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Three Part Question

In [adult patients presenting with a severe exacerbation of asthma minimally or non responsive to standard therapy ] is [ketamine] effective in [reducing intubation, mechanical ventilation]?

Clinical Scenario

An adult patient presents to your emergency department with a severe exacerbation of asthma. Despite multiple rounds of salbutamol and ipratropium with prednisolone and oxygen supplementation the patient continues to deteriorate and plans are made to intubate the patient for mechanical ventilation. You are aware ketamine is the induction agent of choice and wonder if a ketamine infusion may obviate the need for intubation and mechanical ventilation.

Search Strategy

1. Medline (1946-present), EMBASE (1980-present) and CINHAL (1981-present) were searched with use of the HDAS interface with the search criteria 'ketamine' AND (asthma OR asthmatic OR status asthmaticus OR life threatening asthma OR ever asthma OR reactive airways disease OR bronchospasm OR Bronchoconstriction)).ti.ab LIMIT to human and english language.
2. The Cochrane library was accessed and searches made of the Cochrane database of Systematic Reviews (CDSR), Database of Abstracts of Reviews of Effects (DARE) and Cochrane central register of controlled trials.
3. British Library EthOS
4.Clinical trials.gov
5. Manual search of reference lists
6. Authors of the primary studies were contacted

Search Outcome

Strategy 1 yielded 147 papers narrowed to 2 case reports and 1 Double blind randomised controlled trial. Others were excluded based on bronchospasm due conditions other than asthma, review articles and ketamine not studied in isolation.
Strategies 2-6 did not identify any papers of relevance to the clinical question.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Howton JC, Rose J, Duffy S, Zoltanski T, Levitt MA 1996 America	53 patients aged 18-65. 0.2mg/kg bolus of ketamine followed by 0.5mg/kg/hour infusion.	Randomised Double Blind, Placebo Controlled trial of intravenous ketamine in acute asthma.	Peak flow, Borg score, Respiratory rate, FEV1	No statistically significant improvement as compared to placebo.	Those patients unable to perform spirometry and requiring intubation were excluded; excluding those likely representing the most severe exacerbations of asthma. Study protocol changed following dysphoric reactions in the first 9 patients with reduction in ketamine dose. Post-hoc power analysis is calculated however does not state if this is inclusive of the 9 patients prior to protocol change. Ketamine is not investigated in isolation with theophylline, magnesium and ipratropium also used but with no reported frequency or distribution of use. RCT also fails to conform to CONSORT guidelines. Study protocol changed after first 9 patients with reduction in initial bolus of ketamine. Salbutamol therapy prior to ketamine was only 0.5mg Post Hoc power analysis completed however unclear if first 9 patients are included. Theophylline, magnesium and ipratropium also used with no account of frequency or distribution within the study group.
Shlamovitz GZ, Hawthorne T 2011	One patient aged 28 received a 0.75mg/kg bolus followed by 0.15 mg/kg/hour infusion following nebulised albuterol and ipratropium, IM epinephrine, dexamethasone and IV magnesium.	Intravenous ketamine in a dissociating dose s a temporising measure to avoid mechanical ventilation in adult patient with severe asthma exacerbation.	Oxygen saturation	improvement	Single patient case report
			Clinical condition	improvement
Sarma VJ	2 patients aged 40 and 43 years respectively received 0.75mg/kg ketamine followed by a second bolus and infusion of 0.15mg/kg/hour	Use of Ketamine in acute severe asthma	Oxygen saturations, FiO2, ABG's	Improvement	Case report only. One patient still required eventual intubation and ventilation
			Clinical condition	Improvement
			Need for intubation	One patient required intubation 24 hours later following cessation of ketamine.

Comment(s)

Two case reports and one RCT were identified following a literature search. The RCT by Howton et al failed to show a statistically significant improvement in measured outcome measures as compared to placebo. In addition review of the paper identified several factors which limit both internal and external validity and thus its generalizability to routine practice. Furthermore requirement for emergency intubation was an exclusion criteria for this study therefore limiting our ability to address the three part question. Case reports by Shlamovitz and Sarma both highlight the potential for use of ketamine in asthma and in these cases a higher initial bolous dose of ketamine was used as compared to the study protocol used by Howton. Shlamovitz comments on the paper by Howton indicating his belief that the higher dose and subsequent dissociative state is key to the successful use of ketamine in this subset of patients. As case reports the inferences drawn from these cases is limited, and therefore the potential exists for a well designed RCT to be conducted to assess the potential benefit of ketamine use in asthma and avoidance of mechanical ventilation.

Clinical Bottom Line

There is currently no high quality evidence that within a patient with life threatening asthma requiring intubation ketamine can be used to avoid mechanical ventilation.

References

1. Howton JC Randomised Double Blind, Placebo Controlled trial of intravenous ketamine in acute asthma. Annals of Emergency Medicine 1996;27:170-5
2. Shlamovitz GZ Intravenous ketamine in a dissociating dose s a temporising measure to avoid mechanical ventilation in adult patient with severe asthma exacerbation. Journal of Emergency Medicine 2011;41:492-4
3. Sarma VJ Use of Ketamine in acute severe asthma Acta anaesthesiologica Scandinavica 1992; 36:106-7