Category: Medication Safety

Ranitidine Kills Neonates

Specifically, 24 to 32-week premature neonates, but it’s still an interesting demonstration of the unanticipated dangers of reducing the body’s nonimmune defense mechanisms.

This is a non-randomized, controlled, prospective, observational study from Italy that simply looked at how many premature neonates in their NICU received ranitidine treatment for acid suppression.  The secondary endpoints of the study were any observed associations between ranitidine use/non-use and NEC, mortality, sepsis, length of hospitalization, etc.  This is still non-randomized observational data, so the associations may be affected by other unknown confounders – but mortality in the non-ranitidine group was 1.6% and the mortality in the ranitidine group was 9.8%.  This difference is probably all attributable to infection, considering 25.3% of the ranitidine group developed sepsis compared to 8.7% in the non-ranitidine group.

An impressive difference, even in a non-randomized cohort.  Not a lot of obviously significant differences between groups.  We’ve seen similar, smaller increases in infection in ICU adults receiving acid-suppression medication – I wonder if these effects extend to young infants on ranitidine as well?

“Ranitidine is Associated With Infections, Necrotizing Enterocolitis, and Fatal Outcome in Newborns”
http://www.ncbi.nlm.nih.gov/pubmed/22157140

Dexmedetomidine Is Not For ED Sedation

They use alpha-2 agonists for sedation all the time in veterinary medicine – but it doesn’t look like it has a role here in the Emergency Department.

This is a small case-series out of Australia in which they gave dexmedetomidine (Precedex) to the acutely behaviorally challenged – a high-risk population in the Emergency Department, both for the patient and for staff.  Patients became eligible for dexmedetomidine if they had acute behavioral disturbance requiring physical and chemical restraint.  In this hospital, their protocol was to use droperidol 10mg IV for chemical sedation, then a second 10mg dose, and then they became eligible for second-line agents.

Their study population is thirteen patient enrollment over 21 months constituting a heterogenous mix of toxicologic and psychiatric agitation.  Five of the thirteen patients received an IV loading dose only, and the remaining eight received loading dose and infusion.  Of the five who received the loading dose, 2 had effective sedation without adverse effects – and the other 3 were not sedated and one became hypotensive.  Of the other eight, three had effective sedation, one of which developed hypotension and atrial fibrillation.  The other five had only transient or no sedation, four became hypotensive, and two were intubated for persistent agitation.

So, in all, five of the thirteen had adequate sedation using dexmedetomidine as rescue after initial attempts at chemical sedation – but seven had adverse effects.  The authors then conclude that, while it provides an additional, reasonable alternative for sedation, monitoring and managing the adverse effects would be too resource intensive.

Seems reasonable enough.

“Dexmedetomidine in the emergency department: assessing safety and effectiveness in difficult-to-sedate acute behavioural disturbance”
http://www.ncbi.nlm.nih.gov/pubmed/22158533

Why Aren’t You Using Nitrous Yet?

Another massive study reviewing adverse events encountered during procedural sedation – this time with nitrous oxide given in concentrations up to 70%.  It is odd that resistance is encountered regarding high concentrations of nitrous oxide – considering 30% O2 is still greater than the fraction of inspired oxygen on room air – but this, and other studies like it, should help allay any concerns.

Out of their 7,802 nitrous administrations, they recorded 9 “potentially serious” adverse events – eight desaturations and one potential aspiration event requiring oropharyngeal suctioning.  More importantly, a reasonable percentage of these administrations were in children with comorbid diseases or potentially serious illness that needed sedation for significant procedures – LP, CT scans, NG/G-tube placement, and “other” that included EMGs and botulinium toxin injections.  Their rates of serious events are similar to other published series where either zero or <1% potentially serious events occurred – except for the study that reported 30% adverse events, but included “euphoria” and “dreaming” as adverse events.

This is not, however, an ED-only study, and one of the limitations is that they don’t specifically record whether they are able to successfully complete the intended procedure with this method – however, one would imagine, if it didn’t work the first 7,000 times, they wouldn’t have kept doing it…

“Safety of High-Concentration Nitrous Oxide by Nasal Mask for Pediatric Procedural Sedation”
http://www.ncbi.nlm.nih.gov/pubmed/22134227

ED Geriatric CPOE Intervention – Win?

It does seem as though this intervention had a measure of success – based on their primary outcome – but there’s more shades of grey throughout the article.

This is a prospective, controlled trial of a contextual computer decision-support (CDS) incorporated into the computerized provider order entry (CPOE) system of their electronic health record (EHR).  They do a four-phase On/Off intervention where the CPOE either suggests alternative medications or dose reductions in patients >65 years of age.  They look at whether the intervention changed the rate at which medication ordering was compliant with medication safety in the elderly, and then, secondarily, at the rate of 10-fold errors, medication cancellations, and adverse drug event reports.

The oddest part of this study is their choice of primary outcome measure.  Ideally, the most relevant outcome is the patient-oriented outcome – which, in this case, ought to be a specific decrease in adverse drug events in the elderly.  However, and I can understand where they’re coming from, they chose to specifically evaluate the usability/acceptability of the CDS intervention to verify the mechanism of intervention.  There are lots of studies out there documenting “alert fatigue”, resulting in either no change or even increasing error rates.

As far as the main outcome measure goes, they had grossly positive findings – 31% of orders were compliant during the intervention periods vs. 23% of orders during the control periods.  But, 92.5% of recommendations for alternative medications were ignored during the intervention periods – most commonly triggered by diazepam, clonazepam, and indomethacin.  The intervention was successful in reducing doses for NSAIDs and for opiates, but had no significant effect on benzodiazepine or sedative-hypnotic dosing.

However, bizarrely, even though there was just a small difference in guideline-concordant ordering, there was a 4-fold reduction in adverse drug events – most of which occurred during the initial “off” period.  As a secondary outcome, there’s much to say about it other than “huh”.  None of their other secondary outcomes demonstrated any differences.

So, it’s an interesting study.  It is consistent with a lot of previous studies – most alerts are ignored, but occasionally small positive effect sizes are seen.  Their primary outcome measure is one of mostly academic interest – it would be better if they had chosen more clinically relevant outcomes.  But, no doubt, if you’re not already seeing a deluge of CDS alerts, just wait a few more years….

“Guided medication dosing for elderly emergency patients using real-time, computerized decision support”
http://www.ncbi.nlm.nih.gov/pubmed/22052899

TEG and Dabigatran

An interesting mini-letter from my institution regarding dabigatran, thromboelastography, and poor outcomes.

It simply notes and reinforces the fact that conventional coagulation studies in patients on dabigatran will be normal – and therefore conventional reversal options are unlikely to be of value.  The only abnormality detected was prolongation of the activated clotting time, corresponding to inhibition of enzymatic clotting.

Multiple patients have presented after traumatic injury to our institution, and they have universally had poor outcomes.

“Acutely Injured Patients on Dabigatran”
http://www.nejm.org/doi/full/10.1056/NEJMc1111095

No More Excuses For Not Giving TPA

Rather than restrict TPA for acute ischemic stroke to the small cohort of patients identified by strict exclusion criteria in the few completed randomized trials, the current crusade is to continue to try and give it to more patients on the fringes of eligibility.

This article promotes giving TPA to patients with “minor or rapidly improving” strokes, because the lead author (sponsored by Genentech) sees this classification of patients is responsible for 50% of the documented reasons why patients were excluded from receiving TPA.  In fact, if patients with mild and improving strokes received TPA, it would immediately double the rate of TPA use – and provide potentially excellent outcomes at 90 days for the manufacturers.

They base their assertions on a retrospective, uncontrolled evaluation of the discharge disposition of patients in this “minor or rapidly improving” cohort – and observe that only 72% of patients in this group were discharged home.  In their mind, patients could do much better (as measured by disposition location) if they had received TPA – and their final conclusion is that this exclusion criteria should be further studied so that it may be revoked.

But, their conclusions are a preposterous farce conjured out of fictionalization of the data.  Considering the median age of their cohort was 72, 30% of whom had prior stroke/TIAs, 26% were diabetic, 76% were hypertensive, etc. – the sheer fact that only 28% went to rehab/SNF/died is probably rather good performance.  The authors also admit they had no information regarding the initial residence of this mostly elderly cohort and have no idea if the patients discharged to nursing facilities originally resided there.  Finally, the article additionally states “outcomes for patients with mild/rapidly improving stroke were better than for rtPA-treated patients with mild stroke (NIHSS score of 0 to 5) but worse for patients with a final diagnosis of TIA.”

Yes, they compared this mild stroke cohort data to the mild stroke cohort data that received TPA, and all outcomes – adjusted and unadjusted for NIHSS – significantly favored the non-TPA cohort.

….so the obvious conclusion is to find a way to give more of them TPA.

Lunacy.  Another example of bad literature undermining trust in a probably efficacious treatment.

“Outcomes in Mild or Rapidly Improving Stroke Not Treated With Intravenous Recombinant Tissue-Type Plasminogen Activator”
www.ncbi.nlm.nih.gov/pubmed/21903949

Medication Errors During Resuscitation

According to previous literature from 2002, up to 19% of medication doses are administered in error to hospitalized patients.  Presumably, we’ve improved.

Apparently, we haven’t.  This is a prospective observational study by pharmacists in Pittsburgh who observed the inpatient Medical Emergency Team in operation – which in this instance, was a physician-led team with “full” critical care capabilities, as opposed to their non-physician Rapid Response Team.  They observed medication administration during 50 of these calls and found that there were 1.6 errors per medication administration.  Yes, they really observed more than one error per dose – but 66% of those issues involved aseptic technique.  Subtracting those, they observed an error merely every other dose.  46% were prescribing errors, 28% administration technique, 14% mislabeling, 10% preparation, and 2% improper doses.  The authors eventually conclude that 14% of the total non-aseptic errors were truly harmful, not just “errors”.

Despite the small sample size, I think it’s a fair assessment that “medical emergency” situations can be chaotic and error-prone – and we still have a ways to go to implement systemic changes to prevent errors.

In the end, the pharmacists’ solution is – more pharmacists.  Hmmm….

“Medication Errors During Medical Emergencies in a Large, Tertiary Care, Academic Medical Center”
www.ncbi.nlm.nih.gov/pubmed/22001000

Dabigatran Worsens/Does Not Worsen Bleeding

Stroke and Circulation are both Journals under the umbrella of the American Heart Association.  So, when they publish articles that come to contrasting conclusions, I find that entertaining.

Both of these articles are mouse models of bleeding on dagibatran, C57BL/6 or CD-1 mice.  Sadly, they are frighteningly complex in their adjustments and statistical analyses – which means it defeats my ability to concisely summarize the findings and methods.

In short, one of these articles looks at intracranial hemorrhage after collagenase injection for mice receiving several different doses of oral dabigatran, and compare it to controls, warfarin, lepirudin, fondaparinux, and heparin.  It appears, and the author’s final conclusion is, that dabigatran is the least harmful of all anticoagulants – about halfway between controls and the other anticoagulants.  They also shoot the mice with lasers in another portion of the study, and dabigatran “wins” that as well.

The other article looks at trying to reverse dabigatran – which, if you recall the human study I posted a few weeks back, was not successful in humans.  However, human trials were all surrogate markers of bleeding as measured by laboratory measurements of clotting.  What entertains me is, in contrast to the other study, these authors have no trouble inducing bleeding and significant ICH formation with dabigatran.  In any event, once the mice were adequately bleeding, the authors compared prothrombin concentrate complexes (specifically, Beriplex), FFP, and FVIIa for treatment of ICH 30 minutes after induced injury with collagenase.  Happily, PCCs, in a dose-dependent manner, attenuated the induced ICH, while the others failed.

So, perhaps this “novel, reversible” anticoagulant has a treatment option for life-threatening bleeding.  Human confirmation, at least case reports, needed.

“Anticoagulation With the Oral Direct Thrombin Inhibitor Dabigatran Does Not Enlarge Hematoma Volume in Experimental Intracerebral Hemorrhage”
http://circ.ahajournals.org/content/early/2011/09/11/CIRCULATIONAHA.111.035972.abstract

“Hemostatic Therapy in Experimental Intracerebral Hemorrhage Associated With the Direct Thrombin Inhibitor Dabigatran”


A Third of TPA Patients Do Not Have Stroke

…but they almost all do well!  Only 5.1% of patients without stroke who receive TPA end up with intracerebral hemorrhage – so it’s OK that we give TPA to a ton of patients without a confirmed diagnosis of stroke, right?

This is a retrospective Finnish registry study of 1,104 consecutive TPA patients enrolled in a prospective cohort.  Of these, 119 had basilar artery occlusion, which is angiographically proven prior to treatment, and are excluded from their analysis, and a couple others were excluded for other reasons.  This left 985 patients who were initially diagnosed with ischemic stroke, and, eventually, 14 of those patients were diagnosed as a stroke mimic such as migrane, epilepsy, or a demyelinating disorder.  The authors then go on to say that stroke mimics such as these accounted for a mere 1.4% of all TPA patients, and none of them had ICH.

But, this isn’t exactly a true reading of their data.  The authors also state that 275 of their patients had “neuroimaging negative ischemic stroke”, which is to say, their follow-up MRI detected no sign of infarct.  Now, there is a false-negative rate on DWI MRI for stroke, but it’s in the range of 5% for acute infarcts, and generally involves small lacunar, small cortical, and some posterior circulation strokes.  Not only that, it’s reasonable to suggest that around 40% of TIAs actually have DWI or FLAIR sequence abnormalities as well.

So, some of their “neuroimaging negative ischemic stroke” group probably does have ischemic stroke with false negative MRI – but not 30% of the study population.  And, some of their neuroimaging positive group is likely false positive from TIA as well.  These numbers for stroke mimics are also far below other reported case series, which have estimated 10-30% incidence, depending on whether TIAs are included.

I absolutely cannot fathom this line of reasoning and distortion Neurology is developing in justify recklessly pushing TPA onto a larger population.

“Stroke Mimics and Intravenous Thrombolysis”
http://www.ncbi.nlm.nih.gov/pubmed/22000770

N-acetylcysteine Overdose With Anaphylactoid Reaction and Myocardial Infarction

This is another toxicology case that illustrates a point I make (probably too often) to my residents – that every action we take has a risk of harm, whether known or unanticipated.  I’m probably the only attending who cancels their IM ketorolac orders and changes them to PO ibuprofen.  Why?  Because of cases like this.

This is an entirely appropriate therapy – N-acetylcysteine given for hydrocodone-acetaminophen overdose – gone wrong because of a mixing error resulting in 10-fold overdose (126,000mg loading dose!).  Anaphylactoid reactions are known side effects in N-acetylcysteine, and, unfortunately, this patient’s reaction was more severe than most, suffering an inferior MI with a peak troponin of 658ng/mL.  He expired 17 hour after the N-acetylcysteine overdose.

I’ve seen epinephrine given IV instead of SQ more than once (one time resulting in an MI), many medications are tissue toxic if they extravasate, you can get sterile abscess formation from intramuscular injections, etc.  The fewer interventions and the less invasive the interventions, the less risk at which we place our patients.

“Fatal myocardial infarction associated with intravenous N-acetylcysteine error”