The purpose of our systematic review was to summarize the clinical evidence regarding the use of ketamine in patients with severe asthma refractory to conventional medical treatment, selecting higher-quality studies (randomized and prospective only). We found a paucity of data on the possible benefits and complications related to the use of ketamine in this patient population. Together with the reduced quality and quantity of data, we also noted a profound heterogeneity in the control group, where the treatment ranged from placebo to other drugs such as fentanyl and aminophylline. The ketamine dosages used were also largely different between studies. Furthermore, the outcomes evaluated by the included studies, were profoundly variable. Therefore, we could not conduct a quantitative analysis (meta-analysis) and the evaluation remains quite subjective.
Before discussing the results of our systematic review, it may be worth to briefly discuss the pharmacological properties of ketamine that may contribute to its use in patients with asthma. Ketamine is a phencyclidine derivative with non-competitive antagonist effects on N-methyl-D-aspartate (NMDA) receptors. However, it may clinically have numerous other effect sites, both ion channels and receptors (i.e. L-type voltage-gated Ca2 + channels, nicotinic and muscarinic acetylcholine receptors, voltage-sensitive Na + channels, µ and δ opioid receptors, etc). This large number of target sites for ketamine may contribute to the wide range of effects of the drug. Regarding the role of ketamine in asthma, bronchodilation is supposed to be a combination of several targets: direct blockade of NMDA receptor-induced airway constriction, reduction of nitric oxide levels in pulmonary tissues (down-regulation of inducible nitric oxide synthetase activity), increase in synaptic catecholamine levels (blockade of presynaptic re-uptake), inhibition of vagal outflow, direct smooth muscle relaxation by reduction of calcium influx (L-type calcium channels), reduction of inflammation with blunted macrophage recruitment and cytokine production [27–30].
Despite this background, the results obtained from the administration of ketamine in patients with severe refractory asthma seem predominantly neutral or eventually negative. Indeed, from the qualitative analysis of the included studies it would appear that ketamine did not offer particular clinical benefits. Therefore, our systematic review does not offer significant support for the clinical use of ketamine with this indication.
The only study showing some significant benefit from ketamine was conducted by Esmailian et al. on 92 adults. This study was the largest one retrieved by our systematic review and measured the Peak Expiratory Flow Rate (PEFR), evaluating the effects of increasing doses of Ketamine (0.3, 0.4 or 0.5 mg/kg as a bolus only, without continuous infusion) as compared to placebo. In this study, a significant improvement in PEFR occurred for the 0.4 and 0.5 mg/kg bolus doses; however, the authors did not perform any further measurements of respiratory function and mechanics. Furthermore, the authors excluded patients reporting side effects from ketamine treatment. In another study, Nedel et al. compared the effects of ketamine (2 mg/kg bolus and subsequent infusion at 2 mg/kg/h) and fentanyl administration (bolus of 1 mcg/kg and continuous infusion of 1 mcg/kg/h). Main outcomes were changes in respiratory mechanics (Airway Resistances – Rsmax; intrinsic Positive End Expiratory Pressure – PEEPi; and dynamic compliance - Cdyn) at different time-points (pre-treatment, at 3 and 24 hours). In both groups, there was a decrease in Rsmax and a stability of Cdyn (albeit at severely compromised values). In this sense, the decrease in respiratory resistance over the course of 24 hours in these patients was almost identical between groups (ketamine and fentanyl), thus possibly attributable to other treatment strategies (b2-agonist and steroid therapy) or eventually to similar effects of ketamine and fentanyl. Interestingly, there was a progressive increase in PEEPi in both groups at 24 hours. In this sense, it is possible that in the presence of low values of Cdyn, a reduction in Rsmax with an increase in minute-volume ventilation favored air trapping and lung hyperinflation. In one pediatric study, Tiwari et al. compared ketamine to aminophylline and showed similar improvements in the PRAM score and gas exchange in both groups. Furthermore, the evaluation of side effects showed a similar (and high) incidence of tachycardia, while only two patients, both in the ketamine group, had developed hypertension.
Of note, during the screening and the systematic research, among the studies analyzed we also found a national multicenter survey conducted in Chile on a pediatric patient’s population with exacerbation of asthma. In this survey, all patients received salbutamol and 98% received systemic steroid administration. Regarding the additional rescue drug therapies to improve respiratory function, the most used medication was magnesium sulfate (6%) followed by aminophylline (0.8%) and finally by an anecdotic use of ketamine (0.5%, n = 2/396). Although conducted in a single country and limited to the pediatric population, this survey confirms that ketamine remains a drug rarely used in this setting. Notably, ketamine use is banned in some countries and undergoes special legislation for its use in many others.
In summary, from this overview of the included studies we noted an absence of any clear and relevant benefit produced by the administration of ketamine in patients with refractory asthma, and some signals towards side effects related to its use.
However, we also found a randomized study published almost 30 years ago suggesting beneficial effects of ketamine bolus (1 mg/kg) as compared to placebo in mechanically ventilated adult patients admitted to intensive care and developing bronchospasm. In particular, the authors found improvement of gas exchange with increase in oxygenation and stable values of PaCO2 in the ketamine group whilst the oxygenation worsened and the PaCO2 increased in the placebo group. Nonetheless, the benefits of ketamine in patients with refractory asthma seem not clear and its use should be probably reserved for well-structured experimental research setting with clear objectives and outcomes. On the other hand, performing a large randomized study may be challenging as the number of patients presenting with acute refractory asthma is not very large.
Our study presents several limitations. Firstly, the number of included studies was low with a paucity of patients enrolled. Secondly, the design of the papers was not homogeneous, as we considered both randomized and non-randomized prospective clinical trials. Thirdly, the results presented by the included studies were clinically heterogeneous, and therefore a meta-analysis was not feasible. Lastly, we analyzed data from pediatric and adult patients together, possibly facing a risk of bias.