Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0972-5229.117048
Source of Support: None, Conflict of Interest: None
Background and Aims : Status asthmaticus is a common cause of morbidity and mortality. The addition of ketamine to the standard treatment regimen of severe asthma has shown to improve outcome and alleviate the need for mechanical ventilation. The purpose of this review is to determine the pulmonary effects of ketamine and to determine whether sufficient evidence exists to support its use for refractory status asthmaticus. Data Source: MEDLINE, EMBASE, Google Scholar, and Cochrane data bases (from their inception to Jan 2012) using key words "ketamine," "asthma," "bronchospasm," "bronchodilator," and "mechanical ventilation" were searched to identify the reports on the use of ketamine as a bronchodilator in acute severe asthma or status asthmaticus, and manual review of article bibliographies was done. Relevant databases were searched for the ongoing trials on use of ketamine as a bronchodilator. Outcome measures were analyzed using following clinical questions: Indication, dose and duration of ketamine use, main effects on respiratory mechanics, adverse effects, and mortality. Results: Twenty reports illustrating the use of ketamine as a bronchodilator were identified. In total, 244 patients aged 5 months to 70 years received ketamine for bronchospasm. Twelve case reports, 3 double-blind randomized placebo-controlled trials, 2 prospective observational studies, 2 clinical evaluation study, and 1 retrospective chart review were retrieved. Most of the studies showed improved outcome with use of ketamine in acute severe asthma unresponsive to conventional treatment. Patients who received ketamine improved clinically, had lower oxygen requirements, and obviated the need for invasive ventilation. Mechanically-ventilated patients for severe bronchospasm showed reduction in peak inspiratory pressures, improved gas exchange, dynamic compliance and minute ventilation, and could be weaned off successfully following introduction of ketamine. Conclusion: In various studies, ketamine has been found to be a potential bronchodilator in severe asthma. However, a large prospective clinical trial is warranted before laying down any definitive recommendations on its use in status asthmaticus.
Keywords: Bronchodilator, emergency department, intensive care unit, ketamine, status asthmaticus
'Asthma' is a Greek word, which means 'breathless' or 'to breathe with open mouth.' As defined by The Global Strategy for Asthma Management and Prevention Guidelines, "asthma is a chronic inflammatory disorder of the airways associated with increased airway hyper-responsiveness, recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night/early morning." 
Asthma rates are officially low in India, although there are some recent evidences that the true prevalence is higher than previously thought. The total estimated burden of asthma is an overall prevalence of 3% (30 million patients), and among adults over the age of 15, a median prevalence of 2.4%. 
Asthma exacerbations are a frequent cause of morbidity and mortality. It is a dynamic, often life-threatening state, and response to therapy is variable. While majority of the patients respond promptly to conventional therapies like nebulized albuterol (salbutamol), anti-cholinergics, theophylline, epinephrine and corticosteroids, some patients have worsening respiratory distress requiring invasive ventilation. Various anesthetic agents like ketamine, isoflurane, sevoflurane, and halothane have been found to have bronchodilator properties. Despite of case reports and research work reported at different times, no definite dosages and guidelines advocating the use of these drugs in severe refractory status asthmaticus have been framed. In the present review, we discuss the various effects of ketamine on respiratory mechanics along with its beneficial uses in refractory status asthmaticus and potential adverse effects in context with currently available data.
MEDLINE, EMBASE, Google Scholar, and Cochrane data bases (from their inception to Jan 2012) were searched to retrieve scientific reports related with the use of ketamine as a bronchodilator in acute severe asthma or status asthmaticus. The search terms used were "ketamine," "asthma," "bronchospasm," "bronchodilator," and "mechanical ventilation." Manual review of article bibliographies was done to identify the relevant studies. Following databases were searched for the ongoing trials on use of ketamine as a bronchodilator http://www.ctri.in/; http://www.actr.org.au/; and http://www.clinicaltrials.gov/.
Criteria for inclusion of studies
Case reports, case series, clinical studies, retrospective chart reviews, prospective observational studies, and randomized clinical trials were included if they provided sufficient information on use of ketamine as a bronchodilator.
Both children and adults were included.
Data collection and analysis
The abstracts and full texts of relevant studies were assessed, and reports not fulfilling the objective of review were excluded. The study design, setting, age of patients included, dose of ketamine used, mode of administration (bolus/continuous infusion), duration of administration, response to treatment, and any adverse effects were noted. The vital parameters, blood gases, oxygen saturation, ventilator settings like pressure requirements, dynamic compliance, and FiO2 were included as markers of improvement.
Twenty articles illustrating the use of ketamine as a bronchodilator in children and adults were identified. In total, 244 patients received ketamine for bronchospasm. The age of patients ranged from 5 months to 70 years. Out of the total articles, 12 were case report, 2 were clinical evaluation studies, 3 randomized control studies, 2 prospective observational studies, and 1 retrospective chart view.
Ketamine was used as a rescue agent, unresponsive to first-line agents in intensive care unit, in patients with respiratory failure on mechanical ventilation in 13 articles (53 patients). It was used as an anesthetic agent in asthmatic patients intra-operatively in 3 reports (58 patients). Patients coming to emergency department with status asthmaticus were administered ketamine in 3 studies (131 patients) and postoperatively for analgesia and sedation in asthmatics in 1 study (2 patients).
Dose and duration of ketamine
Ketamine was administered in a bolus dose ranging from 0.1 mg/kg to 2 mg/kg. On the basis of initial response, the dose used for continuous infusion ranged from 0.15 mg/kg/hr to 2.5 mg/kg/hr. The duration of infusion ranged from 1 hour to 5 days.
In all cases, ketamine was initiated if there was poor response to first-line agents. In 18 articles, there was a favorable response to ketamine. Patients with severe respiratory distress, improved remarkably clinically, had decreased wheezing sounds and improved oxygen saturation and blood gas. Patients who were intubated and mechanically ventilated for progressive respiratory failure showed improved peak inspiratory pressures, dynamic compliance of lungs, gas exchange, and decreased oxygen requirements. In 2 studies, there was insufficient response to ketamine.
No major adverse effect was reported in any article. Minor adverse effects like dysphoria, hallucinations, increased secretions occurred. Only a few patients developed mild perturbations in heart rate and blood pressure.
Ketamine was originally named 'CI581.' It is a phencyclidine derivative, water-soluble, and is prepared with the sodium salt of benzethonium chloride as preservative. The ketamine molecule contains an asymmetrical carbon atom with 2 enantiomers. The S (+) isomer is 3 times more potent and longer acting than R (-) isomer. , Ketamine contains a chiral center at the C-2 carbon of the cyclohexanone ring so that 2 enantiomers exist, S (+) ketamine and R (-) ketamine. Commercially available racemic ketamine preparations (such as Ketalar) contain equal concentrations of the 2 enantiomers. The dextro-S(-)-isomer of ketamine has approximately 3- to 4-fold the potency of the levo-R(-)- isomer. , The S(+)-isomer appears to be cleared more rapidly than the R(-) isomer, resulting in a shorter duration of effect and more rapid recovery.  Equipotent doses of the S(+)-isomer and the racemate appear to have similar effects on physiologic parameters.  There is evidence to suggest that the R(-)-isomer produces a higher rate of emergence reactions and more agitated behavior than the S(+) isomer. 
Ketamine has a high bioavailability following intravenous or intramuscular administration. The onset of action is rapid, and peak plasma concentrations are seen within 60 seconds of administration. The duration of action after a single bolus injection is 10-15 minutes and distribution half-life is 7-11 minutes. It is cleared via hepatic route with a half-life of 2-3 hours. ,
Mechanism of action of ketamine as a bronchodilator
The major pathophysiology in asthma comprises of airway hyper reactivity, increased vascular permeability, smooth muscle spasm, and release of inflammatory mediators. In many experimental studies, ketamine has been found to alter respiratory mechanics and produce airway relaxation by acting on various receptors and inflammatory cascades, which mediate bronchospasm. Several mechanisms of action have been proposed to explain this effect. ,,,,,,,,
Ketamine as an imunomodulator
It has been demonstrated that the activation of NMDA (N-methyl-D-aspartic acid) receptors in the lung and airway triggers acute lung injury characterized by pulmonary edema and airway constriction. Ketamine blocks NMDA receptor-induced bronchoconstriction. 
It has been demonstrated that increased nitric oxide levels mediate bronchospasm. Ketamine reduces nitric oxide levels by downregulating inducible nitric oxide synthetase enzyme activity. It inhibits overexpression of mRNA and protein of induced nitric oxide synthetase and reduces the production of nitric oxide in pulmonary tissues. 
Release of inflammatory mediators form the central component of inflammatory changes and airway hyper-reactivity in acute asthma. It has been proved that a clinically significant concentration of ketamine can suppress macrophage function, oxidative ability, and inflammatory cytokine production via reduction of mitochondrial membrane potential. Ketamine interferes with the recruitment of macrophages and cytokine production and thus is a potent anti-inflammatory agent useful in acute asthma.  It also reduces Interleukin-4 (IL-4) concentration as shown in rat asthma models.  Ketamine has also been found to reverse histamine-induced bronchoconstriction and enhance adrenaline-induced bronchodilatation. 
Effect of ketamine on catecholamines
One hypothesis is that ketamine increases synaptic catecholamine levels by blocking the re-uptake of norepinephrine into presynaptic sympathetic neurons. These endogenous catecholamines act on β2 receptors and lead to bronchodilation. It has been shown that increase in free norepinephrine parallels the peak bronchodilatory effect of ketamine, and this effect can be diminished by β-adrenergic blockade. 
Effect of ketamine on airway smooth muscles
Ketamine exerts an anti-cholinergic effect on bronchial smooth muscles by inhibiting vagal outflow.  It decreases calcium influx in smooth muscles by inhibiting L-type calcium channels, and resultant decrease in intracellular calcium relaxes airway smooth muscle. 
Effect of ketamine on vagal nerve
It has been studied that not only inflammatory cells but also neural mechanisms, by which tachykinins are released from vagal afferent C-fiber, contribute to asthma. Ketamine and its isomers have spasmolytic effects on airway smooth muscles precontracted with tachykinins, thus causing airway relaxation. 
These postulated mechanisms collectively indicate that ketamine attenuates many of the central components of inflammatory changes and airway hyper-responsiveness in asthma and can act as a suitable therapeutic intervention in status asthmaticus.
Effects of ketamine in children and adults
Ketamine is a water-soluble drug, which permits intramuscular, intravenous, oral, intranasal, and rectal administration. Biotransformation occurs primarily in liver. However, the most important pathway involves N-demethylation to norketamine by the cytochrome p450 enzyme system. Norketamine is an active metabolite with one-third the anesthetic potency of ketamine.  The disposition of ketamine varies in children and adults. The pharmacokinetics is similar in children, except that absorption following intramuscular injection is more rapid and hepatic conversion to norketamine is more rapid. Hence, higher concentrations of norketamine are measured. 
Because of this, in addition to lower adsorption rates compared to intramuscular injection, oral and rectal administration is characterized by a significant first-pass effect necessitating higher doses. , Emergence phenomena appear to occur more frequently in adults (30-50%) than in children (5-15%), in women more than in men, and at higher doses of ketamine. 
Effect of ketamine on respiration
The influence of ketamine on respiration is varied, and available reports are either equivocal or contradictory. In few studies, it has been found that ketamine, in a dose-related manner, causes a shift of the CO 2 dose-response curve to the right but does not change the slope of the curve i.e., ketamine depresses ventilation but does not reduce the respiratory response to rising levels of carbon dioxide.  However, in another study in pediatric age group, it was found that ketamine is a respiratory depressant, particularly after an intravenous bolus dose. It decreases the responsiveness of respiratory center to CO 2 .  Other recent studies demonstrated maintenance of functional residual capacity and minute ventilation in adults  and children. 
Evidences of role of ketamine in status asthmaticus
Status asthmaticus is a unique and dynamic condition requiring rapid and aggressive intervention. Asthmatic patients are predisposed for developing acute exacerbations, which may lead to respiratory failure. In acute asthma, pulmonary mechanisms are severely altered, compromising ventilation and perfusion. There is hyperinflation of lungs, which increases the elastic burden of thorax. Oxygenation, continuous nebulization, inhaled anti-cholinergics, corticosteroids, theophylline, terbutaline, epinephrine, and magnesium sulfate should be introduced simultaneously or in a phased manner, depending on the severity of exacerbation. The potential complications and pitfalls associated with each treatment modality should be identified. Decision of invasive ventilation should not be embarked upon because of its associated complications like air-leak syndromes.
Amongst other unconventional agents, bronchodilator properties of ketamine have been studied extensively in humans as well as in animal models. Few randomized control trials and isolated case reports advocate usage of this drug in severe refractory status asthmaticus unresponsive to standard therapy. The benefits of ketamine in severe status asthmaticus are promising but controversial.
The unidentified role of ketamine as a bronchodilator was first brought to light by Betts and Parkin in 1971.  They described a 5 Ύ-year-old child with severe asthma undergoing extensive allergy skin testing. Ketamine was administered as an anesthetic agent 75 mg/kg intramuscularly. Repeat dosages were given as required. They found that audible wheezing resolved significantly. This suggested that ketamine has some bronchodilator property. The successful resolution of wheezing in this child evoked interest in work on use of ketamine in asthmatic patients.
One year later in 1972, Corssen et al. used ketamine as an anesthetic in the management of 40 asthmatic surgical patients aged between 5 to 70 years.  Fourteen patients were asymptomatic, and 22 had bronchospasm during induction of anesthesia. Ketamine (1%) was administered intravenously at 1-2 mg/kg for induction, for maintenance; additional doses of 0.5-1 mg/kg were given at 15 to 30 minutes intervals or when body movements indicated that a repeat dose is desired. In 22 patients with bronchospasm prior to anesthesia who received ketamine for induction, active wheezing cleared in 19 (86%). Two patients improved markedly after receiving repeat doses of ketamine. Authors of the study concluded that ketamine not only protected against precipitation of asthma in asymptomatic group but also alleviated bronchospasm in patients with respiratory distress prior to induction of anesthesia. It also ameliorated acute bronchospasm occurring with other anesthetic agents.
Continuous infusion of ketamine in mechanically ventilated children with refractory bronchospasm has been found to have beneficial effects.  Seventeen patients ranging between 5 months to 17 years with severe asthma on mechanical ventilation were administered ketamine. These patients had acute respiratory failure associated with severe bronchospasm due to status asthmaticus (n = 11), bronchiolitis caused by respiratory syncytial virus (n = 4), and bacterial pneumonia (n = 2). All patients received conventional treatment for more than 24 hours and mechanical ventilation for 1-5 days prior to initiation of ketamine. An intravenous bolus of 2 mg/kg ketamine, followed by a continuous infusion of 20-60 μg/kg/min, was initiated as an adjunct to conventional management. Mean duration of ketamine infusion was 40 ± 31 hours. The PaO 2 /FIO 2 ratio in all patients (n = 17) and the dynamic compliance in the volume-preset mechanically ventilated patients (n = 12) were calculated. PaO 2 /FIO 2 ratio and dynamic compliance increased significantly (P < 0.0001) after the initiation of the ketamine infusion. All patients were successfully weaned from mechanical ventilation and discharged. It was concluded that ketamine significantly improves gas exchange and dynamic compliance of chest.
The effect of ketamine on bronchospasm during mechanical ventilation was evaluated in a prospective, placebo-controlled, double-blind trial. Fourteen mechanically ventilated patients with bronchospasm were randomly allocated to either ketamine 1 mg/kg or saline placebo group. The ketamine-treated patients showed an improvement by stethoscopic examination, in P O2 and P CO2 , suggesting that ketamine might be useful in treatment of bronchospasm during mechanical ventilation. 
Intravenous ketamine given in a dissociative dose may be an effective measure to avoid mechanical ventilation in patients with severe asthma excaberation.  Strube and Hallam reported favorable outcome in a 13-year-old girl following use of this drug. The patient had severe respiratory compromise, which improved after ketamine infusion and avoided intubation and mechanical ventilation. 
Ketamine can be used safely for post-operative analgesia in asthmatic patients.  Owing to its safety profile, it can be used as an adjuvant in management of refractory asthma, even in the presence of myocardial injury.  Continuous infusion of this drug produces better sedation, increase in arterial pressure, and diminution of bronchospasm in critically ill patients. 
Reduction in airway resistance following ketamine use is directly proportionate to the pre-existing bronchial obstruction. More severe the obstruction and higher the airway resistance, more pronounced is reduction in resistance. 
Petrillo et al. conducted a prospective observational study to evaluate the effects of adding ketamine to standard emergency department therapy for patients with status asthmaticus. Ten children with severe asthma unresponsive to standard therapy were enrolled. Ketamine was given at a loading dose of 1 mg/kg, followed by continuous infusion of 0.75 mg/kg/hr for 1 hour. Clinical asthma score (CAS), vital signs, and peak expiratory flow (PEF) were obtained prior to 10 min and 1 hour after beginning ketamine infusion. There was a significant decrease in CAS, respiratory rate, and oxygen requirement. However, PEF did not show significant improvement.
Heshmati et al. administered ketamine to 11 patients with status asthmaticus in respiratory failure.  These patients received ketamine at a loading dose of 1 mg/kg intravenously followed by a continuous infusion of 1 mg/kg/hr for 2 hours. Peak airway pressure values were obtained from the panel of ventilator while PaO 2 and PaCO 2 were measured by using ABG analyzer. They found that mean peak airway pressure and PaCO 2 decreased significantly (P < 0.005) and PaO 2 increased significantly (P < 0.005) after 15 min and 2 hr of ketamine infusion.
Although studies illustrated that above indicates beneficial effects of ketamine in acute exacerbation of asthma, few randomized trials did not support this role of ketamine. Howton et al. conducted a prospective, randomized, double-blind, placebo-controlled trial at an urban teaching hospital to evaluate the efficacy of ketamine as a bronchodilator in acute severe asthma.  They included 53 consecutive patients aged between 18-65 years with acute asthma exacerbation and peak expiratory flow (PEF) less than 40% after receiving albuterol nebulization thrice. Oxygen, continuous nebulized albuterol, and methylprednisolone sodium succinate were administered to all the patients. Following this, patients received either ketamine 0.2 mg/kg bolus, followed by a continuous i.v. infusion at 0.5 mg/kg/hr for 3 hours or a placebo bolus and infusion for similar duration. Bolus dose of ketamine was reduced to 0.1 mg/kg after first 9 patients due to occurrence of dysphoric reactions. There was significant improvement in PEF (F = 3.637, P = 0.004), Borg Score (F = 22.959, P = 0.001), respiratory rate (F = 8.11, P = 0.0001), and FEV-1 (F = 9.076, P = 0.001) in each treatment group. However, there was no significant difference in outcome between both groups. Authors concluded that ketamine has no bronchodilatory effects, although some satisfaction was there after ketamine use.
Allen et al. also did not find encouraging results with usage of ketamine.  Continuous infusion of ketamine was administered to pediatric patients presenting with acute asthma. Sixty-eight patients were enrolled, 33 randomized to ketamine infusion and 35 to placebo. Exclusion criteria included temperature greater than 39 degrees C (102 degrees F), focal infiltrate on radiograph, or any glucocorticoid use in the last 72 hours. Eligible patients received 3 treatments with albuterol, ipratropium bromide, and a dose of oral or parenteral glucocorticoids. Patients were randomized to receive an intravenous bolus of 0.2 mg/kg of ketamine, followed by a 2-hour ketamine infusion at 0.5 mg/kg/hour or an equal-volume regimen with normal-saline placebo. At completion of infusion, there was no significant improvement in pulmonary index score (15 point score). There were no adverse effects. These trials did not substantiate the role of ketamine in asthma, as their subset of patients did not improve significantly.
However, bronchodilatory effects of ketamine cannot be undermined, and results of these studies cannot be extrapolated. Ketamine is being used sporadically in emergency rooms for severe asthma in pediatric as well as adult age group. The results with use of ketamine in severe refractory status asthmaticus have been satisfactory. However, due to the lack of sufficient randomized, case control, blinded studies, its role as a bronchodilator is not established. Other clinical trials and case reports, which evaluated bronchodilator properties of ketamine in pediatric age group and in adults, are illustrated in [Table 1] and [Table 2], respectively.
Ketamine is a relatively safe drug owing to its property of preservation of airway reflexes. However, it has been known to increase airway secretions, thus requiring anti-sialogogues like atropine and glycopyrrolate. Disorientation, sensory and perceptual illusions, and vivid dreams on recovery might occur. Benzodiazepines have proven to be the most effective agents for prevention of these phenomena. Laryngospasm, transient rise in intracranial pressure, increased muscle tone, apnea with high doses or rapid administration, and nystagmus are the other infrequent adverse effects attributed to ketamine. ,
Ketamine is a versatile and inexpensive drug. Its place in status asthmaticus cannot be overemphasized where most of the patients respond to conventional drugs. It has been empirically used as a bronchodilator in severe status asthmaticus refractory to routine medications and has been found to obviate the need for mechanical ventilation in various studies. The limited magnitude of side effects permits its use in status asthmaticus when all other agents fail. Still, its use in asthma is debatable. There is a dearth of randomized studies to establish its favorable effects in asthmatic patients and paucity of information regarding its optimum dose. Physicians have administered bolus doses ranging from 0.1-2 mg/kg and continuous infusion from 0.15 to 2.5 mg/kg/hr. The few prospective observational studies, which described the use of ketamine in a group of asthmatic patients, had no control groups to further clarify its use. The sample size is small in most of the studies. The dosage and duration of conventional medication have not been mentioned in most of the studies. Reporting bias where negative studies for Ketamine use go unpublished is likely. Keeping these loopholes in mind, it can be concluded that ketamine is a potent bronchodilator to be considered as a rescue therapy in refractory status asthmaticus. However, it warrants further well-designed studies studies to identify its role in acute asthma.
[Table 1], [Table 2]