# Management of Acute Life-Threatening Asthma Exacerbations in the Intensive Care Unit
## 4 Acute Life-Threatening Asthma Advanced Management in the ICU
### Anaesthetic Agents  
#### 4.5.1 Ketamine  
Ketamine is a dissociative anaesthetic used extensively for its sedative and analgesic effects. It is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, which is a derivative of phencyclidine. Its molecule contains an asymmetrical carbon atom with two enantiomers, S (+) ketamine and R (-) ketamine, and racemic preparations commonly contain equal concentrations of the enantiomers. It has excellent bioavailability from both intravenous and intramuscular administration with rapid onset of action and time-to-peak concentration of approximately 60 s. The duration of action of a single bolus is 10-15 min, and its distribution half-life is 7-11 min, being cleared via the hepatic route within 2-3 h [80]. The bronchodilator effect of ketamine was reported not long after its introduction to the market, with its use on children producing remarkable improvements in wheeze and respiratory distress [81]. The use of ketamine in severe refractory asthma has continued since, particularly in the paediatric population. Ketamine's effects appear to be mediated not just via NMDA receptor antagonism but via a myriad of other receptor targets, including dopaminergic, serotonergic, adrenergic, opioidergic, cholinergic, and ion channels, including voltage-gated sodium channels and hyperpolarisation-activated cyclic nucleotide gated channels [82].  
The effect of bronchodilation is thought to be mediated not only by direct antagonism of NMDA receptor-induced bronchoconstriction but by an increase in synaptic catecholamine levels via presynaptic reuptake inhibition, downregulation of intrinsic nitric oxide synthetase activity (and therefore reduction in nitric oxide levels), airway smooth muscle relaxation via reduction of L-type calcium channel-induced calcium influx, and reduction of inflammation via reduction in macrophage recruitment [83; 84; 85]. Ketamine appears to be used more frequently in the paediatric population as an adjunct to standard therapy in refractory asthma exacerbations. Studies in this population, as in adults, have generally not borne out conclusive benefits compared to standard therapy. Few small randomised controlled trials in the adult population have evaluated the use of ketamine in patients with asthma and reported outcomes on respiratory mechanics and gas exchange variables [86; 87]. Another randomised, double-blind, placebo-controlled trial showed no increased bronchodilatory effect when given at a dose low enough to avoid dysphoric reactions when compared with standard therapy for treating asthma exacerbations in the ED [88]. A systematic review of seven prospective studies (including two paediatric studies) concluded that there was no clear benefit from the administration of IV ketamine in patients with refractory asthma, and further multi-centre randomised controlled trials are required to conclusively evaluate this finding [83]. However, ketamine is commonly used as an induction and maintenance of sedation agent in patients with severe asthma [89; 90]. In summary, it appears that although there is a potentially physiological argument for the use of ketamine as an adjunct to improve bronchoconstriction, and anecdotal data appear to suggest some benefit, the literature thus far does not support its use. Larger, high-quality trials are likely required to explore this further.