vande Walle JG. Desmopressin Toxicity Due to Prolonged Half-Life in 18 Patients With Nocturnal Enuresis.
The Journal of Urology, 2006; 176: 754-758 http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B7XMT-4K8Y775-3J&_user=10&_coverDate=08%2F31%2F2006&_alid=707110399&_rdoc=17&_fmt=summary&_orig=search&_cdi=29679&_sort=d&_docanchor=&view=c&_ct=73&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=50356436a760b8c893564231548ead5e
García EBG, Ruitenberg A, Madretsma GS, Hintzen RQ. Hyponatraemic coma induced by desmopressin and ibuprofen in a woman with von Willebrand's disease. Haemophilia 2003; 9: 232-234 http://www.blackwell-synergy.com/doi/abs/10.1046/j.1365-2516.2003.00719.x?prevSearch=allfield%3A%28garcia%29
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In a couple past columns we briefly mentioned a study by McHugh and Stimpfel (McHugh 2012) which showed nurses’ ratings of hospital quality and safety correlate well with more formal measures. Now a new study done in Swedish hospitals extends upon that work (Smeds-Alenius 2016). The study used a survey of nurses in 67 Swedish hospitals and covered over 200,000 general, vascular, and orthopedic surgical procedures. The researchers found that hospitals in the highest tertile of nurses reporting excellent quality of care had a 23% lower odds of 30-day inpatient mortality. Similarly, hospitals in the highest tertile of nurses reporting excellent patient safety had a 26% lower odds of 30-day inpatient mortality. The study validates the previous work of McHugh and Stimpfel and suggests that nurses’ assessments could be used as legitimate measures of quality and patient safety. The authors do recognize that inpatient mortality is a crude measure of both safety and quality (Lilford 2010, Girling 2012). Mortality rates may be appropriate indicators for some conditions but not others. Moreover, patient-related factors and patient socioeconomic factors, advance directive issues, plus other factors impact inpatient mortality rates. Even after risk adjustment for patient-related variables, mortality rates may be less than ideal measures of quality or patient safety. The current study was done in Sweden supposedly to minimize some of the confounding factors seen in the US such as variation in insurance status and correlated health status.
So could nurse assessment be used as a formal measure of quality and patient safety? We would have no qualms about using nurse assessments as an informal measure and we do often ask nurses their opinion on quality and patient safety in their hospitals. It might help inform us in our decisions about whether to have a procedure at their hospital. However, what is unknown is what would happen to the observed correlation between nurse assessment and mortality rates if this were to become a formal measure of quality and patient safety. Would nurses continue to provide honest assessments if they knew that the very viability of their hospital might be jeopardized by public disclosure of such assessments? We may never know the answer to that question.
But when we are asked by someone what is the best way to tell whether a hospital has good quality and safety we have no problem telling them “ask a nurse”!
McHugh MD, Stimpfel AW. Nurse reported quality of care: A measure of hospital quality. Research in Nursing & Health 2012; Article first published online: 21 AUG 2012
Smeds-Alenius L, Tishelman C, Lindqvist R, Runesdotter S, McHugh MD. RN assessments of excellent quality of care and patient safety are associated with significantly lower odds of 30-day inpatient mortality: A national cross-sectional study of acute-care hospitals. International Journal of Nursing Studies 2016; 61: 117–124
Lilford R, Pronovost P. Using hospital mortality rates to judge hospital performance: a bad idea that just won't go away. BMJ 2010; 340: c2016
Girling AJ, Hofer TP, Wu J, et al. Case-mix adjusted hospital mortality is a poor proxy for preventable mortality: a modelling study. BMJ Qual Saf 2012; 21(12): 1052-1056 Published Online First: 15 October 2012
Since the 1990’s one of the key components of “clinical pathways” for cardiac surgery has been early extubation of patients, often protocol-based. That was a key to reducing ICU lengths of stay for such patients.
Indeed, one study heavily weighted toward cardiothoracic surgery patients (Tischenkel 2016) found that intensive care unit extubations at night did not have higher likelihood of reintubation, LOS, or mortality compared to those during the day. In fact, trends in that study favored nighttime extubation for both reintubation rates and mortality and those extubated at night had significantly lower lengths of stay.
Given the complications associated with mechanical ventilation and extended intubation, it might seem wise that patients should be extubated as soon as possible. Those complications include ventilator-associated pneumonias, delirium, neuromuscular syndromes, etc. Hence, there might be theoretical reasons to favor early extubation. But what are the empirical data favoring overnight extubation? A new study looks at patient outcomes in patients who were extubated overnight and has some surprising results (Gershengorn 2016). In a retrospective analysis of a cohort of almost 100,000 mechanically ventilated patients they found 20.1% were extubated overnight and that rate has decreased over time. For those patients who had been mechanically ventilated for less than 12 hours reintubation rates were similar between those extubated overnight vs. during the daytime but mortality was increased for those extubated overnight (5.6% vs. 4.6%). For those mechanically ventilated more than 12 hours, those extubated overnight had higher reintubation rates and higher ICU and hospital mortality with no difference in length of stay.
One intriguing finding was that the odds ratios for increased mortality in those extubated overnight were higher than the odds ratios for reintubations. While several possible reasons were discussed by the authors, they favored a hypothesis that “palliative” extubations may have accounted for this (with the theory that palliative extubations are more likely to take place when family is present at night).
They also attributed the disparity between their study and that by Tischenkel and colleagues (Tischenkel 2016) to a significant difference in the number of patients undergoing cardiothoracic surgery.
Keep in mind that the Gershengorn study was a retrospective cohort study. As pointed out in the accompanying editorial (Moore 2016), though the study had excellent data collection as part of a large collaborative study there was lack of information on the circumstances and reasons for extubation (and reasons why some were not reintubated).
In our September 20, 2016 Patient Safety Tip of the Week “Downloadable ABCDEF Bundle Toolkits for Delirium” we discussed a study (Balas 2013a , Balas 2014) that was a prospective, cohort, before-after study of the ABCDE bundle at a large, tertiary medical center, involving patients from multiple ICU’s. They found patients treated with the ABCDE bundle, which leads to earlier extubation, experience more days breathing without assistance and a shorter duration of ICU delirium. The odds of delirium were cut almost in half. Patients on the bundle were also more likely to be mobilized out of bed during their ICU stay. No significant differences were noted in self-extubation or reintubation rates. But it should be noted that one of the barriers encountered in implementation was that nurses and respiratory therapists were often concerned about spontaneous breathing trials being done at night (Balas 2013b).
Though the findings of the Gershengorn study are associations and do not prove causality, they certainly put to question the practice of overnight extubations. We suspect that there may well be differences in outcomes both by type of ICU and nature of the underlying problem. But it is certainly worth all hospitals taking a look at their current practices and outcomes.
Tischenkel BR, Gong MN, Shiloh AL, et al. Daytime vs nighttime extubations: a comparison of reintubation, length of stay, and mortality. J Intensive Care Med 2016; 31(2): 118-126
Gershengorn HB, Scales DC, Kramer A, Wunsch H. Association between Overnight Extubations and Outcomes in the Intensive Care Unit. JAMA Intern Med 2016; Published Online First September 06, 2016
Moore PK, Matthay MA. Overnight Extubation in Patients with Mechanical Ventilation. Is It Harmful? JAMA Intern Med 2016; Published online September 06, 2016
Balas M, Olsen K, Gannon D, et al. Safety And Efficacy Of The ABCDE Bundle In Critically-Ill Patients Receiving Mechanical Ventilation. Abstract at Society of Critical Care Medicine 42nd Critical Care Congress. Presented January 20, 2013. Crit Care Med 2012; 40(12) (Suppl.): 1
Balas MC, Vasilevskis EE, Olsen KM, et al: Effectiveness and safety of the awakening and breathing coordination, delirium monitoring/management, and early exercise/mobility bundle. Crit Care Med 2014; 42: 1024-1036
Balas MC, Burke WJ, Gannon D, et al. Implementing the awakening and breathing coordination, delirium monitoring/management, and early exercise/mobility bundle into everyday care: opportunities, challenges, and lessons learned for implementing the ICU Pain, Agitation, and Delirium Guidelines. Crit Care Med 2013; 41(9 Suppl 1): S116-127
It’s been over 4 years since the first warnings appeared about the dangers of using codeine in children. Our previous 5 columns on the dangers of codeine in children discussed the multiple safety alerts from the FDA (FDA 2012, FDA 2013, FDA 2015). These columns described cases of death and serious adverse effects in children treated with codeine following adenotonsillectomy for obstructive sleep apnea. The problem originally noted for codeine was that there are genetic variations that cause some people to be “ultra-rapid metabolizers” of codeine, which leads to higher concentrations of morphine in the blood earlier.
In our January 2016 What's New in the Patient Safety World column “FDA Gets Even Tougher on Codeine in Kids” we noted that an advisory committee to the FDA recommended that codeine be contraindicated for pain and cough management in children and adolescents (Firth 2015). They also recommended restricting codeine's over-the-counter availability for this group. Of 29 voting members, 20 voted to contraindicate use of the drug for pain and cough in children younger than 18 years old. Most of the others voted to restrict its use only in younger children. However, the FDA has not yet taken formal action on those recommendations.
While the initial warnings focused on avoiding codeine in children who were undergoing adenotonsillectomy for obstructive sleep apnea (OSA), the dangers apply more globally to children. Now an even tougher stance is being taken by the American Academy of Pediatrics in a statement “Codeine: Time to Say ‘No’ ” (Tobias 2016). That paper reiterates the evidence of adverse effects of codeine in children and their mechanisms. It notes that codeine is still available in over-the-counter cough formulas in 28 states and the District of Columbia without a prescription.
The Tobias paper does discuss the pros and cons of alternatives to codeine in the pediatric population, noting that almost all of them also have some potential downsides. Those alternatives include oxycodone, hydrocodone, oral morphine, and tramadol. It also mentions tapentadol, which is not yet FDA-approved for use in children. It notes that use of acetaminophen and nonsteroidal antiinflammatory drugs (NSAIDs) are legitimate alternatives in many or most children. Regarding the continued presence of codeine in many antitussive formulations, it notes that neither the value of suppressing cough nor the effectiveness of codeine in children with acute illnesses has been shown.
Our May 2014 What's New in the Patient Safety World column “Pediatric Codeine Prescriptions in the ER” noted the continued frequent prescription of codeine-containing products in children despite the previous warnings about adverse reactions. In our November 2015 What's New in the Patient Safety World column “FDA Safety Communication on Tramadol in Children” we noted that education does not seem to have reduced prescription of codeine-containing products. We therefore advocated incorporating “hard stops” (alerts requiring acknowledgement of the warnings about codeine or other opioid in children) into CPOE and e-prescribing systems. We would hope that the FDA takes more forceful action, as recommended by the previous advisory committee and the current American Academy of Pediatrics, to reduce the risk of codeine-associated respiratory depression and other adverse events.
Regardless of whether the FDA takes action or not, you should be monitoring your organization’s prescription of codeine-containing products and taking active steps (like the hard stops noted above) to force your prescribers to think twice when contemplating use of codeine in children.
Some of our previous columns on opioid safety issues in children:
FDA. FDA Drug Safety Communication: Codeine use in certain children after tonsillectomy and/or adenoidectomy may lead to rare, but life-threatening adverse events or death. 8/15/12
FDA. FDA Drug Safety Communication: Safety review update of codeine use in children; new Boxed Warning and Contraindication on use after tonsillectomy and/or adenoidectomy. Update February 20, 2013
FDA (Food and Drug Administration) Briefing Document: The safety of codeine in children 18 years of age and younger. Joint Pulmonary-Allergy Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee Meeting . December 10, 2015
Firth S. FDA Panel Urges Stronger Regulation of Codeine. An FDA advisory committee voted 28-0 to remove the drug from its OTC monograph for cough and cold. MedPage Today 2015; December 11, 2015
Tobias JD, Green TP, Coté CJ, Section on Anesthesiology and Pain Medicine, Committee on Drugs. Codeine: Time to Say “No”. Pediatrics 2016; Originally published online September 19, 2016
One of our columns that surprisingly is near the top of our “hit” list was our November 1, 2011 Patient Safety Tip of the Week “So What’s the Big Deal About Inserting an NG Tube?”. In that column we noted that nasogastric tube (NG tube) insertion is so common that we tend to forget its risks. But if you’ve ever seen a patient die because their enteral feeds were inadvertently given into their lungs or develop meningitis because the NG tube went through a basal skull fracture, you won’t take this cavalier attitude toward NG tubes. We noted 3 Patient Safety Alerts from the UK’s NPSA (NPSA 2005a, NPSA 2005b, NPSA 2011) that reported numerous incidents, including deaths and other bad outcomes related to misplaced NG tubes.
Feeding tube misplacement is an issue not just in the UK. The American Association of Critical-Care Nurses issued a press release (AACN 2016) on September 15, 2016 calling attention to their practice alert “Initial and Ongoing Verification of Feeding Tube Placement in Adults” issued earlier this year. According to that new guideline, the expected practice during the insertion procedure is to use a combination of two or more of the following bedside methods to predict tube location:
Confirmation by radiography is still the most important element but results of the above elements can be used to determine when it is time to use radiography to confirm tube location and they may also be able to reduce the number of confirming radiographs to one.
Just as important, the alert discusses methods of tube location that should not be used. It stresses that nurses should not use the auscultatory (air bolus) or water bubbling method (holding tube under water) to determine tube location.
It also has important considerations for the radiologic confirmation of tube location. Correct placement of a blindly inserted small-bore or large-bore tube should be confirmed with a radiograph that visualizes the entire course of the tube prior to its initial use for feedings or medication administration. Once correct tube placement is confirmed, the exit site from the patient’s nose or mouth should be immediately marked and documented to assist in subsequent determinations of tube location. After feedings are started, tube location should be checked at four-hour intervals.
The practice alert is well-referenced, both in terms of citing the literature on adverse effects of tube misplacement and the supporting evidence for the recommended best practices.
We refer you back to our November 1, 2011 Patient Safety Tip of the Week “So What’s the Big Deal About Inserting an NG Tube?” for other lessons learned and other issues regarding NG and other feeding tubes. Pay particular attention to the section on radiologic confirmation. First, the x-ray requisition should clearly state the x-ray is for determination of tube placement. All too often we still see x-ray requisitions filled out with something like the admission diagnosis rather than the real reason for the x-ray. And you need to make sure that the person doing the interpretation is appropriately credentialed to do so (for example, if someone other than the radiologist is doing the interpretation). And feeding should not be commenced via that tube until the radiologist (or appropriately credentialed person) has documented the tube is in the correct location.
AACN (American Association of Critical-Care Nurses). Feeding Tubes Require Initial and Ongoing Verification to Minimize Complications. American Association of Critical-Care Nurses updates Practice Alert on feeding tube placement. Press Release 15-Sep-2016
AACN (American Association of Critical-Care Nurses). AACN Practice Alert: Initial and Ongoing Verification of Feeding Tube Placement in Adults. CriticalCareNurse 2016; 36(2): e8-e13 April 2016
One of the questions addressed before anyone gets an MRI scan is whether the patient has any sort of implant or device or foreign body that may be adversely affected by the magnetic fields. Sounds simple, doesn’t it? Don’t we just look at a list of those items that would contraindicate an MRI scan?
Well, it is not so simple. Dr. Emanuel Kanal, director of MR services at University of Pittsburgh Medical Center and a well-known expert on MRI safety issues, has developed the MR Safety Implant Risk Assessment app on the IOS (iPhone) platform to address the multiple factors involved. A recent interview with him on AuntMinnie.com, the popular radiology website, discussed the details and intricacies of the app (Ridley 2016).
Factors affecting the safety during MRI include not only the type of implant but also its location, the type of MRI scan being done, the part of the body being imaged, the strength of the magnet and other issues of configuration of the MRI machine, and other considerations such as the location of the various energy sources relative to the patient’s location in the MRI suite. Kamal notes that what is safe in one system may not be safe in another. Moreover, a patient might safely have one part of the body imaged by MRI but not another. Importantly, some patients may be being denied potentially helpful MRI scanning that could be safely performed given the correct type of study and equipment.
The intended audience for the app is MR technologists, radiologists, or MR physicists and it requires technical knowledge about MRI. Kamal describes the app as a teaching tool in addition to its practical utility in determining whether a patient can be safely imaged by MR. Kamal, who is also a licensed pilot, describes the checklist format that forces the user to consider all the potential safety concerns before concluding that the patient may have the MR study safely performed.
The interview is worth your reading and you should make sure that those involved in your MRI unit know about the nature and availability of the app. But the interview was enlightening even for those of us lacking the technical MR expertise. As a neurologist, I highly suspect after reading it that there have been instances where I referred patients for alternative imaging modalities when an MRI actually could have been performed safely.
Speaking of safety in the MRI suite, we should also note that a coalition of societies and organizations dealing with MRI has proposed a delineation of responsibilities for the management of MRI facilities (Calamante 2016).
Some of our prior columns on patient safety issues related to MRI:
Ridley EL. Mobile App Spotlight: Kanal's MR safety implant risk tool. AuntMinnie.com 2016; August 24, 2016
Apple iTunes store. Kanal's MR Safety Implant Risk Assessment (app).
Calamante F, Ittermann B, Kanal E, The Inter-Society Working Group on MR Safety and Norris D. Recommended responsibilities for management of MR safety. JMRI 2016; Early View 3 Jun 2016
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