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ORIGINAL ARTICLE
Year : 2008  |  Volume : 14  |  Issue : 2  |  Page : 97-101

Evaluation of a combination of low-dose ketamine and low-dose midazolam in terminal dyspnea-attenuation of "double-effect"


KOSISH - The Hospice, Qr.2120, Sector 4 C, Bokaro Steel City, Jharkhand - 827004, India

Correspondence Address:
Abhijit Kanti Dam
KOSISH - The Hospice, Qr.2120, Sector 4 C, Bokaro Steel City
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1075.45453

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 » Abstract 

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.
Methods: Sixteen patients with terminal dyspnea, admitted to the Critical Care Unit (CCU) with cancer and other noncancer diagnoses were recruited. The subjective component of dyspnea was assessed using the Graphic Rating Scale (GRS), which has values from 0 - 10, 10 being maximum dyspnea. Each patient received a low-dose of ketamine and midazolam for relief of dyspnea. All the patients received low-flow (2 L/min.) oxygen therapy via nasal cannula. Immediately after admission, all the patients were reassured and nursed in a decubitus position of their choice. The GRS was recorded at the point of admission, 10 minutes after starting oxygen therapy, and ten minutes after administration of low-dose ketamine and midazolam. Hemodynamic parameters were also recorded at these three points.
Result: All the patients who enrolled in our study had significant dyspnea at admission, as was evident from the GRS scores of 8.250 (SD 0.91), respiratory rate of 28.56 (SD 5.0), mean arterial blood pressure (MABP) of 102.7 (SD 14.63), pulse rate of 115.62 (SD 23.3), and SpO2 of 92.43 (SD 2.38). All the patients benefited from the combination of ketamine and midazolam, as evidenced by the statistically significant ( P < 0.01) improvement in all monitored parameters.
Conclusion: The author concludes that a combination of low-dose ketamine and midazolam can be safely 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 were obtained in the study.


Keywords: Ketamine, terminal dyspnea, midazolam


How to cite this article:
Dam AK. Evaluation of a combination of low-dose ketamine and low-dose midazolam in terminal dyspnea-attenuation of "double-effect". Indian J Palliat Care 2008;14:97-101

How to cite this URL:
Dam AK. Evaluation of a combination of low-dose ketamine and low-dose midazolam in terminal dyspnea-attenuation of "double-effect". Indian J Palliat Care [serial online] 2008 [cited 2019 Sep 17];14:97-101. Available from: http://www.jpalliativecare.com/text.asp?2008/14/2/97/45453



 » Introduction Top


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. [1] 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. [1],[2],[3],[4],[5] 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. [6],[7] 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. [8]

Ketamine has minimal effects on the central respiratory drive, as reflected by an unaltered response to CO 2 . [9] It is also a bronchial smooth muscle relaxant and when administered to patients with reactive airway disease and bronchospasm, pulmonary compliance is improved. [10] 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. [11]

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

  • To assess the efficacy of a combination of low-dose (0.2 mg/kg) ketamine and low-dose midazolam (0.02 mg/kg), given intravenously, for relieving terminal dyspnea
  • To note adverse effects, if any, associated with the use of this combination


Study design

Prospective study duly approved by the hospital ethics committee

Statistical analysis

Data collected would be analyzed using the paired t-test with a p value of < 0.05, which is considered to be significant.


 » Methods Top


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. [12],[13] 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.

Exclusion criteria

  • Patients having a Glasgow Coma Scale (GCS) of < 12
  • Evidence of Systemic inflammatory Response Syndrome
  • Mechanical causes of dyspnea (massive ascites, pleural effusion, etc.)
  • Patients requiring mechanical ventilation
  • Hypoxia refractory to oxygen therapy (SpO 2 < 85% despite oxygen therapy)


Monitoring: Pulse, electrocardiogram (ECG), SpO 2 , noninvasive blood pressure (NIBP), and respiratory rate (RR). These were recorded using a Hewlett-Packard monitor.


 » Observations and Results Top


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).


 » Discussion Top


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. [11],[12] 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. [14] A Cochrane review was dubious about the value of benzodiazepines for any aspect of palliative care. [15]

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, [16] 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. [17] 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. [18] 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.[20]


 » Conclusion Top


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.

 
 » References Top

1.Tripathi KD. Essentials of medical pharmacology, 4th ed. Jaypee Publications.  Back to cited text no. 1    
2.Drew Jh, Dripps RD, Comroe JH. The effect of morphine upon the circulation of man and upon the circulatory and respiratory responses to tilting. Anaesthesiology 1946;7:44.  Back to cited text no. 2    
3.Flacke JW, Van Etten AP, Bloor BC, Van Etten AP, Kripke BJ. Histamine release by four narcotics: A double blind study in humans. Anaesth Analg 1987;66:723-30.  Back to cited text no. 3    
4.Hughes S, Calverly P. Heroin inhalation and asthma. Br Med J 1988;297:1511-2.  Back to cited text no. 4    
5.Ahmedzai S. Palliation of respiratory symptoms. Oxford textbook of palliative medicine. 2nd ed. Oxford University Press.  Back to cited text no. 5    
6.Walsh TD, Rivera NI, Kaiko R. Oral morphine and respiratory function amongst hospice in patients with advanced cancer. Support Care Cancer 2003;11:780-4.   Back to cited text no. 6  [PUBMED]  
7.Bruera E. Subcutaneous morphine in terminal cancer. J Pain Symp Manage 1990:5;341-4.  Back to cited text no. 7    
8.Jennings AL, Davies AN, Higgins JP, Gibbs JS, Broadley KE. A systematic review of the use of opioids in the management of dyspnea. Thorax 2002;57:939-44.  Back to cited text no. 8  [PUBMED]  
9.Soliman MG, Brinale GF, Kuster G. Response to hypercapnia under ketamine anaesthesia. Can Anesth Soc J 1975;22:486.   Back to cited text no. 9    
10.Huber FC, Reves JG, GutierrezJ, Corssen G: Ketamine: Its effect on airway resistance in man. South Med J 65:1176, 1972  Back to cited text no. 10    
11.White PF, Way WL, Trevor AJ. Ketamine-its pharmacology and therapeutic use. Anaesthesiology 1982;56:119.   Back to cited text no. 11    
12.Moody L, McCormick K, Williams A. Disease and symptom severity, functional status and quality of life in chronic bronchitis and emphysema. J Behav Med 1990;13:297-304.  Back to cited text no. 12  [PUBMED]  
13.Moody LE, Fraser M, Yarandi H. Effects of guided imagery in patients with chronic bronchitis and emphysema. Clin Nursing Res1993;2:478-86.  Back to cited text no. 13    
14.Ripamonti C. Management of dyspnea in advanced cancer patients. Support Care Cancer 1999;7:233-43.  Back to cited text no. 14  [PUBMED]  
15.Hirst A, Sloan R. Benzodiazepines and related drugs for insomnia in palliative care. Cochrane Database Syst Rev 2002;4:CD003346.  Back to cited text no. 15  [PUBMED]  
16.Miyasaka M, Domino EF. Neuronal mechanisms of ketamine induced anaesthesia. Int J Neuropharmacol 1968;7:557.  Back to cited text no. 16  [PUBMED]  
17.Corssen G, Reves JG, Stanley TH, editors. Dissociative anaesthesia. In Intravenous anaesthesia and analgesia. Philadelphia: Lea and Febiger; 1988. p. 99.  Back to cited text no. 17    
18.Ohtami M, Kikuchi H, Kitahata LH, Taub A, Toyooka H, Hanaoka K, et al . Effects of ketamine on nociceptive cells in the medical medullary reticular formation of the cat. Anaesthesiology 1979;51:414.   Back to cited text no. 18    
19.Gallagher R, Roberts D. A systematic review of oxygen and airflow effect on relief of dyspnea at rest in patients with advanced disease of any cause. J Pain Palliat Care Pharmacother 2004;18:3-15.   Back to cited text no. 19  [PUBMED]  
20.Booth S, Wade R, Johnson M, Kite S, Swannick M, Anderson H, et al . The use of oxygen in the palliation of breathlessness: A report of the expert working group of the Scientific Committee of the Association of Palliative Medicine. Respir Med 2004;98:66-77.  Back to cited text no. 20    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2]



 

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