Sprinkle on a little ketamine

A middle aged patient with a longstanding history of asthma (multiple intubations and ICU stays) presents with 3 days of worsening dyspnea, refractory to home bronchodilators, speaking in 2 word sentences and in tripod position. As oxygen saturations hover in the low 90s, the patient is transferred to critical care area for BiPAP.  As the patient rolls by you plan on BiPAP, solumedrol, epinephrine, and magnesium, and you and your attending think “why don’t we try some ketamine?” 

Severe Respiratory distress (Source imgkid)

Clinical Question: Can ketamine be used as a bronchodilator improve outcomes in patients with severe asthma?

Literature Review: In the review article from 2013 by Goyat et al, 20 articles were examined looking at ketamine for bronchospasm (case series, RCTs, observational, retrospective studies) 3 of which were in the ED.  Ketamine was used as a rescue agent in all studies; general doses were 0.1-0.2mg/kg IVP followed by infusion at 0.15-0.25mg/kg/hr.  Eighteen articles showed a “favorable response”, and 2 studies showed insufficient response.  No major adverse events were reported.  

To review, ketamine has 2 enantiomers: the S is more potent and faster acting, and the R enantiomer may be associated with more emergence reactions.  Most preparations are 1:1 S:R. Peak onset is at 60 seconds with a duration of 10-15 minutes. The distribution half-life is approximately 7-11 minutes and is cleared via the hepatic route with half life of 2-3 hours.  Several mechanisms have been proposed for its effect on bronchospasm: improved airway mechanics, anti-inflammatory properties, airway relaxation, reduction of nitric oxide, inhibition of reuptake of catecholamines at the synapse, and anticholinergic effects.

The first case report of ketamine use for reactive airway disease was in 1972 of a child who had anaphylaxis during skin testing that improved after ketamine, followed by a non-controlled trial in children intubated for asthma that showed a significant difference in PaO2/FiO2 and dynamic compliance after initiation of ketamine infusion.  The first controlled double blind trial in 1994 showed an improvement in “stethoscopic exam” and in Po2 and PCO2.  While it is worth noting the significant change in these objective data points, they are not exactly patient centered outcomes.

One observational study looked at pediatric ED patients. It enrolled 10 patients who were unresponsive to traditional therapy; no change in peak expiratory flow (PEF) was noted at 1 hour, but a significant change in the patients’Asthma Scores and respiratory rates (RR) was noted. 

The next prospective, double blind RCT (Howton, 1996) showed no benefit with ketamine.  Fifty-three consecutive patients with peak flows less than 40% after 3 does of albuterol were enrolled, all were given continuous albuterol, methylpredisolone and oxygen and then either a 0.2mg/kg ketamine bolus followed by 0.5mg/kg/hr x 3 hours, or an equivalent saline dose.  While there was a significant improvement in PEF, RR, FEV-1 in both groups over time, there was no difference between the groups. 

Similarly, a follow up RCT in kids (Allen, 2005), looked at 62 consecutive patients randomized to saline or the same ketamine doses as above, without improvement in pulmonary scores.

 Take-Home Points:
The conclusions of the above review are that ketamine is cheap, has a physiologic rationale, has few adverse effects and has been shown to improve asthma in case series and observational trials, though this has not been born out in the two small RCTs undertaken.  Their suggestion is that it should remain in the ED physicians armamentarium for refractory status asthmaticus and, as always, “further well-designed studies are warranted”.  It is probably not unreasonable for ketamine to be the induction agent of choice for asthmatics, and should be considered whenever NPPV is considered for status asthmaticus. 

Allen JY, Macias CG. The efficacy of ketamine in pediatric emergency department patients who present with acute severe asthma. Annals of Emergency Medicine 2005, 46 (1): 43-50

Howton JC, Rose J, Duffy S, Zoltanski T, Levitt MA. Randomized, double-blind, placebo-controlled trial of intravenous ketamine in acute asthma. Annals of Emergency Medicine 1996, 27 (2): 170-5

Shweta Goyal, Amit Agrawal.  Ketamine in status asthmaticus: A review.  Indian Journal of Critical Care Medicine 2013, 17 (3): 154-61

Submitted by Wes Watkins, PGY-4 
Edited by Louis Jamtgaard, PGY-3 @Lgaard

Faculty Review by Joan Noelker

Steroids for Acute Chest Syndrome?

Clinical Scenario:

A 41 year-old male with a history of well-controlled sickle cell disease and a remote history of CVA and Acute Chest Syndrome (ACS) presents to the ED with three days of left sided chest, shoulder, and flank pain. The pain was subacute in onset, was not pleuritic, was worse with movement, and was not improved with NSAIDs. He also complained of a dry cough but reported no fevers. He had an oxygen saturation of 88% on room air, but his vital signs were otherwise normal. His physical exam demonstrated clear lungs and pain with palpation of his left shoulder and left anterior chest wall. His EKG showed stable borderline LVH. Labs were notable for a negative troponin and Hgb of 5.8, and a left basilar airspace opacity on lateral chest X-ray. He was given IV fluids, morphine, and IV ceftriaxone & azithromycin to cover for Community-Acquired PNA (CAP) triggering Acute Chest Syndrome.

Clinical Question:

Do steroids have a role in treatment of Acute Chest Syndrome?

Plain CXR showing patchy infiltrates of acute chest syndrome. Image credit from AccessMedicine.

Literature Review:

Several retrospective studies from the late 1990s and early 2000s found conflicting results with regards to the effect of steroids on length-of-stay (LOS) and readmission rates [1]. The first RCT designed to answer this question published results in 1998. This group randomized 43 children with ACS to IV dexamethasone or placebo. The authors found that those receiving steroids were admitted an average of 33 fewer hours and had reduced rate of blood transfusion [2].

retrospective review of over 5,000 hospitalizations for ACS at 32 different hospitals over a four year period was undertaken to try to better answer this question. This group found that pediatric patients admitted with ACS who received corticosteroids had longer LOS (8.0 days vs 5.2 days, p < 0.0001) and higher readmission rates (4.4% vs 1.9%) with an OR of 2.4 (95% CI 1.6-3.5) [1]. This study also found considerable variation in use of steroids among the 32 hospitals reviewed, anywhere from 10-86%. The patients who received steroids seemed to be a sicker cohort, as steroid use was associated with comorbid asthma, use of supplemental oxygen, use of inhaled nitric oxide, ICU admission, need for mechanical ventilation, and higher illness severity score. However, the increased LOS and readmission rate trends remained significant even when the authors attempted to control for these factors with propensity score modeling. Interestingly, in this study only 40% of SCD patients with concomitant asthma who were admitted for ACS were given steroids, though it is unclear from this retrospective review of ICD-9 coding whether or not these patients were having an acute exacerbation of asthma.

There is some concern that the variation in steroid use may be related to concerns of steroids causing other clinical complications in these patients. A retrospective case-control study from 2006, which included patients from St. Louis Children’s Hospital, found an association between sickle cell patients with hemorrhagic strokes and recent corticosteroid use [3]. Other studies have found associations of steroid use with higher rates of avascular necrosis and vaso-occlusive crises (presumably the cause of prolonged LOS and readmit rates seen in some studies) [1,4].

A recent review attempted to summarize the available evidence, but in its conclusions the authors noted: "It is clear that the role of corticosteroid therapy in SCD and its complications is anything but settled" [4]. They admit that wide variation in practice pattern as well as use of different agents, dosages, and routes of administration complicates any attempt at meta-analysis. The authors of both the large retrospective study and the review paper admit that patients with comorbid asthma are likely undertreated due to concerns over adverse effects of steroids [1,4]. Though there is not enough evidence to make any definitive recommendation, the authors suggest following standard guidelines for asthma treatment in patients with comorbid asthma and ACS, with the provision that a low-end dose (max 60 mg/day) be utilized and a slow taper employed to avoid "rebound" vaso-occulsive crisis. 


- There does not appear to be strong evidence supporting the routine use of steroids in SCD patients presenting with ACS.

- If the patient has a concomitant condition for which steroids would usually be indicated, particularly acute asthma exacerbation, then their cautious use is likely warranted.

Further FOAMed reading:

1) "Acute Chest Syndrome" from UMEM Educational Pearls.
2) "Acute Chest Syndrome" on Peds EM Morsels. Excellent summary of diagnosis and management.
3) "Sickle Cell Disease, Answers" on EM Lyceum. Evidence-based review of several clinical issues regarding ED management of SCD patients.
4) "Sickle Cell: 10 Things Every EP Should Know About SCD" from EP Monthly. Addresses several common misconceptions about ED management of SCD.

[1] Sobota A, et al. Corticosteroids for acute chest syndrome in children with sickle cell disease: variation in use and association with length of stay and readmission. Am J Hematol 2010; 85:24.
[2] Bernini JC, et al. Beneficial effect of intravenous dexamethasone in children with mild to moderately severe acute chest syndrome complicating sickle cell disease. Blood 1998; 92:3082.
[3] Strouse JJ, et al. Primary hemorrhagic stroke in children with sickle cell disease is associated with recent transfusion and use of corticosteroids. Pediatrics. 2006 Nov;118(5):1916-24.
[4] Ogunlesi F, et al. Systemic Corticosteroids in Acute Chest Syndrome: Friend or Foe? Paediatr Respir Rev. 2013 Oct 31.

Submitted by Brendan Fitzpatrick, PGY-3
Edited by C. Sam Smith, PGY-3
Faculty review by Doug Char

Antihistamines for asthmatics?

You walk into the exam room, and find an older female patient complaining of an asthma exacerbation. She reports three days of symptoms consistent with her prior asthma exacerbations, including dry cough, wheezing, increased work of breathing, and exertional dyspnea. She had tried her home MDI and continued her maintenance medications, but her symptoms had gradually worsened to the point that she did not feel she could manage at home.

Her exam is significant for wheezing bilateral full fields, somewhat prolonged expiratory phase but good air exchange. She is speaking in full sentences, and maintaining adequate SpO2 on room air. She is afebrile, and the rest of her VS are stable. The patient's only other complaint is that her "allergies had been acting up lately." The patient appears to have a life-long history of seasonal and recurrent allergic rhinitis, but is not prescribed a daily antihistamine or other anti-allergy therapy.

Clinical Question:

Is there any evidence that antihistamine treatment has a clinically significant effect on asthma symptoms?

The Literature:

A systematic review of the efficacy of 2nd-generation antihistamines in patients with allergic rhinitis (AR) and comorbid asthma was published in the Journal of Asthma in 2011. Epidemiological and histopathological evidence confirms the strong association of AR and asthma. The two conditions share histaminergic mediators released by mast cells & basophils, and the cumulative weight of clinical & laboratory evidence suggests a strong pathophysiologic role.

The study authors performed a comprehensive literature search for double-blind randomized controlled trials in which patients with both asthma & AR were treated with 2nd-gen antihistamines -- cetirizine, loratadine, & fexofenadine being the most common. The authors first summarized the findings of several older trials which did not meet their inclusion criteria (i.e., were not double-blind RCTs). Overall, 1st-gen antihistamines (e.g., diphenhydramine, doxylamine, hydroxyzine, meclizine) have not been shown to have an effect on asthma symptoms except at doses high enough to cause anti-cholinergic and CNS-related ADRs. Some in vitro studies have suggested a steroid-sparing effect or diminished airway hyperreactivity with 2nd-gen antihistamines, but these results are inconsistent in the literature. There is fairly strong evidence in the form of large retrospective studies that effective treatment of AR reduces health-care utilization and improves quality-of-life scores in patients with concomitant asthma, but these cohorts included patients utilizing other AR therapies such as intranasal steroids as well as antihistamines.

A multicenter RCT with N=274 comparing cetirizine-D (cetirizine + pseudoephredine) to placebo found improvement in AR & PM asthma symptoms, but no significant effect on AM symptoms or pulmonary function scores. Another RCT of cetirizine alone had similar results. Several double-blind RCTs comparing the drug desloratadine to placebo, with total N >1100, showed significant reductions in both AM/PM & total asthma sx scores (including specific scores for wheezing & cough) and rescue inhaler use.

As is the case for 1st-gen antihistamines, in vitro data suggests higher doses may be needed to treat asthma as compared with AR. A small RCT (N=28) compared cetirizine 20mg daily to placebo (usual dosing 5-10mg daily), and found significant improvement in reported asthma & AR symptoms without a significant rate of adverse effects compared to placebo. Unfortunately, this dosing regimen has not been compared to standard dosing.

Take home:

- Overall, these studies suggest that antihistamine treatment may improve overall asthma symptom severity in patients with concomitant allergic rhinitis.
- Unfortunately, no study to date has evaluated effects, if any, of antihistamines during acute asthma exacerbation, or if addition of antihistamine prevents ED visits or hospitalizations.
- It seems reasonable to offer these patients antihistamine prescription if they are not already taking them.

1) J Asthma, 48(2011):965–973.

Contributed by Sam Smith, PGY-3.