Current Medical Research and Opinion
Vol. 4, No. 4, 1976
Lorazepam as a sedative-amnesic in an intensive care unit
J. W. Dundee,* M.D., Ph.D., F.F.A.R.C.S.,M.R.C.P.,
Hilary M. L. Johnston,** M.B., F.F.A.R.C.S., and
Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 12/09/14 For personal use only.
R. C. Gray,*** M.D., F.F.A.R.C.S. The Queen’s University of Belfmt, and Respiratory and Intensive Care Unit, Royal Victoria Hospital, Belfast, Northern Ireland
Curr. Med. Res. Opin., (1976), 4,290.
Received: 4th June 1976
Summary A clinical study was carried out to evaluate the usefulness of intravenous lorazepam, given for sedation instead of opiate narcotics or diazepam, in 25 seriously-ill patients being treated in a respiratory and intensive care unit. All but 3 patients were on assisted ventilation. Standard doses of 4 mg lorazepam were given at 4 or 6-hourly intervals for perioh up to 25 days. ECG, haernodynamic stability and biological determinations were monitored constantly. Apart from some delay in onset of action, lorazepam proved to be a useful sedative with diminished recall on the part of the patients. No side-effects were reported, nor was there any local reaction to the injection. Cardiac output was measured in 9 patients following intravenous administration of a single-dose of either 4 mg or 8 mg lorazepam. No signijicant changes were recorded.
Key words: Lorazepam - tranquillising agents - amnesia - intensive care units
Introduction Sedation of patients in Intensive Care Units poses problems. The opiate narcotics may cause respiratory depression and abstinence symptoms on their withdrawal ; phenothiazines often cause hypotension and tachycardia; barbiturates are frequently followed by restlessness, while most other sedatives are available only in oral form. Diazepam is widely used in this field1 and, although 5 mg to 10 mg has a limited soporific effect in adults, it has proved very satisfactory when given intravenously over a long period of time, with minimal effects on cardiovascular and respiratory systems. A single 10 mg dose has a good amnesic effect which, however, is of short duration, although minor residual sleepiness may persist for up to 24 hours. There is a risk of cumulative effect and prolonged drowsiness when the dose and frequency of administration are not reduced over a long period.2.6 Lorazepamt is a long-acting benzodiazepine which has been used in its oral form in the treatment of various psychiatric di~turbances3,~ and also as pre-anaesthetic medication.8-lOIt is about 2 to 3-times as potent as diazepam but has a slower onset *Professor of Anaesthetics YAtivan’, trade mark Wyeth 290
**Senior Tutor in Anaesthetics
***Consultant Anaesthetist
Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 12/09/14 For personal use only.
J. W. Dundee, Hilary M.L. Johnston and R. C. Gray
of action and a more prolonged effect. A parenteral preparation has recently become available for clinical trials and preliminary studies in this Department have demonstrated its safety in adults in intravenous doses of4 to 8 mg. Because of its anxiolytic and amnesic properties,4,5 it was decided to evaluate its usefulness in seriously-ill patients in a Respiratory and Intensive Care Unit (RICU) where assisted ventilation was often necessary. This paper reports on the use of lorazepam in 25 patients, given over a period of 1 to 25 days. It was used in circumstances where we would normally have used diazepam. In view of the virtual absence of cardiovascular effects of 4 mg lorazepam given intravenously, advantage was taken of our ability to measure cardiac output in the RICU and 9 studies were carried out; 5 of these were with 4 mg and 4 with 8 mg. Only 1 of these patients was part of the sedation study.
Clinical study Patients and methods
The clinical study was carried out on patients admitted to the RLCU of the Royal Victoria Hospital, Belfast. This 12-bed ward includes among its admissions patients suffering from the effects of major trauma, post-operative neurosurgical cases and a variety of respiratory problems. Of the 25 patients reported here, all except 3 of them had a period of artificial ventilation - assisted or controlled. To facilitate ventilation, a neuromuscular blocking drug (pancuronium or tubocurarine) was used, the choice depending mainly on the patient’s heart rate. A variety of narcotic analgesics was used, patients receiving 10 mg morphine, 2 mg levorphanol, 50 mg to 100 mg pethidine or 2 mg phenoperidine at 4 to 6-hourly intervals. Metoclopramide, antibiotics and steroids were given as indicated. The initial part of the study was carried out on patients who were already receiving diazepam, 10 mg of which was replaced by 4 mg lorazepam. When sufficient experience had been gained with lorazepam this was given from the time of admission to the Unit. Lorazepam was always given intravenously, in most instances through a centrally placed venous catheter (Drum Cartridge Catheter, Abbott) which was also used for parenteral nutrition and fluid therapy. Except in 3 patients, the standard dose of 4 mg was given. During the main period of treatment, lorazepam was given at 4 or 6-hourly intervals and the frequency of administration decreased as patients were weaned off all sedation. Each patient had individual nursing attention in the Intensive Care Unit where there was always an anaesthetist present with consultant cover available. The ECG was monitored continuously on all patients; blood pressure, pulse rate and temperature were recorded every half-hour and continuous arterial pressure readings were made in a few patients. Arterial blood gases were measured at least twice per day with electrolyte determinations daily. Liver function tests, haemoglobin determinations, white and red cell counts and other allied tests were carried out every 3 to 4 days. 29 1
Lorazepam as a sedative-amnesic in an intensive care unit
Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 12/09/14 For personal use only.
Results Tables I and It give details of the patients in this study. They are divided into those suffering from the resuits of trauma (Table I) and other conditions (Table 11). They show a wide scatter of duration of treatment and total dosage of lorazepam. It is not possible to list fully all the other drugs which these patients received but the most important are included in these two tables. In addition to those shown, all patients received narcotic analgesics. ClinicalJindings Because of the subjective nature of the study it is difficult to give concise results as regards the efficacy of lorazepam, even in comparison with diazepam. However, Table I. Details of 16 patients suffering from the results of trauma Patient Sex No.
Age (yrs.)
Weight Site of (kg) trauma
Ventilation (no. days)
Lorazepam
Assisted Spon- Days taneous
I
Male
27
75
RTA - limbs
2
Female
I8
56
RTA -limbs (diabetes insipidus)
3
Male
32
68
GSW back and abdomen
43
4
Male
38
65
Abdomen and limbs
37
5
Male
18
65
RTA - head
6
Male
20
60
7
Male
17
55
s
Male
55
82
RTA -limbs (fat emboli) RTA - multiple fractures Flail chest (renal failure)
9
Male
50
80
10
Male
53
I1
Male
12
Total dose (mg)
6
4
24
45
9
I24
21
376
4
18
272
3
2
3
28
3
2
2
16
14
11
6
48
57
32
25
312
RTA - flail chest
24
4
17
264
78
RTA -limbs
38
17
6
116
56
14
34
I2
20
130
Male
25
72
19
4
17
384
13
Male
29
80
I5
3
8
I48
14
Male
30
75
8
4
7
72
15
Male
20
80
RTA - chest and limb RTA abdomen RTA -limb and hsad RTA -limbs (fat emboli) RTA -limbs
20
3
7
120
30
8
6
1 I6
(WlVW
16
Female
53
RTA=road traffic accident
292
65
RTA - chest (bronchitis)
GSW =gunshot wounds
Other drum
Antibiotics, steroids, lignocaine Antibiotics. steroids. chlorpromazine Antibiotics. steroids, diazepam, pentobarbitone Antibiotics, steroids, diazepam, practolol Antibiotics, steroids, diazepam Antibiotics, diaZepMl Antibiotics, steroids, diazepam Antibiotics. steroids, diazepam, isoprenaline, chlorpromazine Antibiotics, diazepam, pentobarbitone, chlorpromazine Antibiotics, diazepam Antibiotics, steroids, diazepam Antibiotics, diazepam Antibiotics. steroids, diazepam Antibiotics. steroids Antibiotics, steroids, diaiepam Antibiotics, steroids, diazepam
J. W. Dundee, Hilary M. L. Johnston and R. C. Gray
Table 11. Details of 9 patients suffering from conditions other than trauma ~
Patient Sex 110.
Age (yrs.)
Weight Cause of (kg) admission
Ventilation (no.days)
Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 12/09/14 For personal use only.
Assisted I
Malc
34
68
Myasthenia gravis
7
Female
66
64
3
Male
24
78
4
Male
18
5
Male
I2
LorazePam
Spon- Days taneous
Total do= (mg)
25
7
25
488
Post-operative gastrectomy Hysteria
3
1
2
8
4
1
8
68
Post-operative cerebral aneurysm
3
1
2
12
42
Respiratory 3 obstruction 15 Aspiration pneumonia (diabetes mellitus and diabetes insipidus) I Post-operative neurosurgery 24 Status asthmaticus
3
I
6
Post-alcohol (?) epilepsy
1
6
Female
15
62
7
Female
36
54
X
Female
37
14
9
Male
53
68
2
4
Other drugs
I0
128
I
8
4
72
2
28
Antibiotics, steroids, diazepam, anticholinesterasea Chlorpromazine, paraldehyde Antibiotics, steroids, diazepam. chlorpromazine
Antibiotics. staoida. diu4paal Antibiotics. steroids, diazepam. chlorpromazine. aminophylline Antibiotics. steroids, diazepam, arninophylline, isoprcnaline Antibiotics. steroids
certain conclusions can be drawn. In the doses used, lorazepam was an effective sedative with no detectable side-effects. It produced an even level of sedation, but in a few instances the delay of onset of action of the initial dose was apparent; this produced no problem with subsequent doses. Some of the patients recovering from trauma (Patient Nos. 6 and 14) had definite fat emboli and lorazepam produced no adverse actions in them. It acted in a predictable manner in patients suffering from a variety of non-surgical conditions (Table 11). These included several patients with raised blood urea, 2 of whom required peritoneal dialysis. With repeated doses of lorazepam, patients who were not curarised remained sufficiently rousable to allow frequent assessment of their level of consciousness. There were no problems with regard to reversal of myoneural blocking drugs and no instances of delayed recovery due to lorazepam. Hypotonus did occur in a few patients following long-term lorazepam; it was not troublesome,but the likelihood of its occurrence should be borne in mind when patients sit up in bed. Several patients in this series had skin rashes before starting lorazepam, probably resulting from antibiotic therapy. However, there were no lorazepam-induced rashes : likewise, there were no haematological changes attributable to the drug. None of the 25 patients who had lorazepam during periods of assisted ventilation had any memory of this time. Being an acute unit, surviving patients were all discharged for further care to other wards in the hospital. Lorazepam had always been discontinued prior to transfer and there were no reports of any delayed or long-term adverse sequelae. 293
Lorazepam as a sedative-amnesicin an intensive care unit
Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 12/09/14 For personal use only.
Cardiovascular study Patients and methods This was carried out in 9 patients who were clinically stable with respect to blood pressure, heart rate, who were being ventilated and who had not previously received lorazepam. Diazepam had not been given for 24 hours, and patients were receiving morphine and a neuromuscular blocking drug at regular intervals. Cardiac output was estimated by the dye dilution technique using indocyanine green. The apparatus was a Columbus Instruments Dye-dilution Cardiac Output Computer coupled to a Washington 400 MD 1 direct writer. Control estimations were carried out at 5-minute intervals until 3 similar readings were obtained. Subsequent determinations, which were carried out at 10,20,30 and 60 minutes after intravenous administration of lorazepam, were done in duplicate at 3-minute intervals. Five patients received 4 mg, and 4 patients received 8 mg lorazepam intravenously.
Results Table In summarises the findings of the cardiovascular study. Table III. Results of cardiovascularstudy in 9 patients receiving either 4 mg or 8 mg lorazepsm intravenously Patient Sex No.
Age
Weight
(yrs.)
(kg)
Cardiac output (l/min.) 0
10
20
30
60 min.
5.45 3.90 7.82 7.81 4.63
5.81 3.62 7.83 7.74 4.28
4.09 2.97 7.91 6.35 4.59
4.60 2.99 7.72 6.66 4.18
5.16 3.95 7.79 6.94 3.97
2.49 5.00 4.27 2.64
2.02 5.30 5.30 2.49
3.03 5.12 4.39 2.69
2.85 5.46 4.63 2.88
2.42 4.90 4.75 2.70
Patients receiving 4 mg lorazepam
I* 2 3 4 5
Male Female Male Male Male
18 69 47 48 56
65 66 58 60 66
Patients receiving 8 mg lorazepam
6 7 8 9
Male Female Male Female
25 53
40 41
74 64 76 49
*Patientincluded in sedation study
There was considerable individual variation in the control readings. The only notable effect following lorazepam occurred in the 20-minute reading. At this time, 2 patients had a 25 % fall in cardiac output and I had an 18 % fall following 4 mg, but in none of these was there an accompanying fall in blood pressure or rise in heart rate. No changes were observed with the higher dose. The average effects of lorazepam on cardiac output were neither of clinical nor statistical significance. These findings are in keeping with the remarkable cardiovascular stability found during this study. 294
J. W. Dundee, Hilary M.L. Johnston and R. C. Gray
Conclusions
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Apart from delay in onset of action, intravenous lorazepam proved to be a useful sedative, free from side-effects even in very large doses, and in our opinion is worthy of more extensive use in its parenteral form.
Acknowledgements Lorazepam was provided by Dr. T. V. A. Harry of Wyeth Laboratories to whom we are grateful for encouragement and support. Thanks are due to our colleagues in the RICU of the Royal Victoria Hospital, Belfast for their co-operation, and to Mr.J. J. Wilson, Chief Technician for assistance with the cardiac output studies.
References I . Abel, R. M., and Reis, R. L., (1971). Intravenous diazepam for sedation following cardiac operations: clinical and haemodynamicassessments. Anesth. Analg. Curr. Res., SO, 244-248. 2. Baird, E. S.,and Hailey, D. M.,(1972). Delayed recovery from a sedative: correlation of the plasma levels of diazepam with clinical effects after oral and intravenous administration. Br. J. Anaesth., 44,803-808. 3. Deberdt, R., (1973). Lorazepam in the treatment of severe anxiety associated with psychotic conditions. Curr. Med. Res. Opin., 1,296-300. 4. George, K. A., and Dundee, J. W., (1976). Relative amnesic actions of diazepam, flunitrazepam and lorazepam in man (benzodiazepineamnesia). Br. J. CIin. Pharntacol. In press. 5. Heisterkamp, D. V., and Cohen, P. J., (1975). The effect of intravenous premdication with lorazepam (Ativan), pentobarbitone or diazepam on recall. Br. J. Anaesth., 47,79-81. 6. Kendall, M. J., and Clarke, S. W.,(1972). Prolonged care after tetanus. Br. Med. J., 1,354-355. 7. Lasich, A. J., (1974). Evaluation of lorazepam as an anxiolytic agent in psychiatric practice. S. Afr. Med. J., 48,681-683. 8. Paymaster, N. J., (1973). Lorazepam h anaesthesia. Curr. Med. Res. Opin., 1,317-322. 9. Turner, D. J., (1973). Lorazepam as a premedicant in anaesthesia: a pilot study. Curr. Med. Res. Opin., 1,302-307. 10. Wilson, J., (1973). Lorazepam as a premedicant for general anaesthesia. C u r . Med. Res. Opin., 1,308-316.
295
Vol. 4, No. 4, 1976
Lorazepam as a sedative-amnesic in an intensive care unit
J. W. Dundee,* M.D., Ph.D., F.F.A.R.C.S.,M.R.C.P.,
Hilary M. L. Johnston,** M.B., F.F.A.R.C.S., and
Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 12/09/14 For personal use only.
R. C. Gray,*** M.D., F.F.A.R.C.S. The Queen’s University of Belfmt, and Respiratory and Intensive Care Unit, Royal Victoria Hospital, Belfast, Northern Ireland
Curr. Med. Res. Opin., (1976), 4,290.
Received: 4th June 1976
Summary A clinical study was carried out to evaluate the usefulness of intravenous lorazepam, given for sedation instead of opiate narcotics or diazepam, in 25 seriously-ill patients being treated in a respiratory and intensive care unit. All but 3 patients were on assisted ventilation. Standard doses of 4 mg lorazepam were given at 4 or 6-hourly intervals for perioh up to 25 days. ECG, haernodynamic stability and biological determinations were monitored constantly. Apart from some delay in onset of action, lorazepam proved to be a useful sedative with diminished recall on the part of the patients. No side-effects were reported, nor was there any local reaction to the injection. Cardiac output was measured in 9 patients following intravenous administration of a single-dose of either 4 mg or 8 mg lorazepam. No signijicant changes were recorded.
Key words: Lorazepam - tranquillising agents - amnesia - intensive care units
Introduction Sedation of patients in Intensive Care Units poses problems. The opiate narcotics may cause respiratory depression and abstinence symptoms on their withdrawal ; phenothiazines often cause hypotension and tachycardia; barbiturates are frequently followed by restlessness, while most other sedatives are available only in oral form. Diazepam is widely used in this field1 and, although 5 mg to 10 mg has a limited soporific effect in adults, it has proved very satisfactory when given intravenously over a long period of time, with minimal effects on cardiovascular and respiratory systems. A single 10 mg dose has a good amnesic effect which, however, is of short duration, although minor residual sleepiness may persist for up to 24 hours. There is a risk of cumulative effect and prolonged drowsiness when the dose and frequency of administration are not reduced over a long period.2.6 Lorazepamt is a long-acting benzodiazepine which has been used in its oral form in the treatment of various psychiatric di~turbances3,~ and also as pre-anaesthetic medication.8-lOIt is about 2 to 3-times as potent as diazepam but has a slower onset *Professor of Anaesthetics YAtivan’, trade mark Wyeth 290
**Senior Tutor in Anaesthetics
***Consultant Anaesthetist
Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 12/09/14 For personal use only.
J. W. Dundee, Hilary M.L. Johnston and R. C. Gray
of action and a more prolonged effect. A parenteral preparation has recently become available for clinical trials and preliminary studies in this Department have demonstrated its safety in adults in intravenous doses of4 to 8 mg. Because of its anxiolytic and amnesic properties,4,5 it was decided to evaluate its usefulness in seriously-ill patients in a Respiratory and Intensive Care Unit (RICU) where assisted ventilation was often necessary. This paper reports on the use of lorazepam in 25 patients, given over a period of 1 to 25 days. It was used in circumstances where we would normally have used diazepam. In view of the virtual absence of cardiovascular effects of 4 mg lorazepam given intravenously, advantage was taken of our ability to measure cardiac output in the RICU and 9 studies were carried out; 5 of these were with 4 mg and 4 with 8 mg. Only 1 of these patients was part of the sedation study.
Clinical study Patients and methods
The clinical study was carried out on patients admitted to the RLCU of the Royal Victoria Hospital, Belfast. This 12-bed ward includes among its admissions patients suffering from the effects of major trauma, post-operative neurosurgical cases and a variety of respiratory problems. Of the 25 patients reported here, all except 3 of them had a period of artificial ventilation - assisted or controlled. To facilitate ventilation, a neuromuscular blocking drug (pancuronium or tubocurarine) was used, the choice depending mainly on the patient’s heart rate. A variety of narcotic analgesics was used, patients receiving 10 mg morphine, 2 mg levorphanol, 50 mg to 100 mg pethidine or 2 mg phenoperidine at 4 to 6-hourly intervals. Metoclopramide, antibiotics and steroids were given as indicated. The initial part of the study was carried out on patients who were already receiving diazepam, 10 mg of which was replaced by 4 mg lorazepam. When sufficient experience had been gained with lorazepam this was given from the time of admission to the Unit. Lorazepam was always given intravenously, in most instances through a centrally placed venous catheter (Drum Cartridge Catheter, Abbott) which was also used for parenteral nutrition and fluid therapy. Except in 3 patients, the standard dose of 4 mg was given. During the main period of treatment, lorazepam was given at 4 or 6-hourly intervals and the frequency of administration decreased as patients were weaned off all sedation. Each patient had individual nursing attention in the Intensive Care Unit where there was always an anaesthetist present with consultant cover available. The ECG was monitored continuously on all patients; blood pressure, pulse rate and temperature were recorded every half-hour and continuous arterial pressure readings were made in a few patients. Arterial blood gases were measured at least twice per day with electrolyte determinations daily. Liver function tests, haemoglobin determinations, white and red cell counts and other allied tests were carried out every 3 to 4 days. 29 1
Lorazepam as a sedative-amnesic in an intensive care unit
Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 12/09/14 For personal use only.
Results Tables I and It give details of the patients in this study. They are divided into those suffering from the resuits of trauma (Table I) and other conditions (Table 11). They show a wide scatter of duration of treatment and total dosage of lorazepam. It is not possible to list fully all the other drugs which these patients received but the most important are included in these two tables. In addition to those shown, all patients received narcotic analgesics. ClinicalJindings Because of the subjective nature of the study it is difficult to give concise results as regards the efficacy of lorazepam, even in comparison with diazepam. However, Table I. Details of 16 patients suffering from the results of trauma Patient Sex No.
Age (yrs.)
Weight Site of (kg) trauma
Ventilation (no. days)
Lorazepam
Assisted Spon- Days taneous
I
Male
27
75
RTA - limbs
2
Female
I8
56
RTA -limbs (diabetes insipidus)
3
Male
32
68
GSW back and abdomen
43
4
Male
38
65
Abdomen and limbs
37
5
Male
18
65
RTA - head
6
Male
20
60
7
Male
17
55
s
Male
55
82
RTA -limbs (fat emboli) RTA - multiple fractures Flail chest (renal failure)
9
Male
50
80
10
Male
53
I1
Male
12
Total dose (mg)
6
4
24
45
9
I24
21
376
4
18
272
3
2
3
28
3
2
2
16
14
11
6
48
57
32
25
312
RTA - flail chest
24
4
17
264
78
RTA -limbs
38
17
6
116
56
14
34
I2
20
130
Male
25
72
19
4
17
384
13
Male
29
80
I5
3
8
I48
14
Male
30
75
8
4
7
72
15
Male
20
80
RTA - chest and limb RTA abdomen RTA -limb and hsad RTA -limbs (fat emboli) RTA -limbs
20
3
7
120
30
8
6
1 I6
(WlVW
16
Female
53
RTA=road traffic accident
292
65
RTA - chest (bronchitis)
GSW =gunshot wounds
Other drum
Antibiotics, steroids, lignocaine Antibiotics. steroids. chlorpromazine Antibiotics. steroids, diazepam, pentobarbitone Antibiotics, steroids, diazepam, practolol Antibiotics, steroids, diazepam Antibiotics, diaZepMl Antibiotics, steroids, diazepam Antibiotics. steroids, diazepam, isoprenaline, chlorpromazine Antibiotics, diazepam, pentobarbitone, chlorpromazine Antibiotics, diazepam Antibiotics, steroids, diazepam Antibiotics, diazepam Antibiotics. steroids, diazepam Antibiotics. steroids Antibiotics, steroids, diaiepam Antibiotics, steroids, diazepam
J. W. Dundee, Hilary M. L. Johnston and R. C. Gray
Table 11. Details of 9 patients suffering from conditions other than trauma ~
Patient Sex 110.
Age (yrs.)
Weight Cause of (kg) admission
Ventilation (no.days)
Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 12/09/14 For personal use only.
Assisted I
Malc
34
68
Myasthenia gravis
7
Female
66
64
3
Male
24
78
4
Male
18
5
Male
I2
LorazePam
Spon- Days taneous
Total do= (mg)
25
7
25
488
Post-operative gastrectomy Hysteria
3
1
2
8
4
1
8
68
Post-operative cerebral aneurysm
3
1
2
12
42
Respiratory 3 obstruction 15 Aspiration pneumonia (diabetes mellitus and diabetes insipidus) I Post-operative neurosurgery 24 Status asthmaticus
3
I
6
Post-alcohol (?) epilepsy
1
6
Female
15
62
7
Female
36
54
X
Female
37
14
9
Male
53
68
2
4
Other drugs
I0
128
I
8
4
72
2
28
Antibiotics, steroids, diazepam, anticholinesterasea Chlorpromazine, paraldehyde Antibiotics, steroids, diazepam. chlorpromazine
Antibiotics. staoida. diu4paal Antibiotics. steroids, diazepam. chlorpromazine. aminophylline Antibiotics. steroids, diazepam, arninophylline, isoprcnaline Antibiotics. steroids
certain conclusions can be drawn. In the doses used, lorazepam was an effective sedative with no detectable side-effects. It produced an even level of sedation, but in a few instances the delay of onset of action of the initial dose was apparent; this produced no problem with subsequent doses. Some of the patients recovering from trauma (Patient Nos. 6 and 14) had definite fat emboli and lorazepam produced no adverse actions in them. It acted in a predictable manner in patients suffering from a variety of non-surgical conditions (Table 11). These included several patients with raised blood urea, 2 of whom required peritoneal dialysis. With repeated doses of lorazepam, patients who were not curarised remained sufficiently rousable to allow frequent assessment of their level of consciousness. There were no problems with regard to reversal of myoneural blocking drugs and no instances of delayed recovery due to lorazepam. Hypotonus did occur in a few patients following long-term lorazepam; it was not troublesome,but the likelihood of its occurrence should be borne in mind when patients sit up in bed. Several patients in this series had skin rashes before starting lorazepam, probably resulting from antibiotic therapy. However, there were no lorazepam-induced rashes : likewise, there were no haematological changes attributable to the drug. None of the 25 patients who had lorazepam during periods of assisted ventilation had any memory of this time. Being an acute unit, surviving patients were all discharged for further care to other wards in the hospital. Lorazepam had always been discontinued prior to transfer and there were no reports of any delayed or long-term adverse sequelae. 293
Lorazepam as a sedative-amnesicin an intensive care unit
Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 12/09/14 For personal use only.
Cardiovascular study Patients and methods This was carried out in 9 patients who were clinically stable with respect to blood pressure, heart rate, who were being ventilated and who had not previously received lorazepam. Diazepam had not been given for 24 hours, and patients were receiving morphine and a neuromuscular blocking drug at regular intervals. Cardiac output was estimated by the dye dilution technique using indocyanine green. The apparatus was a Columbus Instruments Dye-dilution Cardiac Output Computer coupled to a Washington 400 MD 1 direct writer. Control estimations were carried out at 5-minute intervals until 3 similar readings were obtained. Subsequent determinations, which were carried out at 10,20,30 and 60 minutes after intravenous administration of lorazepam, were done in duplicate at 3-minute intervals. Five patients received 4 mg, and 4 patients received 8 mg lorazepam intravenously.
Results Table In summarises the findings of the cardiovascular study. Table III. Results of cardiovascularstudy in 9 patients receiving either 4 mg or 8 mg lorazepsm intravenously Patient Sex No.
Age
Weight
(yrs.)
(kg)
Cardiac output (l/min.) 0
10
20
30
60 min.
5.45 3.90 7.82 7.81 4.63
5.81 3.62 7.83 7.74 4.28
4.09 2.97 7.91 6.35 4.59
4.60 2.99 7.72 6.66 4.18
5.16 3.95 7.79 6.94 3.97
2.49 5.00 4.27 2.64
2.02 5.30 5.30 2.49
3.03 5.12 4.39 2.69
2.85 5.46 4.63 2.88
2.42 4.90 4.75 2.70
Patients receiving 4 mg lorazepam
I* 2 3 4 5
Male Female Male Male Male
18 69 47 48 56
65 66 58 60 66
Patients receiving 8 mg lorazepam
6 7 8 9
Male Female Male Female
25 53
40 41
74 64 76 49
*Patientincluded in sedation study
There was considerable individual variation in the control readings. The only notable effect following lorazepam occurred in the 20-minute reading. At this time, 2 patients had a 25 % fall in cardiac output and I had an 18 % fall following 4 mg, but in none of these was there an accompanying fall in blood pressure or rise in heart rate. No changes were observed with the higher dose. The average effects of lorazepam on cardiac output were neither of clinical nor statistical significance. These findings are in keeping with the remarkable cardiovascular stability found during this study. 294
J. W. Dundee, Hilary M.L. Johnston and R. C. Gray
Conclusions
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Apart from delay in onset of action, intravenous lorazepam proved to be a useful sedative, free from side-effects even in very large doses, and in our opinion is worthy of more extensive use in its parenteral form.
Acknowledgements Lorazepam was provided by Dr. T. V. A. Harry of Wyeth Laboratories to whom we are grateful for encouragement and support. Thanks are due to our colleagues in the RICU of the Royal Victoria Hospital, Belfast for their co-operation, and to Mr.J. J. Wilson, Chief Technician for assistance with the cardiac output studies.
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