Category Archives: Pharmacy

How Many Salt Tabs In A Liter Of Saline?

Seems like a simple, silly question, right? I dare you to figure it out without reading this post!

horse-salt-block-lick2

On occasion, our brain injured trauma patients have sodium issues. You know, cerebral salt wasting. Trying to maintain or regain the normal range, without making any sudden moves can be challenging. There are a lot of tools available to the trauma professional, including:

  • Saline
  • Hypertonic saline
  • Salt tablets
  • Fluid restriction
  • Some combination thereof

Fun times are had trying to figure out how much extra sodium we are giving with any of the first three items. This is important as you begin to transition from the big guns (hypertonic), to regular saline, and then to oral salt tabs.

Below is a quick and dirty conversion list. I won’t make your heads explode by trying to explain the math involved changing between meq, mg, moles, sodium and sodium chloride.

  • The “normal saline” bags we use are actually 0.9% saline (9 gm NaCl per liter)
  • Hypertonic saline can be 3% or 5% (30 gm or 50 gm per liter)
  • Salt tabs are usually 1 gm each (and oh so yummy)

Therefore, a liter of 0.9% normal saline is the same as 9 salt tabs.

A liter of 3% hypertonic saline is the same as 30 salt tabs. The usual 500cc bag contains 15.

A liter of  5% hypertonic saline is the same as 50 salt tabs. The usual 500cc bag contains 30.

To figure out how many tablets you need to give to match their IV input, calculate the number of liters infused, then do the math! And have fun!

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What Should We Call Them? NOAC vs DOAC

They are the bane of trauma professionals, the anticoagulants that cannot be easily or cheaply reversed. Yes, I’m talking about the direct thrombin inhibitors and the Factor Xa inhibitors. They were originally called NOACs, or novel oral anticoagulants since they were newer than the old standard, warfarin. But they’ve also been listed as DOACs (direct) or TSOACS (target-specific, just rolls off the tongue doesn’t it?).

Here’s a nice table I put together recently showing the all the common oral agents available. Click the image for a full-size, more readable image.

Dabigatran was the first of the newer oral agents, and it is the only direct thrombin inhibitor in the group. The rest are Factor Xa inhibitors. This is easy to remember if you look at their generic name. Each will contain “xaban.” Get it? Xa ban.

The daily cost of warfarin is about $7, while the daily cost of the others is around $16 per day. However, that does not take into account the cost of blood work to monitor INR in those taking warfarin, so it’s cost will be higher.

What I found most interesting was the cost of the reversal agents, if any. For warfarin it’s either a hit of 4-factor prothrombin complex concentrate or many bags of plasma. Praxbind for the DTI dabigatran appears to be a bargain! But look at the agent for the Xa inhibitors, Andexxa! Almost $50K per pop!

And what about the asterisk, you ask? That means that there is no literature available that shows that these expensive drugs are clinically effective! But they seem like they should work. Hmm.

Anyway, back to the nomenclature. NOACs or DOACs? Opinion is moving away from NOAC because it can be misinterpreted as “no anticoagulants.” The International Society on Thrombosis and Haemostasis polled their members, and the consensus opinion was that DOAC should be adopted for common use.  They add that the specific mechanism of action (direct thrombin vs Xa inhibitor) should be specified in addition to the DOAC acronym when clinically relevant.

Bottom line: DOAC wins! So hopefully we can all converge on using one common term for this group of drugs. Yet I still shudder when I have a head injured patient that tells me they are taking any of them!

Reference: Recommendation on the nomenclature for oral anticoagulants: communication from the SSC of the ISTH.  J Thrombosis Haemostasis 13(6):1154-1156, 2015.

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Platelet Transfusion In Patients Taking Anti-Platelet Drugs

These days, trauma professionals see quite a few patients who take antiplatelet agents for cardiovascular comorbidities. These drugs can be problematic when the patients sustain injuries that result in bleeding in problematic areas like the cranial vault.

Aspirin and clopidogrel are the most common medications, and they irreversibly inhibit platelet aggregation.  All exposed platelets essentially quit working for the remainder of their 10-day lifespan. Platelet aggregation improves slowly over time after cessation of the drug as new platelets are added to the circulation from the bone marrow.

But what can you do if you are concerned that your patient is bleeding after injury because their platelets are not working? It seems logical that you would just transfuse some new platelets. But you should know by now that not everything that makes sense really works. A group in France designed a study to test this premise in patients taking either aspirin or clopidogrel. They performed a prospective, observational study on patients presenting with potentially life-threatening hemorrhage.

The authors used the Verify Now device to measure platelet response to the two drugs. Patients who had normal platelet function in the first place (not compliant or not a responder to the therapy) were excluded. All patients had initial platelet counts greater than 100K/ml. They underwent platelet transfusion for management of hemorrhagic shock, intracranial hemorrhage, or an emergent neurosurgical procedure.

Here are the factoids:

  • Only 25 patients were enrolled during the three year study; 13 were receiving only aspirin, 8 clopidogrel only, and 4 combined therapy
  • Average transfusions were 1-2 apheresis packs of platelets (6-12 units)
  • For aspirin patients, all showed significant platelet dysfunction before transfusion, and all but one showed recovery of function post-transfusion
  • For clopidogrel patients, platelet function remained impaired; the percent of inhibited platelets decreased but remained above the study threshold for “normal” of 20%

Bottom line: This is a very small study, but drives home the point that clopidogrel and its relatives may be problematic in bleeding patients. The active metabolites of this drug class are not well understood. But they are most likely still circulating in the blood in patients actively taking them, and deactivate new platelets as soon as they are transfused (assuming that the transfused platelets have good function in the first place). 

This issue requires further study so we can really tease out the actions of the drugs and their effect on transfused platelets. Until then, carefully consider whether platelet transfusion will be helpful in your bleeding patients, and if it is even worthwhile giving them or waiting for them to finish prior to going to the operating room.

Reference: Is platelet transfusion efficient to restore platelet reactivity in patients who are responders to aspirin and/or clopidogrel before emergency surgery? J Trauma 74(5):1367-1369, 2013.

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Calcitonin Nasal Spray And Osteoporosis

Osteoporosis is a major risk factor for fractures in our elderly patients, particularly postmenopausal females. A number of treatment modalities have been introduced, primarily medications. One of the less expensive of these is salmon calcitonin nasal spray. This drug has been used sporadically in the spine surgery community and I’ve always been curious about the supporting data. So I finally looked into it and wanted to share my findings.

The earliest research that most tend to hang their hat on is the Prevent Recurrence of Osteoporotic Fractures (PROOF),  a five-year study from the early 90’s published in 2000. It was a double-blind placebo controlled study involving 47 centers in the US and UK. All subjects received supplemental calcium and Vitamin D daily. They also received one of three different doses of nasal calcitonin or a placebo daily.

Completion rates were dreadful. A total of 1,255 women with established osteoporosis started the study. Only 783 made it to 3 years and 511 to 5 years. Partly, this was due to the fact that the patients’ repeat bone density results were unblinded to the investigators, and the “statistically significant” increase in this value was only about 1.5%. I don’t believe that this is even close to clinically significant. Thus, the investigators and patients may have seen this as ineffective, dropped out of the study, and switched to some newer treatment.

As I mentioned, the study used a placebo dose of nasal spray, as well as 100, 200, or 400 unit doses daily. It is puzzling that only the 200 unit dose showed any statistically significant decline in recurrent spine fracture rate. Since the numbers in each analysis group were low due to patient attrition (about 275 in each group), this raises the question of whether this is a statistical anomaly. One would expect to see some sort of dose-response curve, not just a result only for the middle of the road dose.

The authors concluded that the 200 unit dose significantly reduces the risk of new vertebral fractures in postmenopausal women with osteoporosis. And unfortunately, multiple authors and clinicians have taken this to heart without questioning the real results in the paper.

A newer study, Oral Calcitonin in Postmenopausal Osteoporosis (ORACAL), published in 2012, compared oral vs nasal calcitonin in 565 women. Their endpoints were changes in bone density and markers of bone turnover. The oral group had a whopping increase (haha) in lumbar bone density of 1.5%, while nasal and placebo dosing were the same at about 0.5-0.8%. This is in no way clinically significant. And paradoxically this bone density increase appeared to peak by week 24 and then slowly decline.

Similarly, bone turnover markers decreased. Interestingly, of the three markers measured, some were statistically significant for oral, nasal, and even placebo. There was no consistent pattern. And furthermore, there is no way to translate these lab tests into risk for fracture.

Bottom line: Although nasal calcitonin spray is cheap (about $1 per day), there is no valid literature that supports that it decreases the risk of future vertebral fractures. Always remember that there is a difference between what is significant to the statisticians, and what is clinically significant to your patient. Incidentally, between 10% and 40% of these patients had adverse effects from the medication, usually GI in nature. So if a drug has a measurable risk but little actual benefit, is it worth even a buck?

Osteoporosis takes decades to develop and become clinically significant. It is unlikely that a quick fix like a drug, sprayed, swallowed, or injected will make a difference in the short term. The best treatments are free (diet and exercise) but must be adopted long before it becomes a problem.

References:

  1. A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the prevent recurrence of osteoporotic fractures study. Am J Med 109(4):267-276, 2000.
  2. A phase 3 trial of the efficacy and safety of oral recombinant calcitonin: The oral calcitonin in postmenopausal osteoporosis (ORACAL) trial. J Bone Mineral Res 27(8):1821-1829, 2012.
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Opioids In Trauma Care: A Suggestion?

In my last post, I reviewed a paper that showed how disorganized we are at responsibly prescribing and providing instructions for use of opioid pain medications. Today, I’ll look at a paper that attempts to provide a bit more concrete guidance on what to do.

This study was performed at Dartmouth, and consisted of a questionnaire sent to a group of patients who had undergone an inpatient general surgical procedure during a 6-month period. These were not trauma procedures, but included gastric bypass, sleeve gastrectomy, lap or open ventral hernia repair, laparoscopic fundoplication, hepatectomy, lap or open pancreatectomy, and lap, open, or robotic colectomy. The authors specifically looked at opioid use before discharge, length of stay and complications, and opioid prescriptions and refills.

After excluding patients who had preop opioid use or abuse, and those who developed postop complications, there were 234 study patients. Here are the factoids:

  • Overall, 85% patients were given opioid prescriptions, and only 38% of the medication prescribed was taken
  • Patients discharged on postop day 1 had different requirements from those who were discharged later, and were studied separately
  • 88% of patients discharged on day 1 had their opioid needs satisfied by 15 pills
  • For patients discharged after day 1, there was a very strong correlation with home needs and the amount of opioid required on the before discharge
  • 41% of patients took no pills the day prior to discharge, 33% took 1 to 3, and 26% took more than 4
  • Proper disposal of unused meds was extremely variable

Based on this information, the authors calculated that 85% of patients’ home opioid use would be met by using the following guideline:

  • If no pills were used the day prior to discharge, none were prescribed
  • If 1-3 were taken, 15 were prescribed
  • If 4 or more were taken, 30 were prescribed

The authors estimated that, if these guidelines had been followed in the patients reviewed, the number of pills prescribed would have decreased by about 40%.

Bottom line: This is an interesting attempt to answer our questions about opioid use after discharge. Of course, there are limitations in extrapolating this to the trauma population. The pain patterns in patients with fractures, chest trauma, or multiple injuries are very different than those with abdominal general surgical procedures,  especially those performed with a laparoscope  or robot. But it does demonstrate some key concepts:

  • It should be possible to systematize discharge prescribing in a significant number of patients
  • We need to provide guidelines and expectations to our patients to help them minimize their use of opioids after discharge
  • We also need to make sure that our patients know what to do if they run out of medication
  • These guidelines must include safe disposal instructions for unused meds so they can’t be diverted for inappropriate use

I’m looking forward to more papers that help quantify these concepts. In the meantime, I guess I’ll hit the drawing board and start sketching out an interim guideline to tide me over until that happens!

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