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Date: November 28th, 2017

Reference: Motov S et al. A Prospective Randomized, Double-Dummy Trial Comparing Intravenous Push Dose of Low Dose Ketamine to Short Infusion of Low Dose Ketamine for Treatment of Moderate to Severe Pain in the Emergency Department. AJEM 2017.

Guest Skeptic: Dr. Salim Rezaie is a faculty physician at Greater San Antonio Emergency Physicians (GSEP) in San Antonio, Texas. He is the founder and creator of REBEL EM and REBEL Cast.

Case: A 54-year old female patient with acute back pain comes to your emergency department for her forth visit in seven days for recurring pain.  She was lifting something heavy and felt a“pop” in her back.  She denies bowel or bladder issues, saddle paresthesia, lower extremity weakness, but does feel radicular pain down both of her legs.  She has been given intravenous hydromorphone, diazepam, and ketorolac without relief of her symptoms.  You decide to give her low dose ketamine, as this has worked in the past.

Background: Low back pain is a common and challenging presentation to the emergency department. While the vast majority of presentations are benign, these cases can be time consuming and frustrating for both patients and physicians.

Physician frustrations with managing acute non-traumatic low back pain include considering rare dangerous back pain patient (epidural abscesses, osteomyelitis, pathological fractures, etc), patients demanding imaging, difficulty in relieving pain and concern about opiate abuse or diversion.

There are multiple “Red Flag” lists to help identify patients at risk for more serious causes of their back pain. One simple red flag list is called TUNA FISH.

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Other things to consider would be immunocompromised patients besides just those on steroids (ex: patients with HIV, diabetes, alcoholics or taking biologic agents) who are at risk for spinal epidural abscess, discitis, or osteomyelitis.

When it comes to patient demands for imaging, Choose Wisely from ACEP and CAEP encourages emergency physicians to avoid ordering lumbar spine imaging in patients without serious underlying conditions (red flags).

As mentioned, it can be difficult to treat low back pain in the emergency department. Many different treatment modalities have been tried to treat low back pain with limited success. A systematic review was just published in the Emergency Medicine Journal looking at 43 management of acute low back pain in the ED. The conclusions…we need more evidence.

Then there is the issue of opioids use for low back pain. ACEP has guidelines with the American Pain Society from 2007 on the use of opioids. They state opioids should be reserved for severe, disabling pain that is not controlled or not likely to be controlled with NSAIDs or acetaminophen. This will be a challenge considering the limited effectiveness of NSAIDs and acetaminophen for low back pain.

ACEP also has a clinical policy on prescribing opioids and specifically addresses patients with acute low back pain. They give three Level C recommendation:

  1. For the patient being discharged from the ED with acute low back pain, the emergency physician should ascertain whether nonopioid analgesics and nonpharmacologic therapies will be adequate for initial pain management.
  2. Given a lack of demonstrated evidence of superior efficacy of either opioid or nonopioid analgesics and the individual and community risks associated with opioid use, misuse, and abuse, opioids should be reserved for more severe pain or pain refractory to other analgesics rather than routinely prescribed.
  3. If opioids are indicated, the prescription should be for the lowest practical dose for a limited duration (eg, 1 week), and the prescriber should consider the patient’s risk for opioid misuse, abuse, or diversion.

Another thing to remember is to manage patients’ expectations. We do not want to set them up for failure. They need to know their pain might not be completely relieved in the emergency department and that most patients will have persistent symptoms a week after presentation and many will have continued pain and functional impairment months after symptom onset (Itz et al 2013 , Donelson et al 2012  and Costa et al 2012).

Ketamine is a drug that is getting a lot of attention right now for acute pain. We have covered ketamine a number of times on the SGEM. This has included the use for procedural sedation and for pain control.

  • SGEM#114: Ketofol – Does It Take Two to Make a Procedure Go Right?
  • SGEM#111: Comfortably Numb – Low dose Ketamine as Adjunct for ED Pain Control
  • SGEM#130: Low Dose Ketamine for Acute Pain Control in the Emergency Department

The clinical reasons for using ketamine for pain control are easy to understand. It is a N-Methyl-D-aspartate (NMDA) receptor antagonist that exerts sedative, amnestic, and analgesic effects as a dissociative anesthetic. Ketamine does not only reduce acute pain, but it also decreases persistent chronic and neuropathic pain as well. More importantly, use of low-dose ketamine (0.1 – 0.3 mg/kg IV) has been demonstrated to be opioid sparing.

Some of the major issues with IV push low-dose ketamine include its adverse effects, such as feelings of unreality, nausea/vomiting, and dizziness. Many emergency medical providers have anecdotally noticed a decrease in adverse effects when ketamine is given slowly.

Clinical Question: Does increasing the duration of the ketamine from IV push (3 – 5 min) to a slow infusion (10 – 15 min) mitigate some of the untoward side effects, while maintaining analgesic efficacy?

Reference: Motov S et al. A Prospective Randomized, Double-Dummy Trial Comparing Intravenous Push Dose of Low Dose Ketamine to Short Infusion of Low Dose Ketamine for Treatment of Moderate to Severe Pain in the Emergency Department. AJEM 2017.

  • Population: Adults 18 to 65 years of age presenting to the emergency department with a primary complaint of acute abdominal, flank, back, traumatic chest or musculoskeletal pain with a pain intensity of ≥5 on the numeric pain rating scale (NRS).
    • Exclusion criteria included pregnancy, breast-feeding, altered mental status, allergy to ketamine, weight <46 kg or >115 kg, unstable vital signs (systolic blood pressure <90 or >180 mm Hg, pulse rate <50 or >150 beats/min, and respiration rate <10 or >30 breaths/min), and medical history of acute head or eye injury, seizure, intracranial hypertension, renal or hepatic insufficiency, alcohol or drug abuse, psychiatric illness, or recent (4 h before) analgesic use.
  • Intervention: IV ketamine 0.3mg/kg mixed in 100mL of normal saline via short infusion (over 15 minutes).
  • Comparison: IV ketamine 0.3mg/kg via IV push (ver 3 – 5 minutes).
  • Outcome:
    • Primary Outcomes: Rates of nine specific side effects and the severity of the side effects rated from 0-4 on the Side Effects Rating Scale for Dissociative Anesthetics (SERSDA) and severity of agitation and/or sedation on the nine point Richmond Agitation-Sedation Scale (RASS). These were measured at, 15, 30, 60, 90, and 120 minutes post administration
    • Secondary Outcomes: Analgesic efficacy via numerical pain rating scale (NRS 0 – 10 with 0 being no pain and 10 being the most pain), changes in vital signs and need for rescue analgesia.
Dr. Sergey Motov

Dr. Sergey Motov

Dr. Sergey Motov is an Emergency Physician in the Department of Emergency Medicine, Maimonides Medical Center in New York City. Last time Sergey was on the SGEM he was dancing on the ceiling with ketorolac (SGEM#175). 

Authors’ Conclusions: “Low-dose ketamine given as a short infusion is associated with significantly lower rates of feeling of unreality and sedation with no difference in analgesic efficacy in comparison to intravenous push.”

checklistQuality Checklist for Randomized Clinical Trials:

  1. The study population included or focused on those in the emergency department. Yes. These were patients presenting to the emergency department at Maimonides Medical Center.
  2. The patients were adequately randomized. Yes. Participants were allocated to two groups according to a predetermined randomization list which was generated using a computer software.
  3. The randomization process was concealed. Yes. According to the paper, the preparing ED pharmacist, research manager, and statistician were the only ones with knowledge of the medication route while treating providers, participants, and the data collecting research team were blinded to the medication route received
  4. The patients were analyzed in the groups to which they were randomized. Yes
  5. Study patients were recruited consecutively (i.e. no selection bias). Yes/No. All potentially qualifying participants were approached but only Monday to Friday from 8am to 8pm when the emergency department pharmacist was available for blinded medication preparation.
  6. The patients in both groups were similar with respect to prognostic factors. Yes. Importantly the mean baseline NRS pain score was >8 in both groups.
  7. All participants (patients, clinicians, outcome assessors) were unaware of group allocation. Yes
  8. All groups were treated equally except for the intervention. Yes
  9. Follow-up was complete (i.e. at least 80% for both groups). Yes. 21 out of 24 in both groups .
  10. All patient-important outcomes were considered. Yes. Pain relief and adverse effects.
  11. The treatment effect was large enough and precise enough to be clinically significant. Yes. Patients pain was reduced equally in both groups

Key Results: They enrolled 48 patients with 24 in the push group and 24 in the drip group. The mean age was in the early 40’s and mean pain score was between 8 and 9 on the NRS.

Less feeling of unreality and sedation with slow infusion of low-dose ketamine vs. IV push

  • Primary Outcomes:
    • Side Effects – Feeling of Unreality on SERSDA
      • IVP: 91.7% vs. IV Infusion: 54.2% p = 0.008 NNH = 3
    • Rates of Sedation – RASS scale at 5 min was greater in the IVP
      • Median RASS − 2.0 versus 0.0 (p = 0.01)
  • Secondary Outcomes:
    • No difference in the reduction in pain scores, change in vital signs or need for rescue analgesia.

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Listen to the podcast on iTunes to hear Sergey’s responses to our five nerdy questions.

  1. Convenience Sample vs. Consecutive Sample: The two types of patient sampling are very similar, apart from convenience sampling including all accessible patients as part of the sample. This is considered the ideal non-probability sampling. Although, it is cheaper and easier to do convenience sampling, the inability to include all comers forces us to extrapolate results as some populations may be under- or over-represented (i.e. in this study no patients recruited on nights or weekend).
  1. Sample Size: No sample will ever be perfect when compared to the entirety of a population, but the latter is also not very feasible. The authors did do a sample size calculation stating they needed 24 patients per group for an 80% power to detect effect size of the SERDSA. Unfortunately, only 21 patients were evaluated in each group. Why did they not over recruit by 10-20% to anticipate people dropping out? This is often seen in other studies.
  1. Single Center Study: Although this is also a cheaper way to conduct small scale studies, many studies often recruit too few patients, carrying a significant risk of failing to demonstrate a treatment difference when one really exists. Secondly, a single center trial fails to recruit subjects from a wider population in a broader range of clinical settings, therefore making it difficult to generalize the results to all populations or clinical situations.
  1. Multiple Primary Outcomes: Just like the Highlander said…there can be only one…primary outcome. In this study, there were two primary outcomes. One of the primary outcomes look at nine side effects. Both of the primary outcomes were measured at five different times. This seemed like making a big target with multiple opportunities to find something “significant”. 
  1. External Validity: These were patients who did not take anything prior to arrival and did not receive anything in the emergency department unless they needed rescue medication. This would narrow down the generalizability of the results.

Is there anything else you would like the SGEMers to know about this study or the topic of using ketamine as an adjunct for pain control in the emergency department?

Comment on Authors’ Conclusion Compared to SGEM Conclusion: We agree with the authors’ conclusions.

SGEM Bottom Line: Slowing down the rate of low-dose IV ketamine infusion to 15 minutes significantly reduces rates of the feeling of unreality and sedation with no difference in analgesic efficacy when compared to IV push over 3 – 5 minutes.

Case Resolution: You explain to your patient that giving ketamine over a longer period of time should decrease the feelings of unreality she may have experienced in the past while still helping to improve her pain. Your patient is given IV low-dose ketamine over 15 minutes without any of the untoward side effects and almost complete resolution of her pain.

Dr. Salim Rezaie

Dr. Salim Rezaie

Clinical Application: Low dose ketamine of 0.3mg/kg, mixed into 100 ml of Normal Saline given over slow infusion (15 minutes) has a decreased side effect (i.e hallucinations or dizziness) and equal analgesic profile when compared to IV push (5 minutes) low dose ketamine.

What do I tell my patient? By slowing down the infusion of ketamine we can still relieve your pain, and potentially mitigate some of the bad side effects of this medication.

Keener Kontest: Last weeks’ winner was Ian Lewins a Children’s Emergency Medicine Consultant in Derbyshire. He knew that intubation of the trachea, rather than the more invasive tracheostomy, was first described for a case of diphtheria.  It was Dr. Eugene Bouchut, a French paediatrician in 1858 who did this to bypass a laryngeal obstruction from a pseudomembrane.

Listen to the podcast on iTunes for this weeks’ keener question. If you think you know the answer then send an email to TheSGEM@gmail.com with “keener” in the subject line. The first correct answer will receive a cool skeptical prize.

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