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Date: June 15, 2023

Reference: Rees CA et al. Intranasal fentanyl and discharge from the emergency department among children with sickle cell disease and vaso-occlusive pain: A multicenter pediatric emergency medicine perspective. American Journal of Hematology Jan 2023

Guest Skeptic: Dr. Amy Drendel is a pediatric emergency medicine physician and physician scientist at Children’s Wisconsin. She is a Professor of Pediatrics and Interim Chief of the Section of Pediatric Emergency Medicine at the Medical College of Wisconsin. Her research interests include optimizing pain treatment in children. She has been a principal investigator and co-investigator on multiple collaborative grants evaluating effectiveness of analgesic regimens for children.

Dr. Amy Drendel

Case: A 14-year-old male with sickle cell disease (SCD) presents to your emergency department (ED) with a vaso-occlusive pain episode (VOE) of his bilateral legs and back. He tells you that he has had similar pain from previous VOEs, but his sister is graduating from high school tomorrow, and he really hopes he can go home so he can attend her graduation. He denies any fever or difficulty breathing. On exam, he appears uncomfortable with tenderness to palpation of the bilateral shins and lower back. The rest of his exam is unremarkable. As you begin ordering bloodwork and a dose of intravenous (IV) morphine, his nurse says to you, “He looks very uncomfortable. Do you want to give him a dose of intranasal (IN) fentanyl while we’re waiting for an IV?”

Background: Children feel pain but are often under-treated. There are many options available to treat pediatric pain both pharmacologically (analgesics, NSAIDS, nerve blocks, sub-dissociative dose ketamine, and opioids) and non-pharmacologically (distraction, music, and splinting). [1-6]

Children with SCD presenting to the ED with VOE require timely and effective pain control. Opioids are the primary therapy. The National Heart, Lung, and Blood Institute (NHLBI) released an expert panel report in 2014 with evidence-based guidelines for management of sickle cell disease recommending timely administration of parenteral opioids for VOE. [7] However, multiple barriers including ED crowding, boarding, and staffing shortage contribute to delays in care.

IN fentanyl has been safely used to treat pain in pediatric patients. It offers a way to deliver analgesia without IV access. We have covered the use of IN fentanyl in children before in SGEM #123 and SGEM #242.

Clinical Question: How does intranasal fentanyl for the treatment of vaso-occlusive pain episodes in children with sickle cell disease impact disposition?

Reference: Rees CA et al. Intranasal fentanyl and discharge from the emergency department among children with sickle cell disease and vaso-occlusive pain: A multicenter pediatric emergency medicine perspective. American Journal of Hematology Jan 2023

  • Population: Children aged 3-21 years old, with sickle cell disease (Hemoglobin SS disease or Hemoglobin Sβ Thalassemia) who presented with vaso-occlusive pain episodes to
    • Excluded: Children with upper respiratory infection, concern for stroke or altered mental status, or head injury, acute chest
  • Intervention: Intranasal fentanyl (50 mcg/mL) delivered via atomizer with maximum of 100 mcg
  • Comparison: No intranasal fentanyl administration
  • Outcome:
    • Primary Outcome: Discharge home from the emergency department
    • Secondary Outcomes: Dose and route of opioids administered, the time of opioid administration, non-steroidal anti-inflammatory drug administration, use of IV fluid, time of ED or triage arrival to first opioid administration, time of day patient presented to the ED
  • Type of Study: Secondary analysis of a cross-sectional study from 20 academic pediatric emergency departments in the United States and Canada

Authors’ Conclusions: “Children with sickle cell disease who received intranasal fentanyl for vaso-occlusive pain episodes had greater odds of being discharged from the emergency department than those who did not receive it.”

Quality Checklist for Observational Study:

  1. Did the study address a clearly focused issue? Yes
  2. Did the authors use an appropriate method to answer their question? Unsure
  3. Was the cohort recruited in an acceptable way? Yes
  4. Was the exposure accurately measured to minimize bias? Yes
  5. Was the outcome accurately measured to minimize bias? Yes
  6. Have the authors identified all-important confounding factors? Unsure
  7. Was the follow up of subjects complete enough? Yes
  8. How precise are the results? Unsure
  9. Do you believe the results? Unsure
  10. Can the results be applied to the local population? Unsure
  11. Do the results of this study fit with other available evidence? Yes
  12. Funding of the Study: No financial conflicts of interest

Results: They included 400 patients with 54% being female. The median age was 14.6 years [IQR 9.8, 17.6]. Most patients (92%) had hemoglobin SS disease while the other 8% had Hemoglobin β Thalassemia. The overall rate of admission was 67%. 19% received IN fentanyl.

Key Results: Intranasal fentanyl administration for VOE in children with SCD was associated with greater odds of discharge from ED compared to those who did not receive it.

1.Selection Bias: The authors had investigators from the 20 sites review the charts of 20 consecutive children. The authors write that the annual volume of patients with SCD VOE at these emergency departments ranges from 80 to 700.

How were these 20 patients selected out of all those visits? Do they accurately represent the overall population that sought care for VOE? We are not sure.

Additionally, we do not have a detailed breakdown of the patient population by pain score. The authors mention that there was no difference in the mean change in pain scores among children who received IN fentanyl (mean -2.2, SD 2.54) compared to those who did not (mean -2.5, SD 3.28). They also found that children presenting with lower pain scores, larger reduction in pain scores, and lower overall morphine equivalent dosages of opioids had higher odds of ED discharge. These two points may mean that the patients who received IN fentanyl potentially had less severe pain or that children with lower pain scores may have received intranasal fentanyl preferentially.

2.Time and Dose of Opioid Administration: Children who received intranasal fentanyl received their first dose of parenteral opioid significantly faster compared to the children who did not. The authors looked at parenteral opioid administration ≤30 minutes after presentation to the ED and ≤60 minutes after presentation to the ED.

≤30 minutes:   OR 9.38, 95% CI 5.22-16.83

≤60 minutes:   OR 9.83, 95% CI 4.87-19.85

Time to administration of parenteral opioid pain medication is a metric that is tracked in EDs for patients with SCD and important factor in pain control. It’s possible that the faster administration of opioid therapy in general plays a bigger role in ability to discharge a SCD patient with VOE than simply the administration of IN fentanyl.

The multivariable analysis did NOT find that timeliness of opioid administration was associated with decreased odds of hospital admission which goes against this theory. However, based on best-practice and in alignment with the NHLBI recommendations, the more rapidly that pain treatment can be initiated for these kids, the better!

Children who received intranasal fentanyl received higher overall total parenteral opioid morphine equivalents (0.36 mg/kg, SD 0.14) compared to children who did not (0.22 mg/kg, SD 0.25). We are not sure if this also confounded the results. Ensuring adequate analgesia is important in the treatment of SCD with VOEs.

3.Admission Criteria: Overall hospital admission rate was 67%, which ranged from 45-90%. That is quite a bit of variability across these sites and does make us wonder if there is something about the patients, the treatments, or differences in practice at the different sites that might explain some of the variability.

IN fentanyl administration was still significantly associated with discharge even accounting for pain scores and opioid administration. Further, when the analysis includes only sites that administer IN fentanyl, the association is even stronger.

4.Additional Treatments: Almost 70% of patients who were admitted received bolus IV fluids compared to approximately 57% of patients who were discharged. Previous studies in this population have suggested that receiving IV fluid boluses of normal saline may be associated with worsening pain from VOE and volume overload.[8] It is unclear how this practice contributed to the results.

Knowing the variability in admissions it makes you wonder if there is a guideline or practice at sites with higher admission rates that supports administration of a bolus? Or is IV bolus just an indicator of pain severity.

Additionally, the authors found that administration of oral opioids was also associated with increased odds of discharge from the ED [OR 3.03 (95% CI 1.43, 6.60)]. Again, we are not sure why. Did these patients receive oral opioids in the ED because of difficulty with IV access or maybe they did not take any oral opioids at home prior to presentation? Or maybe this is an indicator of lower pain severity? We don’t really know. We also do not have any information about what other medications these patients received prior to arriving in the ED. We would like to know what the initial pain scores were for those patients receiving an oral opioid to support that theory.

5.Generalizability: This study had 15 out of 20 sites who had the ability to administer IN fentanyl. Out of those 15 sites, only 10 sites administered IN fentanyl. Was the use of IN fentanyl simply not part of the institutional culture or a standardized pathway for treating VOE? Or perhaps patient preferences played a role and IN fentanyl was offered but declined. This practice also requires buy-in from the nurses.

Some patients prefer to wait for the IV instead. There should be shared decision-making with patients on their preference with their acknowledgement that it may take longer to get that IV started. Another issue to consider is how IN fentanyl is incorporated into the ED workflows. If the patient is given IN fentanyl and then put back into the waiting room, this would not be a valued workflow compared to the use of the IN dose as a bridge to assure the IV is placed before the next dose of opioid is due for administration (30 minutes based on NHLBI guidelines).

It is difficult to generalize these findings and the use of IN fentanyl outside of these academic settings. It is possible that many community ED’s do not have access or protocols for administering IN fentanyl for sickle cell VOE.

However, adopting IN fentanyl administration practices are not difficult and can be a game-changer for community hospitals that may not be as facile with IV starts in kids.

Comment on Authors’ Conclusion Compared to SGEM Conclusion: We agree with the authors’ conclusions. But this is a non-randomized retrospective study. We need more prospective randomized, controlled trials to investigate this topic.

SGEM Bottom Line: Intranasal fentanyl may be helpful for children with SCD presenting with VOE but prioritize the timely and adequate administration of parenteral opioids.

Case Resolution: You decide to give the patient a dose of IN fentanyl while he is awaiting IV access. After IV access is obtained, he receives a few doses of parenteral morphine and tells you that he feels like his pain is much better controlled. He is discharged from the ED.

Clinical Application: Intranasal fentanyl offers a quick and effective method of providing pain control for children with SCD presenting with VOE. This is important to keep in mind especially in situations where IV access is difficult and delayed. If the nurses are struggling to get that IV access, after two tries sometimes the kids will change their mind about using IN fentanyl. It was also noted in the study that some kids received only IN fentanyl and did not require an IV.

While this study suggests that administration of IN fentanyl is associated with increased odds of discharge from the ED, there is a wide confidence interval and multiple confounders. Given the boarding crises we are facing it is not unreasonable to try IN fentanyl in hopes of being able to discharge a patient home from the ED, but multicenter, prospective randomized, controlled trials are needed.

Interestingly, the authors mention in their discussion that there was a study protocol published in 2012 for a randomized, controlled trial comparing IN fentanyl to IV morphine for severe SCD-associated pain but it has not yet been published.[9] We reached out to the investigators to see whether they would be willing to share the results but have not heard from them yet.

What Do I Tell My Patient? I am sorry you are so uncomfortable. I want to get an IV and give you some IV pain medications. There is some research to suggest that a dose of fentanyl through your nose will help with pain but also may increase the chances of you going home. Let’s give it a try as we are waiting for your IV to be placed. Does that sound okay?

Other FOAMed:

Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.

References:

  1. Cimpello LB et al. Practice patterns of pediatric versus general emergency physicians for pain management of fractures in pediatric patients. Pediatr Emerg Care 2004
  2. Kircher J et al. Pediatric musculoskeletal pain in the emergency department: A medical record review of practice variation. CJEM 2014
  3. Poonai N et al. Opiod analgesia for acute abdominal pain in children: A systematic review and meta-analysis. Acad Emerg Med 2014
  4. Harman S et al. Efficacy of pain control with topical lidocaine-epinephprine-tetracaine during laceration repair with tissue adhesive in children: a randomized controlled trial. CMAJ 2013
  5. Hartling L et al. Music to reduce pain and distress in the pediatric emergency department: a randomized clinical trial. JAMA Pediatr 2013
  6. Tanabe P et al. The effect of standard care, ibuprofen, and distraction on pain relief and patient satisfaction in children with musculoskeletal trauma. J Emerg Nurs 2002
  7. National Heart Lung, and Blood Institute. Evidence-Based Management of Sickle Cell Disease: Expert Panel Report, 2014. Accessed May 5, 2023. https://www.nhlbi.nih.gov/health-topics/evidence-based-management-sickle-cell-disease
  8. Ojo AS, Ojukwu S, Asmare W, Odipe O, Larbi D. Intravenous fluid administration and the risk of adverse outcomes in sickle cell disease patients hospitalized for vaso-occlusive crisis. J Hematol. 2022;11(5):159-166.
  9. Barrett MJ, Cronin J, Murphy A, et al. Intranasal fentanyl versus intravenous morphine in the emergency department treatment of severe painful sickle cell crises in children: study protocol for a randomised controlled trial. Trials. 2012;13:74.
  10. Murad MH, Chu H, Lin L, Wang Z. The effect of publication bias magnitude and direction on the certainty in evidence. BMJ Evid Based Med. 2018;23(3):84-86.