Without evidence of benefit, an intervention should not be presumed to be beneficial or safe.

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Fentanyl in the out-of-hospital setting: variables associated with hypotension and hypoxemia

ResearchBlogging.org

Also posted over at Paramedicine 101 (now at EMS Blogs) and at Research Blogging. Go check out the rest of the excellent material at these sites.

On the most recent episode of the EMS Research Podcast,[1] Harry Mueller, Bill Toon, and I discuss a recently published paper examining what effect prehospital fentanyl has on hypoxemia or on hypotension.

This study’s objectives were to assess for association between prehospital fentanyl administration and the occurrence of either of the following: hypotension, defined as a drop in systolic blood pressure (SBP) to below 90 mm Hg in a patient at least 5 years of age, or hypoxemia, defined as a drop in peripheral oxygen saturation (SpO2) to below 90%.[2]

There were 500 patients and many of them received more than one dose of fentanyl. Several received 6 separate doses of fentanyl.

Even with so many doses given, the mean dose and maximum dose were not that high.[3]

The median dose of fentanyl per administration was 1.1 µg/kg (IQR 0.8–1.4; range 0.25–3.5 µg); the mean dose was 1.1 µg/kg (SD 0.46). Expressed as a total dose per patient (i.e., summing all doses in a given patient), the median dose was 2.5 µg/kg (IQR 1.7–3.9) with a mean of 3.0 µg/kg (SD 1.8).[2]

1.1 µg/kg per dose.

The maximum single dose is unusual and is not explained. range 0.25–3.5 µg which should be /kg.

How did one patient receive such a large single dose – 3.5 µg/kg? The thing that makes the most sense (if this was a dosing error) is that this was a small pediatric patient. I carry fentanyl in syringes that contain 100 µg in 2 ml (50 µg/ml), but they might carry vials that have a larger volume. for example, below is packaging for 250 µg in 5 ml (also 50 µg/ml). If an entire vial were given to a 140 kg patient, that would be a dose of 3.5 µg/kg.

Is that what happened?

I don’t know – and that is presuming that this is a dosing error, which may not be valid to presume.


Image credit.[4]

I like the idea of carrying 10 mg morphine syringes and 100 µg fentanyl syringes. The total dose of each syringe is roughly equivalent in its effect on a patient. Except in very unusual circumstances, even a full 10 mg morphine, or 100 µg fentanyl, is not going to produce significant problems – and that is assuming that there is no judgment going into the dosing of patients.

Should we assume that there is no judgment going into the dosing of patients?

No, but I will get back to this in a little bit.

If this was not a dosing error, it is extremely aggressive dosing. I am comfortable giving a bit more than 1 µg to otherwise healthy trauma patients or burn patients, but I will at least give this a couple of minutes to have some kind of effect and reassess the patient before giving more. Similarly, with morphine, I might give up to 0.15 mg/kg to these same patients. 3.5 µg/kg is about three times higher than I am comfortable with.

Does that make the dose inappropriate?

Without knowing the specifics, we really cannot tell.

Should we assume that there is no judgment going into the dosing of patients?

There are prior data to support the safety of appropriately administered opioids, including fentanyl. The study of Kanowitz et al., although more methodologically rigorous than most reports, is typical in its demonstration of safety: of 2129 patients receiving an opioid (fentanyl), only 12 (0.6%) had a medication-related vital sign abnormality and an intervention was required only once (in a patient who had no sequelae)(8) [2]

What about in this study?

It is noteworthy that, although the study HEMS program’s fentanyl protocol does not proscribe use of the drug in hypotensive patients, the crew are required to use the agent judiciously (in other words, at the lower end of the recommended dosage range). This means that the safety of fentanyl as demonstrated in the current study may be related to more conservative dosing in unstable patients, but the parallel message is that experienced EMS crews are able to exercise judgment in determining which patients should receive cautious drug dosing.[2]

Should we assume that there is no judgment going into the dosing of patients?

experienced EMS crews are able to exercise judgment in determining which patients should receive cautious drug dosing.

The authors of this study do not come to the conclusion that EMS crews cannot make dosing decisions independently. The authors come to exactly the opposite conclusion.

What about the hypotension and hypoxemia?

New hypotension (i.e., post-fentanyl SBP < 90 in a patient at least 5 years of age, with pre-fentanyl SBP at least 90) was seen in 28 administrations (2.7% of 1055 administrations, 95% CI 1.8–3.8%).[2]

Vital signs were measured within ten minutes of each dose of fentanyl (usually within 5 minutes).

Does hypotension developing so soon after fentanyl mean that the fentanyl caused the hypotension?

No.

It is possible that fentanyl did cause the hypotension.

It is possible that fentanyl did contribute to a drop in the blood pressure.

It is possible that fentanyl did not affect the blood pressure at all.

It is possible that fentanyl had the effect of increasing the blood pressure, but that increase was outweighed by something else causing a greater drop in blood pressure.

We do not have enough information to determine what effect fentanyl has on blood pressure in these patients, but we no longer have a good reason for expecting that fentanyl will produce hypotension.

There are many possible side effects of fentanyl, but even in hypotensive patients we should not expect any sudden deterioration in blood pressure with judicious administration of fentanyl by competent EMS personnel.

The authors do make one error here. They use the total number of administrations of fentanyl in their calculation of the rate of new hypotension to come up with 2.7%.

Overall, in 45 cases (4.3% of 1055), fentanyl was administered to patients who were hypotensive.[2]

Those 45 patients should be excluded from the calculation of new hypotension. Therefore the rate should be 2.8%, rather than 2.7%. This does not change the conclusions in any way. This is just a technicality.

What about those 45 patients who were hypotensive before receiving fentanyl?

In 53% of these cases, hypotension (predictably) remained after the opioid was given—but in 47% of cases in which fentanyl was administered to hypotensive patients, the next SBP exceeded 90.[2]

About half of the patients who were hypotensive before fentanyl were not hypotensive after fentanyl.

While 45 is a small number of hypotensive patients, how many of us would like to have a treatment for hypotension that is effective on half of our patients?

I am only partly kidding.

We do not know what other treatments were being provided, but how many of these patients may have had changes to their vital signs due to severe pain?

We presume that fentanyl will make vital signs worse, but that is a mistake. We may make less of a mistake with worrying that morphine will cause hypotension, based its potential for histamine release.

What was the effect of fentanyl on vital sign abnormalities in the Kanowitz study of fentanyl?

Of the 2,315 patients who received fentanyl in the field, 66 patients had a vital sign abnormality. Of those 66 patients, three were excluded because they received a sedative in addition to the fentanyl. There were 46 patients who were excluded because their vital sign abnormalities occurred before the administration of fentanyl. Of the 46 patients who had a vital sign abnormality before the administration of fentanyl, 38 patients’ vital signs improved after the administration of fentanyl, eight patients’ vital signs remained the same, and none worsened.[5]

Of the 46 patients who had a vital sign abnormality before the administration of fentanyl, 38 patients’ vital signs improved after the administration of fentanyl, eight patients’ vital signs remained the same, and none worsened.

It is possible that fentanyl is improving vital signs by decreasing pain.

The problem is that so many of us do not take the pain of others seriously, so we do not expect pain to lead to problems with vital signs.

Does the improvement in vital signs so soon after fentanyl mean that the fentanyl caused the improvement in vital signs?

No.

It is possible that fentanyl did cause the improvement in vital signs.

It is possible that fentanyl did contribute to an improvement in vital signs.

It is possible that fentanyl did not affect the vital signs at all.

It is possible that fentanyl had the effect of worsening the vital signs, but that worsening was outweighed by something else causing a greater improvement in vital signs.

We do not have enough information to determine what effect fentanyl has on vital signs in these patients, but we no longer have a good reason for expecting that fentanyl will frequently produce bad vital signs. Fentanyl was much more likely to be followed by an improvement in vital signs.

We almost forgot about hypoxemia. Hypoxemia is an even bigger concern than hypotension.

What effect did fentanyl have on hypoxemia?

Assessment of the 522 administrations in 279 non-intubated patients revealed no difference in the mean SpO 2 readings before (98.8%, 95% CI 98.5–98.9) and after (98.6%, 95% CI 98.3–99.0) fentanyl administration. There were no instances of hypoxemia in these non-intubated patients receiving fentanyl (one-sided 97.5% CI for 0/279: 0–1.3%).[2]

Not even a single instance of hypoxemia.

None.

This was such a big concern that one of the helicopter services near me (based in a university hospital) only permitted flight crews to give fentanyl after a patient was intubated.

No tube – no fentanyl.

Myth busted.

We do need to be cautious about the administration of fentanyl to any patient. We should continually monitor ECG, SpO2, blood pressure, respiratory drive, and level of consciousness. With higher doses we should also continuously monitor waveform capnography.

Fentanyl is safe in the hands of competent EMS providers.

Fentanyl should not require medical command contact for any dose.

Go listen to the podcast.

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Footnotes:

[1] Fentanyl Study: EMS Research Episode 9
EMS Research Podcast
Podcast

[2] Fentanyl in the out-of-hospital setting: variables associated with hypotension and hypoxemia.
Krauss WC, Shah S, Shah S, Thomas SH.
J Emerg Med. 2011 Feb;40(2):182-7. Epub 2009 Mar 27.
PMID: 19327928 [PubMed – in process]

Full Text PDF Download at medicalscg.

[3] Mean, Median, Mode, and Range
Purplemath
Article

It is good to be clear on what the meaning of the terminology. This has the simplest explanation I found in a very brief search.

The “mean” is the “average” you’re used to, where you add up all the numbers and then divide by the number of numbers. The “median” is the “middle” value in the list of numbers. To find the median, your numbers have to be listed in numerical order, so you may have to rewrite your list first.

[4] FENTANYL CITRATE injection, solution
[Baxter Healthcare Corporation]

FDA Label
DailyMed
How Supplied
Free Full Text FDA Label from DailyMed with links to Free Full Text PDF Download.

[5] Safety and effectiveness of fentanyl administration for prehospital pain management.
Kanowitz A, Dunn TM, Kanowitz EM, Dunn WW, Vanbuskirk K.
Prehosp Emerg Care. 2006 Jan-Mar;10(1):1-7.
PMID: 16418084 [PubMed – indexed for MEDLINE]

Free Full Text PDF Download from MSTC.

Krauss, W., Shah, S., Shah, S., & Thomas, S. (2011). Fentanyl in the Out-of-Hospital Setting: Variables Associated with Hypotension and Hypoxemia The Journal of Emergency Medicine, 40 (2), 182-187 DOI: 10.1016/j.jemermed.2009.02.009

Kanowitz A, Dunn TM, Kanowitz EM, Dunn WW, & Vanbuskirk K (2006). Safety and effectiveness of fentanyl administration for prehospital pain management. Prehospital emergency care : official journal of the National Association of EMS Physicians and the National Association of State EMS Directors, 10 (1), 1-7 PMID: 16418084

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