HYMR1

Wednesday, February 24, 2016

Weighing In On Alteplase Dosing: Is Estimating Weight Harming Our Patients?

When a stroke victim rolls into the emergency department (ED) we know we have a limited time window to administer alteplase (recombinant tissue-type plasminogen activator [r-tPA]). The pressure of this narrow therapeutic window often pressures hospital staff to administer the potentially brain-saving medication as early as possible. Often, administration is hastened by estimating patient weight as a basis for calculating the critical 0.9 mg/kg weight-based dose.

However, the question remains if we are appropriately estimating patient weight and if not, what consequences does this bear on the patient?

A retrospective analysis by Barrow et al. recently published in Stroke is the largest study to date on this topic.1 The study analyzed 242 patients with stroke who received an alteplase dose based on an estimated body weight. Following determination of actual patient weight investigators calculated the dosing error. Primary outcome measures included improvement in National Institute of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS) scores.

Alarmingly, investigators found that 19.7% of patients received an inappropriate dose (as defined by a deviation of at least 10% from appropriate calculated dose). Clinicians in the study significantly over-dosed the lightest patients and under-dosed the heaviest patients.

Dosing errors did not significantly affect mRS scores or rate of intracranial hemorrhage (ICH). However, NIHSS score improvement was greater in the subset of patients of the lightest weight in comparison to the subset of patients of the heaviest weight (p = 0.048). These results conflict with earlier findings by Messé et al. citing an increased trend of ICH in patients who received higher doses due to overestimation of weight with no findings of decreased efficacy in patients who received lower doses due to underestimation of weight.2

Of notable importance, heavier patients in the study were associated with higher baseline NIHSS scores, implying that heavier patients had more severe strokes (p < 0.001).1 Thus, whether the heavier patients in the study had poorer outcomes due to under-dosing, higher stroke severity, or a combination of the two remains unclear.

What is clear? Estimating weight for alteplase dosing is clearly unreliable and an error rate of nearly 20% is alarming and consistent with prior findings.

Hall et al. found that an ED provider cohort made up of physicians, paramedics, nurses, and medical students appropriately estimated weight within 5 kg in only 28.1% of patients.3 Additional research from the WAIST-study also revealed an error rate of 33% and also described a trend of worse outcomes in under-dosed stroke patients.4

Based on the consistent erroneous findings of weight estimating in stroke patients across various studies, the utilization of beds in the ED with the capability of measuring weight should be used whenever possible in order to minimize weight-based dosing errors and their potentially negative impact on patient outcomes.

Laura C. Johnson, PharmD
PGY-1 Pharmacy Resident
Trinity Mother Frances Hospital
Tyler, Texas

Peer reviewed by:
Craig Cocchio, PharmD, BCPS

References:

1. Barrow T, Khan MS, Halse O et al. Estimating weight of patients with acute stroke when dosing for thrombolysis. Stroke. 2016;47(1):228-31.
2. Messé SR, Tanne D, Demchuk AM et al. Dosing errors may impact the risk of rt-PA for stroke:
the Multicenter rt-PA Acute Stroke Survey. J Stroke Cerebrovasc Dis. 2004;13(1):35-40.
3. Hall WL, Larkin GL, Trujillo MJ et al. Errors in weight estimation in the emergency department: comparing performance by providers and patients. J Emerg Med. 2004;27(3):219-24.
4. Breuer L, Nowe T, Huttner HB et al. Weight approximation in stroke before thrombolysis: the WAIST-Study: a prospective observational "dose-finding" study. Stroke. 2010;41(12):2867-71.

Thursday, February 11, 2016

Gabapentin Misuse: A Growing Challenge

With the opioid abuse epidemic that we clinicians in the emergency department encounter as part of our daily practice, the movement towards the use of alternative agents continues to evolve for the management of pain in our patients. In taking advantage of traditional and novel mechanisms of action of these agents, acute pain in patients in the emergency department may be managed appropriately without posing the risk of introducing opioid-naive patients to opioids or worse, exacerbating pain that is inadequately treated with opioids in the first place.

For patients who may present with neuropathic pain, one agent that has been advocated in recent years is gabapentin (GBP), which is considered to be an off-label use of this agent. In fact, it is said that this agent possesses far more off-label indications than those approved by the FDA, the former which include diabetic neuropathy, trigeminal neuralgia, and maintenance of abstinence secondary to drug and alcohol withdrawal (1). Anecdotally speaking, a modest proportion of patients who present to the emergency department at my institution are on GBP as chronic outpatient therapy for these and other conditions.
In terms of its activity, although it is structurally similar to gamma aminobutyric acid, GBP does not exert its action associated with the management of neuropathic pain within this system. It functions by binding to the alpha-2/delta subunit at voltage-gated sensitive calcium channels that leads to modulation of the influx of calcium, which ultimately reduces the extent of pain associated with neuropathy by minimizing the release of excitatory neurotransmitters responsible for this sensation such as glutamate, norepinephrine, and substance P (2-4).

The latest Cochrane review related to the utility of GBP for the management of neuropathic pain and fibromyalgia has suggested that it may indeed be beneficial in some patients for these conditions, but as is the case with these somewhat challenging conditions, it may be difficult to predict who may actually benefit from treatment, with the risk of adverse events leading to some patients being unable to tolerate treatment with GBP altogether (5).

However, recent literature has suggested while GBP is widely prescribed for a multitude of conditions in patients across the globe, there is a concern for misuse (and abuse) of GBP that is seemingly on the rise, and should not go unrecognized.

Et tu, gabapentin?

In one review, of those cohort of patients with established recognition of opioid abuse, the misuse of GBP within this population is estimated to occur at a rate of upwards of 22%, and among this subgroup, between 40 and 65% of patients had a prescription for GBP for predominantly off-label use (6). Substantial misuse of GBP has been noted to occur within England, Scotland, and Finland (7-10), but observations of misuse are being increasingly reported to take place in the United States. In fact, a recently published prospective analysis of 503 subjects in Kentucky who reported diversion and non-medical use prescription opioids highlights that 15% of patients utilized GBP to achieve a state of being "high" in 2014, which represents a nearly 3000% increase in this trend compared to 2008 (11).

In most cases, higher than prescribed doses are often utilized for this purpose, and the descriptions of patient experiences related to the "high" experienced with GBP are eerily not dissimilar to those related to opioids and benzodiazepines (6, 12). Furthermore, GBP has been reported to be used as a means to potentiate the "high" associated with misuse of other agents, including buprenorphine and methadone (8, 13).

The incidence of withdrawal is also not uncommon with GBP, with signs and symptoms occurring as early as 24 hours and as late as 7 days following abrupt cessation of therapy. Signs and symptoms consistent with GBP withdrawal include agitation, confusion, disorientation, diaphoresis, hypertension, and insomnia (12). In addition, there is one documented case in the literature thus far of neonatal withdrawal secondary to gabapentin (14).

Interestingly enough, as discussed in a previous blog post written by Craig, the "evil stepsister" of GBP, pregabalin, which shares some structural similarities to its sister compound, is categorized as a schedule V substance in the United States. This certainly begs the question as to whether the same should apply to GBP itself.

Part of the challenge related to this issue is that GBP has traditionally held a long reputation of being a relatively inexpensive medication that is widely available, safe, and effective and not capable of misuse or diversion. However, this claim to fame of minimal to no abuse potential associated with GBP has never been formally evaluated nor established in a controlled clinical environment since its approval by the FDA in 1993. Time will tell whether this will occur in the future, given the growing challenges and issues that GBP has posed to countries across in the EU and the increased recognition of these same issues here in the United States.

References:
  1. Mack A. Examination of the evidence for off-label use of gabapentin. J Manag Care Pharm 2003; 9(6):559-68.
  2. Stahl SM. Anticonvulsants as anxiolytics, part 2: Pregabalin and gabapentin as alpha(2)delta ligands at voltage-gated calcium channels. J Clin Psychiatry 2004; 65(4):460-1.
  3. Bockbrader HN, Wesche D, Miller R, et al. A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin. Clin Pharmacokinet 2010; 49(10):661-9.
  4. Kukkar A, Bali A, Singh N, et al. Implications and mechanism of action of gabapentin in neuropathic pain. Arch Pharm Res 2013; 36(3):237-51.
  5. Moore RA, Wiffen PJ, Derry S, et al. Gabapentin for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev 2014; 4:CD007938.
  6. Smith RV, Havens JR, Walsh SL. Gabapentin misuse, abuse, and diversion: A systematic review. Addiction 2016 [Epub ahead of print].
  7. Kapil V, Green JL, Le Lait MC, et al. Misuse of the γ-aminobutyric acid analogues baclofen, gabapentin and pregabalin in the UK. Br J Clin Pharmacol 2014;78(1):190-1.
  8. Baird CR, Fox P, Colvin LA. Gabapentinoid abuse in order to potentiate the effect of methadone: A survey among substance misusers. Eur Addict Res 2014; 20(3):115-8.
  9. Smith BH, Higgins C, Baldacchino A, et al. Substance misuse of gabapentin. Br J Gen Pract  2012; 62(601):406-7.
  10. Häkkinen M, Vuori E, Kalso E, et al. Profiles of pregabalin and gabapentin abuse by postmortem toxicology. Forensic Sci Int. 2014; 241:1-6.
  11. Smith RV, Lofwall MR, Havens JR. Abuse and diversion of gabapentin among nonmedical prescription opioid users in Appalachian Kentucky. Am J Psychiatry 2015; 172(5):487-8.
  12. Mersfelder TL, Nichols WH. Gabapentin: Abuse, dependence, and withdrawal. Ann Pharmacother 2015 [Epub ahead of print].
  13. Reeves RR, Ladner ME. Potentiation of the effect of buprenorphine/naloxone with gabapentin or quetiapine. Am J Psychiatry 2014; 171(6):691.
  14. Carrasco M, Rai SC, Bearer CF, et al. Neonatal gabapentin withdrawal syndrome. Pediatr Neurol 2015; 53(5):445-47.

Wednesday, February 3, 2016

Managing Rate Control in the Face of Borderline Hypotension

Encountering patients in afib with RVR is a daily occurrence in the emergency department. Rate control with AV blocking drugs are standard approaches for stable patients and good ol’ electricity for those who are unstable. But there is a group in-between that presents a different challenge. Those who are in afib but are relatively hypotensive, by which I mean SBPs in the 90’s or low 100’s. In these patients, pharmacologic rate control may improve SBPs by slowing the ventricular rate sufficiently to allow for adequate filling and thus improve cardiac output. But that is almost always balanced by the risk of hypotension caused by drugs like diltiazem or metoprolol.

In order to avoid the initiation of amiodarone or digoxin, two drugs notorious for a myriad of short term adverse events, long term toxicity and clinically significant drug-drug interactions, there are certain strategies that seem to be overlooked. Those strategies include using low-dose diltiazem, extended bolus diltiazem, or esmolol. (Administration of calcium prior to CCB has been covered elsewhere, but is generally not regarded as effective.)
 
Traditional teachings of rate control with diltiazem quote doses starting at 0.25 mg/kg followed by 0.35 mg/kg if the first bolus is unsuccessful. While certainly effective and are associated with lower incidences of hypotension versus verapamil, these doses may be less than ideal in every patient. Individualizing doses for patients in this relative hypotension range poses a potential advantage. In one study from 2011, investigators randomized an ED population of patients presenting with afib + rvr to low (< 0.2 mg/kg), standard (> 0.2 to < 0.3 mg/kg) or high dose diltiazem (> 0.3 mg/kg) to achieve a positive clinical response defined as a reduction in ventricular response rate (VRR) to 100 bpm or a VRR reduction of at least 20% from baseline within 30 minutes.1 Safety was also assessed when episodes of SBP < 90, or reduction of at least 20% from baseline, respiratory failure requiring intubation, cardiac arrest or onset of unstable rhythms occurred within 30 minutes.

Patients who received low dose (0.14 mg/kg + 0.04) achieved a similar rate of overall clinical success (p = 0.605) but a lower incidence of overall complications (p = 0.025). This rate of overall complications was driven by a lower incidence of reductions of SBP by at least 20% between groups (low: 18.0%; standard: 33.7%; high 38.9%, p = 0.047). However, these patients were normotensive at the time of study drug administration, limiting the ability to extrapolate to the relative hypotensive population in question. Never the less, there is virtually no evidence, aside from scant case reports to go on. The authors concluded that this is a promising dosing alternative, but certainly not ready for widespread implementation.

A slightly different approach to diltiazem in this scenario is a bolus-from-the-bag approach. Credit to emcrit (http://emcrit.org/podcasts/crashing-a-fib/) for pointing in this direction in an old podcast, administering diltiazem 2.5mg/min (maximum 50 mg, or 20 minutes) until desired HR is achieved. Although studied in an SVT, this seems to be a reasonable approach that maximizes dose but can limit hypotension by infusing the bolus much slower than would normally be done in the ED.2


Esmolol is on its way to being one of the ED’s new favorite drugs (at least in my opinion). As a result of its relative "newness" and the association of it with the high cost during its branded days, esmolol is often not thought of as a therapeutic option. But over recent years, esmolol has developed a following for its novel application in septic shock and refractory ventricular fibrillation.3,4 Although, afib with RVR still underutilizes this drug particularly in the relative hypotensive patient. Taking advantage of it’s rapid-on, rapid-off kinetics (onset in seconds with a half-life of ~ 9 minutes), if hypotension were to occur it could quickly be shut off. Evidence is lacking, unfortunately, in the ED, let alone in the relative hypotensive patient. Most research with this drug comes from PACU/post-op settings with limited generalizability. However, the pharmacology/kinetics and lack of alternatives make it a promising option.

Critical to the effectiveness of esmolol is administering the bolus. I’ve experienced (anecdotally) if 500 mcg/kg is recommended, it’s perceived to be a high dose and avoided. But simply taking advantage of the metric system, and recommending 0.5 mg/kg followed by the drip at 50 mcg/kg/min tends to be more successful.

There is no good answer in choosing a rate control strategy for the afib with rvr patient who’s SBP is in the 90’s to low 100’s and otherwise not hemodynamically unstable. Most of the time, slowing the ventricular rate will improve the patients SBP, but there may an opportunity to use alternative dosing strategies for diltiazem or another drug altogether in esmolol.

References:
  1. Lee J, et al. Low-dose diltiazem in atrial fibrillation with rapid ventricular response. Am J Emerg Med. 2011 Oct;29(8):849-54.
  2. Lim SH, et al. Slow-infusion of calcium channel blockers in the emergency management of supraventricular tachycardia. Resuscitation. 2002 Feb;52(2):167-74.
  3. Morelli A, et al. Effect of heart rate control with esmolol on hemodynamic and clinical outcomes in patients with septic shock: a randomized clinical trial. JAMA. 2013 Oct 23;310(16):1683-91.
  4. Driver BE, et al. Use of esmolol after failure of standard cardiopulmonary resuscitation to treat patients with refractory ventricular fibrillation. Resuscitation. 2014 Oct;85(10):1337-41.

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