Evaluation of a combination of low-dose ketamine and low-dose midazolam in terminal dyspnea-attenuation of "double-effect"
Aim: Of all symptoms in palliative medicine those concerning respiration are most excruciating and difficult to treat. Reticence about the use of morphine for palliation of dyspnea is common, especially in nonmalignant diseases, as there is a fear of causing respiratory depression, particularly where Chronic Obstructive Pulmonary Disease (COPD) exists. This factor is also compounded by the lack of availability of morphine in parts of developing countries. Ketamine has excellent anesthetic and analgesic effects in addition to being easily available. It produces bronchodilatation and does not produce respiratory or cardiovascular depression. The author seeks to evaluate the role of low-dose (0.2 mg/kg) ketamine and midazolam (0.02 mg/kg) in the attenuation of terminal dyspnea.
Keywords: Ketamine, terminal dyspnea, midazolam
Dyspnea is the sensation of difficulty or distress in breathing. It is very frightening and occurs in about 21 to 78.6% of all patients in palliative care.  Reticence about the use of morphine for palliation of dyspnea is common, especially in nonmalignant diseases, as there is a fear of causing respiratory depression, particularly where COPD exists. Moreover, morphine can cause histamine release and thus aggravate bronchospasm, especially in COPD patients, and can thus also lead to hypotension. ,,,, This factor is also compounded by the lack of availability of morphine in parts of developing countries and the consideration of a "double-effect". The principle of double effect is used to justify the administration of medications to relieve pain even though it may lead to the unintended, although foreseen, consequence of hastening death by causing respiratory depression. However numerous studies on the use of oral morphine in the management of dyspnea have confirmed its safety. , However, a meta-analysis on the use of opioids in the management of dyspnea reported that the clinical effects of systemic and oral opioids was relatively small. 
Ketamine has minimal effects on the central respiratory drive, as reflected by an unaltered response to CO 2 .  It is also a bronchial smooth muscle relaxant and when administered to patients with reactive airway disease and bronchospasm, pulmonary compliance is improved.  It does not produce respiratory or cardiovascular depression. However, it has the propensity to produce "emergence phenomenon", which can be attenuated by the addition of low-dose midazolam. 
Keeping the above facts in mind, the following study was designed to evaluate the efficacy of low-dose ketamine and midazolam in relieving terminal dyspnea.
Aims and objectives
Prospective study duly approved by the hospital ethics committee
Data collected would be analyzed using the paired t-test with a p value of < 0.05, which is considered to be significant.
Patients with terminal dyspnea admitted to the CCU included both cancer and noncancer patients. Patients having evidence of Systemic inflammatory Response Syndrome (SIRS) were excluded from the study. Only adult patients were enrolled. Self-assessment of dyspnea was performed by every patient using the GRS, which has values from 0-10, 10 being maximum dyspnea. , Each patient received one low-dose of ketamine and midazolam for relief of dyspnea. All patients received low-flow (2 L/min) oxygen therapy via nasal cannulae. All the patients were managed in the CCU of a tertiary care hospital. Immediately after admission all the patients were reassured and nursed in the propped up position. The GRS, as described by the patients, was recorded by a blinded observer at the point of admission, ten minutes after starting oxygen therapy, and ten minutes after administration of low-dose ketamine and midazolam. All hemodynamic monitoring was also recorded at these three points.
Monitoring: Pulse, electrocardiogram (ECG), SpO 2 , noninvasive blood pressure (NIBP), and respiratory rate (RR). These were recorded using a Hewlett-Packard monitor.
A total of 16 patients were studied, which included patients with cancer as well as patients without cancer. The demographic data and diagnoses of the patients were as follows [Table 1]:
Graph showing the mean of the pulse rate, mean arterial blood pressure, and oxygen saturation, measured at admission, after starting oxygen therapy, and after administration of ketamine and midazolam
The following graph shows the changes in respiratory rate and Graphic rating scale measured at admission, after starting oxygen therapy, and after administration of ketamine and midazolam
It is evident from our study that all the patients who enrolled in the study had significant dyspnea at admission, as is evident from the GRS scores of 8.250 (SD 0.91), respiratory rate of 28.56 (SD 5.0), MABP of 102.7 (SD 14.63), pulse rate of 115.62 (SD 23.3) and SpO2 of 92.43 (SD 2.38).
Reassurance, positioning in the propped up position, and administration of oxygen by nasal cannulae afforded a significant degree of relief, as is evident from the changes in scores, which were further improved after administration of ketamine and midazolam [Table 2],[Figure 1] and [Figure 2].
The average duration of relief from dyspnea after the administration of ketamine and midazolam was 36.75 minutes (SD 5.23).
The patients who enrolled in our study included both cancer and noncancer patients, in whom the main focus of therapy was palliation of symptoms. All the patients had significant dyspnea on admission, as was evident from the GRS scores of 8.25 (SD 0.90). Administration of O 2 therapy by nasal cannulae was acceptable to the patients and did not pose a barrier to effective communication. Above all, it did provide a statistically significant ( p < 0.01) reduction in GRS scores. However the few published studies do not clearly demonstrate that oxygen relieves dyspnea. , There is conflicting evidence, particularly in lung cancer patients who are not significantly hypoxaemic. In this study, the SpO 2 increased from a mean of 92.4 to 96.3% after O 2 therapy, which was statistically significant ( p < 0.01).
Thus, in this study, oxygen therapy afforded relief in dyspnea, which was validated by both subjective (GRS scores) and objective (SpO 2 , pulse) parameters.
Moreover, all the patients benefited from the administration of a combination of ketamine and midazolam, as evidenced by a statistically significant ( p < 0.01) improvement in all monitored parameters. Studies using benzodiazepines in terminal dyspnea demonstrated that they failed to work in four trials out of five.  A Cochrane review was dubious about the value of benzodiazepines for any aspect of palliative care. 
However in this study, midazolam has been used in combination with ketamine in a dose of 0.02 mg/kg, which is a very low dose, mainly with the objective of negating the undesirable effects of ketamine. This is the first study of its kind.
The combination of a benzodiazepine with ketamine attenuates or eliminates unwanted tachycardia or hypertension as well as psychological derangements.
In addition, the use of ketamine and midazolam afforded a statistically significant ( P < 0.01) degree of improvement in all measured parameters, when compared with not only baseline values but also O 2 therapy.
This is the first study where ketamine in a low dose has been used to palliate dyspnea, with excellent results. The exact mechanism of action in the palliation of dyspnea is unclear as of now. The primary site of the central nervous system action of ketamine appears to be the thalamoneocortical projection system,  selectively depressing the neuronal function in parts of the cortex (especially the association areas) and thalamus, while simultaneously stimulating parts of the limbic system. This process creates a functional disorganization of nonspecific pathways in the midbrain and thalamic areas.  There is also evidence that it depresses transmission of impulses in the medial medullary reticular formation, important for transmission of the affective-emotional components of nociception from the spinal cord to the higher brain centers.  Also it has opioid m-receptor activity and N-Methyl-D-Aspartate (NMDA) receptor antagonistic activity, which accounts for its analgesic effects. Ketamine does not cause significant respiratory depression at standard doses. The ventilatory response to CO 2 is preserved with the use of ketamine. It also has bronchodilatory effects resulting from an increase in sympathetic tone. Low-dose ketamine as an analgesic has been used after thoracic surgery, in which its lack of respiratory depressant properties is used to an advantage.
On the basis of this study, the author concludes that a combination of low-dose ketamine and midazolam can safely be used in the palliation of terminal dyspnea, with excellent results. The duration of action of this combination, in providing symptomatic relief, is however short-lived, being 36.7 minutes on an average (SD 5.23), thus necessitating intermittent IV top-ups. No adverse reports have been obtained in this study. Oxygen therapy by nasal cannulae at 2 L/minute improved oxygen saturation, however, it did not significantly improve the breathlessness.
The use of low-dose ketamine and midazolam is especially useful in a country like ours, where we have a problem with the availability of opioids. It also has an excellent safety profile.
[Figure 1], [Figure 2]
[Table 1], [Table 2]