Anaesthesia, 1990, Volume 45, pages 366-372
Propofol for long-term sedation in the intensive care unit* A comparison with papaveretum and midazolam
C. E. HARRIS, R . M. GROUNDS, A. M . MURRAY, J. LUMLEY, D. ROYSTON MORGAN
AND
M.
Summary Thirty-seven patients with a wide range of illnesses were studied during mechanical ventilation of the lungs in an intensive care unit. Fifteen were sedated with a continuous propofol infusion, with analgesia provided by bolus doses of papaveretum. Twelve received a continuous infusion of papaveretum, supplemented by bolus doses of midazolam. The level of sedation was assessed every four hours and measurements were made of haemodynamic and respiratory variables. Levels of sedation were generally satisfactory in both groups. Six patients who received propofol required the use of muscle relaxants, because of their strong respiratory drives, to achieve synchronisation with the ventilator. There was no signi3cant difference in respiratory or haemodynamic variables between the groups, but several patients required inotropic support because of their disease. There was no evidence of inhibition of adrenal steroidogenesis in the propofol group. Propofol can be a useful sedative agent in the intensive cure unit, but sedative regimens should be tailored to individual patient requirements.
Key words Anaesthetics , intravenous; pr opofol . Intensive care.
Patients who require artificial ventilation of the lungs whilst in the intensive care unit invariably need some form of sedation for at least part of their stay. The ideal intravenous agent for use in this way would be short acting and noncumulative and thus allow rapid recovery for neurological assessment and early weaning from artificial ventilation. Such a drug should be free from adverse effects on the various organs of the body and not influence the metabolism of other drugs that might be used in these patients. The short acting intravenous anaesthetics Althesin and etomidate approached the ideal for this purpose and were extensively used, but unfortunately were withdrawn, the former because of an unacceptably high incidence of allergic reactions to its solubilising agent, and the latter because suppression of cortisol production was implicated in an increased mortality in severely injured patients.’,2The resultant gap was difficult to fill and most centres resorted to use of a benzodiazepine and an opioid. Initial pharma-
cokinetic studies with midazolam seemed to promise rapid recovery,’ but there is growing evidence that it is not a suitable drug for use in the critically ill.4.5 Propofol is characterised by a short half-life6and initial studies on its use for short periods in the intensive care unit are very e n ~ o u r a g i n g .The ~ . ~ present study was designed to assess the suitability of continuous infusions of propofol to provide sedation in patients for artificial ventilation in the intensive care unit and to compare it with the standard method in use in the unit, namely an infusion of papaveretum supplemented with bolus injections of midazolam.
Methods The study was approved by the local ethics committee and the Committee on Safety of Medicines. Informed written consent was obtained from the patients, or when this was not possible because of their illness, from their next of kin.
*Propofol is not yet licensed for use by infusion in intensive care units in the United Kingdom and this study was carried out with a clinical trial certificate from the Committee on Safety of Medicines. Accepted 18 October 1989. C.E. Harris,? FFARCS, R.M. Grounds,$ MD, FFARCS, A.M. Murray,§ FFARCS, Senior Registrars, J. Lumley, FFARCS, Consultant, D. Royston, FFARCS, Senior Lecturer, M. Morgan, FFARCS, Reader, Department of Anaesthetics, Royal Postgraduate Medical School, Hammersmith Hospital, Du Cane Road, London W12 OHS. ?Present position: Senior Registrar in Intensive Therapy, Mersey Region. $Present position: Consultant Anaesthetist, St George’s Hospital, London. §Present position: Consultant Anaesthetist, Basildon Hospital, Essex. Correspondence should be addressed to Dr M. Morgan, please. 0003-2409/90/050366 + 07 $03.00/0
@ 1990 The Association of Anaesthetists of Gt Britain and Ireland
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PropofoI f o r long-term sedation in the ICU Patient selection. Male or female patients aged 16-80 years who required mechanical ventilation of the lungs were admitted to the trial. Exclusion criteria were: known allergy to any of the trial drugs, pregnancy, patients who had undergone routine cardiac surgery, head injuries, those who had an established sedation regimen in the previous 24 hours and those with disorders of lipid metabolism. APACHE I1 scoring9 was performed o n all patients who were then randomly divided t o receive either a propofol or papaveretum infusion. Infusion regimens. An intravenous infusion of propofol was started a t a rate of 1-3 mg/kg/hour, preceded by a bolus of 1.0 mg/kg if clinically indicated. The rate of infusion was adjusted.to maintain a sedation level between 2 and 5 on the scoring system described by Ramsay and his colleagues,I0 although preferably a t level 3 . Intravenous bolus doses of papaveretum 2.5-5.0 m g were given to provide analgesia when required. An infusion-of papaveretum in the other group was started at a rate of 2.0 mg/hour and adjusted to maintain sedation at the required level. This was supplemented by intravenous boluses of midazolam 2.5-5.0 mg t o achieve
Table 1. Details of patients with duration of sedation and ventilation and number of survivors. Propofol
n = I5
Papaveretum n = 12
4 : 11 8
6:6 7
Age, years (SEM) Weight, kg (SEM) Height, cm (SEM)
47.8 (3.7) 61.3 (3.8) 162.4 (2.2)
54.6 (5.9) 70.4 (4.4) 167.6 (3.2)
Duration of ventilation, hours Mean (SEM) Range
101.6 (19.9) 18.3-240
66.6 (20.3) 15-236
Duration of sedation, hours Mean (SEM) Range
84.5 (15.4) 18-189
66.9 (20.5) 9.5-236
Male : female Survivors
adequate sedation when necessary. Neuromuscular relaxants were used in either group when it proved impossible to achieve synchronisation with the ventilator by other means.
Table 2. Details of patients in propofol group. ~
~~
Patient No.
Reason for admission to ICU
Concurrent disease
APACHE I1 score
Outcome
1
Acute tubular necrosis, ARDS
Paget’s disease
34
Survived
2
Acute respiratory failure, pneumonia
Chronic granulocytic leukaemia; bone marrow transplant, immunosuppressed
15
Survived
3
Acute respiratory failure, pneumonia
Chronic granulocytic leukaemia, bone marrow transplant, pulmonary fibrosis, immunosuppressed
24
Died
4
Multiple trauma
None
13
Survived
5
Acute respiratory failure, asthma
Obesity, steroid therapy
10
Survived
6
Acute respiratory failure, asthma
Aortic valve replacement, steroid therapy
19
Survived
7
Acute respiratory failure, cytomegalovirus
Fibrosing alveolitis, immunosuppressed
22
Withdrawn, died
8
Postoperative emergency mitral valve replacement
None
24
Died
9
Acute respiratory failure, pneumonia
Acute myeloid leukaemia, bone marrow transplant, cytomegalovirus infection, immunosuppressed
22
Died
10
Postoperative peritonitis, pancreatitis
Subphrenic abscess, acute tubular necrosis
11
Acute respiratory failure, pneumonia, pneumocystis
Chronic granulocytic leukaemia, bone marrow transplant, immunosuppressed
14
Died
12
Acute respiratory failure, pneumonia
Polyarteritis nodosa, pneumocystis, immunosuppressed
17
Survived
13
Postrespiratory arrest, cerebral haemorrhage
Spinal cord tumour, renal transplant, fungal pneumonia, Parkinson’s disease, immunosuppressed
17
Died
14
Post aortobifemoral graft
Asthma, diabetes, ischaemic heart disease,
15
Died
15
Postrespiratory arrest
Chronic renal failure, renal transplant, fungal pneumonia
18
Withdrawn, died
ARDS, adult respiratory distress syndrome.
9
Survived
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C.E. Harris et at.
Monitoring Sedation. This was assessed every 4 hours using the Ramsay scale, while in addition one of the investigators assessed the quality of sedation every 24 hours o n a fourpoint scale: excellent, good, adequate or poor. The nursing staff made a global assessment of the quality of sedation at the end of the study period and also the ease with which it was managed, again o n a four-point scale, excellent, easy, adequate or poor. Patients who had received neuromuscular blocking drugs were scored at level 6. The time taken to resumption of spontaneous ventilation and to obey a simple command was recorded at the end of treatment. Cardiovascular. Heart rate, arterial and central venous pressures were aontinuously displayed and recorded every 4 hours. Cardiac output and pulmonary artery wedge pressure were measured if insertion of a pulmonary artery catheter was indicated. Respiratory. Respiratory rate, minute volume, inspired oxygen concentration and arterial blood gases were noted every 4 hours. The alveolar-arterial oxygen tension difference (A-aDo,) was also calculated at this time. The shunt fraction was measured in those in whom a pulmonary arterial catheter was inserted. Biochemical. Cortisol levels were measured before the start of sedation and a t 24 and 48 hours. The response to synacthen 250 pg intravenously was assessed a t 30 and 60 minutes after the start of sedation and after 24 and 48 hours. Haemoglobin, packed cell volume, white cell and platelet counts, prothrombin time, urea and electrolytes, creatinine, albumin, aminotransferase and alkaline phos-
phates were measured before the start of sedation and also a t 24 and 48 hours, but the results are not presented.
Statistical analysis Statistical tests used were: analysis of variance, the paired and unpaired t-tests, the Mann-Whitney U test and the Chi-square test.
Results Patient details. Twenty-seven patients were admitted to the trial, 15 of whom received propofol. Their anthropometric data are shown in Table 1; there was no significant difference between the groups in this respect. Eight patients in the propofol group survived, and seven who received papaveretum and midazolam, although one of the latter died 24 hours after leaving the intensive care unit. Three patients were withdrawn from the trial, two after propofol. The data from these patients, u p to the time of their withdrawal from the trial, were included in the results. One of these latter was a 60-year-old man with fibrosing alveolitis who became hypotensive as the propofol dose was increased in an attempt to achieve synchronisation with the ventilator; the other was a 48-year-old woman in renal failure who developed lipaemia once parenteral nutrition was started. Sedation was stopped to allow neurological assessment in one patient in the control group and was never restarted. The reasons for admission to the intensive care unit, the APACHE I1 scores on admission and the outcome for each patient are shown in Tables 2 and 3. There was no significant difference between the scores in the two groups
Table 3. Details of patients in papaveretum group. ~~~
Patient No.
Reason for admission to ICU
1
Acute respiratory failure
2
Acute respiratory failure, pulmonary oedema Peritonitis, acute respiratory failure
3
4
Postcardiorespiratory arrest, pulmonary embolus
Concurrent disease Chronic granulocytic leukaemia, pulmonary fibrosis, immunosuppressed Hypothyroidism, diabetes primary biliary cirrhosis Chronic renal failure scleroderma, systemic lupus erythematosis, pulmonary fibrosis, immunosuppressed Aortobifemord graft, atrial fibrillation
Ischaemic heart disease
APACHE I1 score
Outcome
23
Survived
12
Survived
29
Died 24 hours after leaving unit
14
Died
23 2
Died Survived
16
Survived
I
Survived
Gross obesity
15
Survived
Ischaemic heart disease
22
Died
Newly diagnosed severe hypothyroidism
16
Withdrawn. died
5
Postlaparotomy for bleeding, 6
Septic shock, fecal peritonitis
7
Pulmonary oedema
8
Postoperative partial hepatectomy
9
Multiple trauma, partial hepatectomy Postoperative respiratory depression, hysterectomy Postoperative respiratory failure, aortobifemoral graft Septic shock
10
I1 12
Caesarean section for placenta praevia, hysterectomy, massive transfusion Carcinoid syndrome, massive transfusion None
Propofol f o r long-term sedation in the ICU
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Table 4. Drug doses.
Propofol group Dose of drug (mg)
Propofol
Papaveretum
Papaveretum
Midazolam
Total, mean (SEM) range
7600 (2458) 263-36000
55.0 (30.9) 0-444
433.5 (128) 50-1200
14.2 (5.9) 0-75
128.8 (46.4) 5.8-720
0.86 (0.45) 0-64
6.3 (1.8) 0.7-1 8.1 0.1 (0.013) 0.04-0.17
0.2 (0.09) 0-1.13
mg/kg/hour, mean (SEM) range
1.32 (0.24) 0.23-3.73
(Mann-Whitney U test). Multiple pathology was the rule rather than the exception in these patients. Duration of venlilation. The durations of ventilation and sedation in the two groups are shown in Table 1 . The propofol figures for time of ventilation exclude one patient who was initially weaned from ventilation, but her trachea was not extubafed and she continued to receive intermittent mandatory ventilation for 2 months, and required virtually no sedation. The durations of ventilation and sedation were longer in those who received propofol, but the differences were not significant. Drug doses. The doses of the drugs used are shown in Table 4. The mean total dose of papaveretum used in conjunction with propofol was 55 mg (range W 4 mg). Relatively little midazolam was given to the papaveretum group, a mean of 14.2 mg, although one woman received 75 mg over a period of 120 hours. Cardiorespiratory measurements. Inotropic support with dopamine or adrenaline was required in eight patients given propofol and five who received papaveretum in order
P,
140
Papaveretum group
r
c
140r
\
T
8OL
.-
2 O r
V
g:"o
4
8
12 16 20 24 28 32 36 40 44 48 Time ( b u r s )
Fig. 1. Systolic arterial pressure, heart rate and central venous pressure during first 48 hours of sedation. 0 . . . 0 , propofol; 0-0,
t r
3
0 0
-
to maintain haemodynamic measurements within normal limits. There were no significant differences from control within either group for any of the measurements, nor between the groups (Figs 1 and 2). Increase in sedative drug dose was associated with hypotension in five patients given propofol, one who was withdrawn from the trial (maximum infusion rate of propofol 33 mg/kg/hour), and in three who received papaveretum. Similarly, no differences in any of the respiratory measurements were seen between, or within, the two groups (Fig. 3). Cortisol. The results of the cortisol measurements are shown in Table 5. Nine propofol patients and four papaveretum were already receiving steroid therapy on admission to the unit. The mean cortisol levels were high in the other patients, 1121 nmol/litre and 1169 nmol/litre for the propofol and papaveretum groups respectively. The results of the synacthen tests a t 48 hours are also shown in Table 5. Four of the six patients given propofol who were not receiving steroids had short synacthen tests and all showed a positive response. Two of seven patients on steroids in this group also had a positive test, which was negative in the other five. Six of the seven patients in the papaveretum group who did not receive steroids on admission showed a positive result, while the other, a young man with multiple trauma, was negative; the one patient who received steroids and who was tested had n o response to synacthen. Assessment of sedation. The overall sedation scores are shown in Table 6. Patients were maintained between seda-
25
3
-
papaveretum.
011 0
4
I
I
I
I
'
I
I
I
I
8 12 16 20 24 28 32 36 40 44 48 Time (hours)
Fig. 2. Cardiac index and pulmonary artery wedge Pressure during first 48 hours of sedation. 0 . . . a , propofol; 0-0, papaveretum.
370
C.E. Harris et al. Table 6. Sedation scoring. Time spent (%) at each level. ~
~~
Sedation level
Propofol
Papaveretum
1
5.1Yo 28.8% 13.5% 23.1Yo 15.4% 14.1Yo
6.1Yo 26.3% 20.2% 25.2% 18.2% 4.0%
2 3
4 5 6
Table 7. Global assessment of sedation.
Propofol I
50-
8
0
A
20'1 0
I
4
I
I
"
I
I
I
8 12 16 20 24 2 8 3 2 3 6 4 0 4 4 48 Time (hours)
Fig. 3. pH, Pacq and A-am, during first 48 hours of sedation. 0 . . .0,
propofol;
0-0,
papavereturn.
tion levels 2 and 5 for 80.8% of time in the propofol group and for 89.9% of the time in those who received papaveretum. The relatively high number of scores of 6 after propofol (14.1% of the time) is due to the assessment of paralysed patients. The time spent at sedation level 6 decreases to 1.5% and the time spent at the 2-5 levels increases to 92.6%, if these results are excluded, and these modified results are shown in Figure 4. The global assessment of sedation by the investigators and nursing staff at 24 and 48 hours is shown in Table 7. The number of poor assessments in the propofol patients is again attributable to the use of neuromuscular blocking drugs. Recovery. Eight propofol patients and seven papaveretum survived. The majority (four in both groups) were able to obey commands before cessation of sedation and were also able to breathe spontaneously before sedation was stopped. One of the four others in the propofol group was able to obey commands when the sedation was
Nursing staff Overall management of patient Excellent Easy Adequate Poor Quality of sedation Excellent Good Adequate Poor Medical staff Excellent Good Adequate Poor
4
5 3
3
4 5 2 4
4 3
4 4
stopped, two 15 minutes after and one 2.5 hours after. One of the three who remained in the papaveretum group was able to obey commands 30 minutes after sedation was stopped, one 1.25 hours and the other 7.25 hours.
Discussion There are many factors involved in the provision of comfort for the patient in the intensive care unit and sedation may not always be beneficial." In practice, however, most patients will not tolerate artificial ventilation and the intensive care environment without some form of sedation. The agent used should ideally be free from harmful short- and long-term side effects, be easy to manage, have inactive metabolites and be noncumulative. This would allow rapid recovery for neurological assessment when required. The most commonly used regimen in
Table 5.
Number receiving steroids Mean cortisol on admission in those patients not receiving steroids mean, nmol/litre (SEM) range Synacthen test Not receiving steroids
Papaveretum
Propofol
Papaveretum
9
4
1121 (547) 547-2430
1629 (907) 548-3 110
4+ve
6+ve 1 -ve
Receiving steroids
2+ve
1 -ve
Not done
5-ve 4
4
Propofol for long-term sedation in the ICU
40c
8
~edotonlevel
.,
Fig. 4. Percentage of time spent at each sedation level excluding those patients who received neuromuscular blocking drugs. propofol; papaveretum.
m,
the United Kingdom is an infusion of opioids supplemented by a benzodiazepine,12 but this has the disadvantage of relatively prolonged recovery, respiratory depression in spontaneously breathing patients and gastrointestinal stasis. A previous study from this department? compared propofol with papaveretum and midazolam as the sedative regimens in postoperative cardiac surgical patients who required artificial ventilation and showed propofol to be the superior; these patients, however, represented a relatively homogeneous group. The present report illustrates many of the problems of comparative studies in patients in an intensive care unit. The multiple pathology and diversity of the clinical problems makes comparisons extremely difficult. All the patients were severely ill, which is reflected in the high mortality. Many of the patients required inotropic support because of their illness, so it is difficult to draw many conclusions from the measured cardiovascular data. Hypotension occurred in both groups, occasionally related to the administration of midazolam. There was a tendency for hypotension to occur more frequently in the propofol group; the one patient who was withdrawn from the study in this group for this reason was deliberately kept relatively hypovolaemic. The hypotensive effect of propofol is mainly the result of a decrease in systemic vascular resistance,” and in the present series where cardiac output was measured it was maintained. It is important that the circulating volume be maintained to minimise any decreases in arterial pressure when propofol is used to produce sedation. Similarly, respiratory variables are adjusted to maintain values as near normal as possible. Respiratory depression during weaning was not a problem in either group in the survivors. Bolus doses of propofol are associated with quite marked respiratory depression,14although this is much less when it is used by infusion to produce light sleep.i5 Six patients in the propofol group (numbers 7, 9, 11, 12, 13 and 15, Table 2) required neuromuscular blocking drugs in order to control ventilation adequately, compared to none who received papaveretum and midazolam. The reason for the use of relaxants in this group and not in the other may be related to the individual pathologies of the six patients, five of whom were immunosuppressed and all of whom had strong respiratory drives. This may also be related, in
371
retrospect, to inadequate use of papaveretum in these patients, with increased infusion rates of propofol in an attempt to deepen sedation to achieve synchronisation with the ventilator. Relatively small doses of midazolam were given in the other group, which reflects the policy in this unit to limit the use of benzodiazepines as far as possible. The mean infusion rate of propofol used in these patients (1.32 mg/kg/hour) was higher than in our previous series in cardiac surgical patient^,^ although the latter had received high dose fentanyl anaesthesia. It will not be possible to recommend a standard infusion of propofol for sedation in the intensive care unit since it will depend, not only on the level of sedation required, but particularly on the condition of the patients and the nature of their pathology.I6 Thus young, previously healthy patients who require artificial ventilation for thoracic trauma will require considerably larger doses of sedative drugs than those who require ventilation for a short time after cardiac surgery. The only incidence of adrenocortical suppression in a patient not already on steroids occurred in the control group. There is no evidence that midazolam causes depression of adrenal function.” Propofol only causes suppression of cortisol production at very high doses which are well outside the clinical range, and etomidate has been estimated to be 1500 times more potent in this respect.18 No effect on adrenocortical function was shown after 8 hours propofol infusionR and this is confirmed for the more prolonged periods of infusion described here. The objective assessment of sedation showed little difference between the two groups, although this was influenced by the number of patients who required relaxants. Nevertheless, the nursing staff and the investigators expressed a preference for propofol because it was so easy to manage, although this may reflect observer bias. Sedation was achieved with either an infusion of propofol or midazolam; analgesia was provided with morphine in a multicentre trial which involved 100 patients admitted to the intensive care unit.19 The majority of these patients were admitted after general surgery. The results were broadly similar to ours. The desired level of sedation was achieved easily in most patients in both groups. Duration of sedation was much shorter than in the present series (mean 20.2 hours in the propofol group compared to 84.5 hours) and the rate of propofol infusion slightly higher (1.77 mg/kg/hour compared to 1.32 mg/kg/hour). The authors found that propofol was a satisfactory agent for sedation in these critically ill patients. Propofol is a very useful addition to the agents that can be used to provide sedation in the intensive care unit. Some patients did present management problems and it was not possible to achieve adequate synchronisation with the ventilator with propofol alone. The possibility that drug combinations may be superior to one drug alone in order to achieve optimum sedation in the intensive care unit must always be considered. Acknowledgments
The authors thank Imperial Chemical Industries PLC for the supplies of propofol and for their help with this project; the staff in the intensive care unit for their assistance; V. Aber for advice on the statistical analysis; the Medical Illustration Department for preparation of the diagrams and Mrs S. Richens for typing the manuscript.
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References 1. LEDINCHAM IM, WATTI. Influence of sedation on mortality in critically ill, multiple trauma patients. Lancet 1983; i: 1270.
2. WAGNER RL, WHITEPF, KANPB, ROSENTHAL MH, FELDMAN D. Inhibition of adrenal steroidogenesis by the anesthetic etomidate. New England Journal of Medicine 1984; 310 14I 5-2 1. 3. DUNDEE JW, SAMUEL 10, TONER W, HOWARDPJ. Midazolam, a water soluble benzodiazepine. Studies in volunteers. Anaesthesia 1980; 35 454-8. 4. BYATT CM, LEWIS LD, DAWLINGS, COCHRANEGM. Accumulation of midazolam after repeated dosage in patients receiving mechanical ventilation in an intensive care unit. British Medical Journal 1984; 289 799-800. 5. SHELLYMP, MENDELL, PARKGR. Failure of critically ill patients to metabolise midazolam. Anaesthesia 1987; 4 2 619-26. 6 . COCKSHOTT ID. Propofol (‘Diprivan’) pharmacokinetics and metabolism-an overview. Postgraduate Medical Journal 1985; 61 (SUPPI.3): 45-50. 7. GROUNDS RM, LALORJM, LUMLEY J, ROYSTON D, MORGAN M. Propof91 infusion for sedation in the intensive care unit: preliminary, report. British Medical Journal 1987; 294 397400. 8. NEWMAN LH, MCDONALD JC, WALLACE PGM, LEDINCHAM IMcA. Propofol infusion for sedation in intensive care. Anaesthesia 1987; 4 2 929-37. 9. KNAUSWA, DRAPEREA, WAGNERDP, ZIMMERMAN JE. Apache 11: A severity of disease classification system. Critical Care Medicine 1985; 1 3 818-29. 10. RAMSAYMAE, SAVEGETM, SIMPSONBRJ, GOODWINR. Controlled sedation with alphaxolone-alphadolone. British Medical Journal 1974; ik 6 5 6 9 .
11. NIMMO WS, MACRAEWA. Sedation and analgesia. In: LEDINCHAM IMcA, HANNINGCD, eds. Recent advances in critical care medicine, 2. Churchill Livingstone, 1983: 2945. 12. BION JF, LEDINGHAM IMcA. Sedation in intensive care-a postal study. Intensive Care Medicine 1987; 1 3 215-6. 13. GROUNDSRM, TWIGLEY AJ. CARLI F, WHITWAMJG, MORGANM. The haemodynamic effects of intravenous induction. Comparison of the effects of thiopentone and propofol. Anaesthesia 1985; 40: 73540. 14. TAYLORMB, GROUNDSRM, MULROONEY PD, MORGANM. Ventilatory effects of propofol during induction of anaesthesia. Comparison with thiopentone. Anaesthesia 1986; 41: 816-20. 15. ALLSOP P, TAYLORMB, GROUNDSRM, MORGANM. Ventilatory effects of a propofol infusion using a method to rapidly achieve steady state equilibrium. European Journal of Anaesthesiology 1988; 5 293-303. 16. MORGANM. Post cardiac surgery sedation. Journal of Drug Development 1989. 2 (Suppl. 2): 119-24. 17. SHAPIROJM, WESTPHALLM, WHITE PF, SLADENRN, ROSENTHAL MH. Midazolam infusion for sedation in the intensive care unit: effect on adrenal function. Anesthesiology 1986; 64: 394-8. 18. ROBERTSON WR, READER SCJ, DAVISON B, FROST J, MITCHELL R, KAYTE R, LAMBERT A. On the biopotency and site of action of drugs affecting endocrine tissues with special reference to the antisteroidogenic effect of anaesthetic agents. Postgraduate Medical Journal 1985; 61 (Suppl. 3): 145-51. 19. AITKENHEAD AR, PEPPERMAN ML, WILLATTS SM, COATES PD, PARK GR, BODENHAMAR, COLLINSCH, SMITH MB, LEDINCHAM IM, WALLACE PGM. Comparison of propofol and midazolam for sedation in critically ill patients. Lancet 1989; 11: 704-9.
Propofol for long-term sedation in the intensive care unit* A comparison with papaveretum and midazolam
C. E. HARRIS, R . M. GROUNDS, A. M . MURRAY, J. LUMLEY, D. ROYSTON MORGAN
AND
M.
Summary Thirty-seven patients with a wide range of illnesses were studied during mechanical ventilation of the lungs in an intensive care unit. Fifteen were sedated with a continuous propofol infusion, with analgesia provided by bolus doses of papaveretum. Twelve received a continuous infusion of papaveretum, supplemented by bolus doses of midazolam. The level of sedation was assessed every four hours and measurements were made of haemodynamic and respiratory variables. Levels of sedation were generally satisfactory in both groups. Six patients who received propofol required the use of muscle relaxants, because of their strong respiratory drives, to achieve synchronisation with the ventilator. There was no signi3cant difference in respiratory or haemodynamic variables between the groups, but several patients required inotropic support because of their disease. There was no evidence of inhibition of adrenal steroidogenesis in the propofol group. Propofol can be a useful sedative agent in the intensive cure unit, but sedative regimens should be tailored to individual patient requirements.
Key words Anaesthetics , intravenous; pr opofol . Intensive care.
Patients who require artificial ventilation of the lungs whilst in the intensive care unit invariably need some form of sedation for at least part of their stay. The ideal intravenous agent for use in this way would be short acting and noncumulative and thus allow rapid recovery for neurological assessment and early weaning from artificial ventilation. Such a drug should be free from adverse effects on the various organs of the body and not influence the metabolism of other drugs that might be used in these patients. The short acting intravenous anaesthetics Althesin and etomidate approached the ideal for this purpose and were extensively used, but unfortunately were withdrawn, the former because of an unacceptably high incidence of allergic reactions to its solubilising agent, and the latter because suppression of cortisol production was implicated in an increased mortality in severely injured patients.’,2The resultant gap was difficult to fill and most centres resorted to use of a benzodiazepine and an opioid. Initial pharma-
cokinetic studies with midazolam seemed to promise rapid recovery,’ but there is growing evidence that it is not a suitable drug for use in the critically ill.4.5 Propofol is characterised by a short half-life6and initial studies on its use for short periods in the intensive care unit are very e n ~ o u r a g i n g .The ~ . ~ present study was designed to assess the suitability of continuous infusions of propofol to provide sedation in patients for artificial ventilation in the intensive care unit and to compare it with the standard method in use in the unit, namely an infusion of papaveretum supplemented with bolus injections of midazolam.
Methods The study was approved by the local ethics committee and the Committee on Safety of Medicines. Informed written consent was obtained from the patients, or when this was not possible because of their illness, from their next of kin.
*Propofol is not yet licensed for use by infusion in intensive care units in the United Kingdom and this study was carried out with a clinical trial certificate from the Committee on Safety of Medicines. Accepted 18 October 1989. C.E. Harris,? FFARCS, R.M. Grounds,$ MD, FFARCS, A.M. Murray,§ FFARCS, Senior Registrars, J. Lumley, FFARCS, Consultant, D. Royston, FFARCS, Senior Lecturer, M. Morgan, FFARCS, Reader, Department of Anaesthetics, Royal Postgraduate Medical School, Hammersmith Hospital, Du Cane Road, London W12 OHS. ?Present position: Senior Registrar in Intensive Therapy, Mersey Region. $Present position: Consultant Anaesthetist, St George’s Hospital, London. §Present position: Consultant Anaesthetist, Basildon Hospital, Essex. Correspondence should be addressed to Dr M. Morgan, please. 0003-2409/90/050366 + 07 $03.00/0
@ 1990 The Association of Anaesthetists of Gt Britain and Ireland
366
367
PropofoI f o r long-term sedation in the ICU Patient selection. Male or female patients aged 16-80 years who required mechanical ventilation of the lungs were admitted to the trial. Exclusion criteria were: known allergy to any of the trial drugs, pregnancy, patients who had undergone routine cardiac surgery, head injuries, those who had an established sedation regimen in the previous 24 hours and those with disorders of lipid metabolism. APACHE I1 scoring9 was performed o n all patients who were then randomly divided t o receive either a propofol or papaveretum infusion. Infusion regimens. An intravenous infusion of propofol was started a t a rate of 1-3 mg/kg/hour, preceded by a bolus of 1.0 mg/kg if clinically indicated. The rate of infusion was adjusted.to maintain a sedation level between 2 and 5 on the scoring system described by Ramsay and his colleagues,I0 although preferably a t level 3 . Intravenous bolus doses of papaveretum 2.5-5.0 m g were given to provide analgesia when required. An infusion-of papaveretum in the other group was started at a rate of 2.0 mg/hour and adjusted to maintain sedation at the required level. This was supplemented by intravenous boluses of midazolam 2.5-5.0 mg t o achieve
Table 1. Details of patients with duration of sedation and ventilation and number of survivors. Propofol
n = I5
Papaveretum n = 12
4 : 11 8
6:6 7
Age, years (SEM) Weight, kg (SEM) Height, cm (SEM)
47.8 (3.7) 61.3 (3.8) 162.4 (2.2)
54.6 (5.9) 70.4 (4.4) 167.6 (3.2)
Duration of ventilation, hours Mean (SEM) Range
101.6 (19.9) 18.3-240
66.6 (20.3) 15-236
Duration of sedation, hours Mean (SEM) Range
84.5 (15.4) 18-189
66.9 (20.5) 9.5-236
Male : female Survivors
adequate sedation when necessary. Neuromuscular relaxants were used in either group when it proved impossible to achieve synchronisation with the ventilator by other means.
Table 2. Details of patients in propofol group. ~
~~
Patient No.
Reason for admission to ICU
Concurrent disease
APACHE I1 score
Outcome
1
Acute tubular necrosis, ARDS
Paget’s disease
34
Survived
2
Acute respiratory failure, pneumonia
Chronic granulocytic leukaemia; bone marrow transplant, immunosuppressed
15
Survived
3
Acute respiratory failure, pneumonia
Chronic granulocytic leukaemia, bone marrow transplant, pulmonary fibrosis, immunosuppressed
24
Died
4
Multiple trauma
None
13
Survived
5
Acute respiratory failure, asthma
Obesity, steroid therapy
10
Survived
6
Acute respiratory failure, asthma
Aortic valve replacement, steroid therapy
19
Survived
7
Acute respiratory failure, cytomegalovirus
Fibrosing alveolitis, immunosuppressed
22
Withdrawn, died
8
Postoperative emergency mitral valve replacement
None
24
Died
9
Acute respiratory failure, pneumonia
Acute myeloid leukaemia, bone marrow transplant, cytomegalovirus infection, immunosuppressed
22
Died
10
Postoperative peritonitis, pancreatitis
Subphrenic abscess, acute tubular necrosis
11
Acute respiratory failure, pneumonia, pneumocystis
Chronic granulocytic leukaemia, bone marrow transplant, immunosuppressed
14
Died
12
Acute respiratory failure, pneumonia
Polyarteritis nodosa, pneumocystis, immunosuppressed
17
Survived
13
Postrespiratory arrest, cerebral haemorrhage
Spinal cord tumour, renal transplant, fungal pneumonia, Parkinson’s disease, immunosuppressed
17
Died
14
Post aortobifemoral graft
Asthma, diabetes, ischaemic heart disease,
15
Died
15
Postrespiratory arrest
Chronic renal failure, renal transplant, fungal pneumonia
18
Withdrawn, died
ARDS, adult respiratory distress syndrome.
9
Survived
368
C.E. Harris et at.
Monitoring Sedation. This was assessed every 4 hours using the Ramsay scale, while in addition one of the investigators assessed the quality of sedation every 24 hours o n a fourpoint scale: excellent, good, adequate or poor. The nursing staff made a global assessment of the quality of sedation at the end of the study period and also the ease with which it was managed, again o n a four-point scale, excellent, easy, adequate or poor. Patients who had received neuromuscular blocking drugs were scored at level 6. The time taken to resumption of spontaneous ventilation and to obey a simple command was recorded at the end of treatment. Cardiovascular. Heart rate, arterial and central venous pressures were aontinuously displayed and recorded every 4 hours. Cardiac output and pulmonary artery wedge pressure were measured if insertion of a pulmonary artery catheter was indicated. Respiratory. Respiratory rate, minute volume, inspired oxygen concentration and arterial blood gases were noted every 4 hours. The alveolar-arterial oxygen tension difference (A-aDo,) was also calculated at this time. The shunt fraction was measured in those in whom a pulmonary arterial catheter was inserted. Biochemical. Cortisol levels were measured before the start of sedation and a t 24 and 48 hours. The response to synacthen 250 pg intravenously was assessed a t 30 and 60 minutes after the start of sedation and after 24 and 48 hours. Haemoglobin, packed cell volume, white cell and platelet counts, prothrombin time, urea and electrolytes, creatinine, albumin, aminotransferase and alkaline phos-
phates were measured before the start of sedation and also a t 24 and 48 hours, but the results are not presented.
Statistical analysis Statistical tests used were: analysis of variance, the paired and unpaired t-tests, the Mann-Whitney U test and the Chi-square test.
Results Patient details. Twenty-seven patients were admitted to the trial, 15 of whom received propofol. Their anthropometric data are shown in Table 1; there was no significant difference between the groups in this respect. Eight patients in the propofol group survived, and seven who received papaveretum and midazolam, although one of the latter died 24 hours after leaving the intensive care unit. Three patients were withdrawn from the trial, two after propofol. The data from these patients, u p to the time of their withdrawal from the trial, were included in the results. One of these latter was a 60-year-old man with fibrosing alveolitis who became hypotensive as the propofol dose was increased in an attempt to achieve synchronisation with the ventilator; the other was a 48-year-old woman in renal failure who developed lipaemia once parenteral nutrition was started. Sedation was stopped to allow neurological assessment in one patient in the control group and was never restarted. The reasons for admission to the intensive care unit, the APACHE I1 scores on admission and the outcome for each patient are shown in Tables 2 and 3. There was no significant difference between the scores in the two groups
Table 3. Details of patients in papaveretum group. ~~~
Patient No.
Reason for admission to ICU
1
Acute respiratory failure
2
Acute respiratory failure, pulmonary oedema Peritonitis, acute respiratory failure
3
4
Postcardiorespiratory arrest, pulmonary embolus
Concurrent disease Chronic granulocytic leukaemia, pulmonary fibrosis, immunosuppressed Hypothyroidism, diabetes primary biliary cirrhosis Chronic renal failure scleroderma, systemic lupus erythematosis, pulmonary fibrosis, immunosuppressed Aortobifemord graft, atrial fibrillation
Ischaemic heart disease
APACHE I1 score
Outcome
23
Survived
12
Survived
29
Died 24 hours after leaving unit
14
Died
23 2
Died Survived
16
Survived
I
Survived
Gross obesity
15
Survived
Ischaemic heart disease
22
Died
Newly diagnosed severe hypothyroidism
16
Withdrawn. died
5
Postlaparotomy for bleeding, 6
Septic shock, fecal peritonitis
7
Pulmonary oedema
8
Postoperative partial hepatectomy
9
Multiple trauma, partial hepatectomy Postoperative respiratory depression, hysterectomy Postoperative respiratory failure, aortobifemoral graft Septic shock
10
I1 12
Caesarean section for placenta praevia, hysterectomy, massive transfusion Carcinoid syndrome, massive transfusion None
Propofol f o r long-term sedation in the ICU
369
Table 4. Drug doses.
Propofol group Dose of drug (mg)
Propofol
Papaveretum
Papaveretum
Midazolam
Total, mean (SEM) range
7600 (2458) 263-36000
55.0 (30.9) 0-444
433.5 (128) 50-1200
14.2 (5.9) 0-75
128.8 (46.4) 5.8-720
0.86 (0.45) 0-64
6.3 (1.8) 0.7-1 8.1 0.1 (0.013) 0.04-0.17
0.2 (0.09) 0-1.13
mg/kg/hour, mean (SEM) range
1.32 (0.24) 0.23-3.73
(Mann-Whitney U test). Multiple pathology was the rule rather than the exception in these patients. Duration of venlilation. The durations of ventilation and sedation in the two groups are shown in Table 1 . The propofol figures for time of ventilation exclude one patient who was initially weaned from ventilation, but her trachea was not extubafed and she continued to receive intermittent mandatory ventilation for 2 months, and required virtually no sedation. The durations of ventilation and sedation were longer in those who received propofol, but the differences were not significant. Drug doses. The doses of the drugs used are shown in Table 4. The mean total dose of papaveretum used in conjunction with propofol was 55 mg (range W 4 mg). Relatively little midazolam was given to the papaveretum group, a mean of 14.2 mg, although one woman received 75 mg over a period of 120 hours. Cardiorespiratory measurements. Inotropic support with dopamine or adrenaline was required in eight patients given propofol and five who received papaveretum in order
P,
140
Papaveretum group
r
c
140r
\
T
8OL
.-
2 O r
V
g:"o
4
8
12 16 20 24 28 32 36 40 44 48 Time ( b u r s )
Fig. 1. Systolic arterial pressure, heart rate and central venous pressure during first 48 hours of sedation. 0 . . . 0 , propofol; 0-0,
t r
3
0 0
-
to maintain haemodynamic measurements within normal limits. There were no significant differences from control within either group for any of the measurements, nor between the groups (Figs 1 and 2). Increase in sedative drug dose was associated with hypotension in five patients given propofol, one who was withdrawn from the trial (maximum infusion rate of propofol 33 mg/kg/hour), and in three who received papaveretum. Similarly, no differences in any of the respiratory measurements were seen between, or within, the two groups (Fig. 3). Cortisol. The results of the cortisol measurements are shown in Table 5. Nine propofol patients and four papaveretum were already receiving steroid therapy on admission to the unit. The mean cortisol levels were high in the other patients, 1121 nmol/litre and 1169 nmol/litre for the propofol and papaveretum groups respectively. The results of the synacthen tests a t 48 hours are also shown in Table 5. Four of the six patients given propofol who were not receiving steroids had short synacthen tests and all showed a positive response. Two of seven patients on steroids in this group also had a positive test, which was negative in the other five. Six of the seven patients in the papaveretum group who did not receive steroids on admission showed a positive result, while the other, a young man with multiple trauma, was negative; the one patient who received steroids and who was tested had n o response to synacthen. Assessment of sedation. The overall sedation scores are shown in Table 6. Patients were maintained between seda-
25
3
-
papaveretum.
011 0
4
I
I
I
I
'
I
I
I
I
8 12 16 20 24 28 32 36 40 44 48 Time (hours)
Fig. 2. Cardiac index and pulmonary artery wedge Pressure during first 48 hours of sedation. 0 . . . a , propofol; 0-0, papaveretum.
370
C.E. Harris et al. Table 6. Sedation scoring. Time spent (%) at each level. ~
~~
Sedation level
Propofol
Papaveretum
1
5.1Yo 28.8% 13.5% 23.1Yo 15.4% 14.1Yo
6.1Yo 26.3% 20.2% 25.2% 18.2% 4.0%
2 3
4 5 6
Table 7. Global assessment of sedation.
Propofol I
50-
8
0
A
20'1 0
I
4
I
I
"
I
I
I
8 12 16 20 24 2 8 3 2 3 6 4 0 4 4 48 Time (hours)
Fig. 3. pH, Pacq and A-am, during first 48 hours of sedation. 0 . . .0,
propofol;
0-0,
papavereturn.
tion levels 2 and 5 for 80.8% of time in the propofol group and for 89.9% of the time in those who received papaveretum. The relatively high number of scores of 6 after propofol (14.1% of the time) is due to the assessment of paralysed patients. The time spent at sedation level 6 decreases to 1.5% and the time spent at the 2-5 levels increases to 92.6%, if these results are excluded, and these modified results are shown in Figure 4. The global assessment of sedation by the investigators and nursing staff at 24 and 48 hours is shown in Table 7. The number of poor assessments in the propofol patients is again attributable to the use of neuromuscular blocking drugs. Recovery. Eight propofol patients and seven papaveretum survived. The majority (four in both groups) were able to obey commands before cessation of sedation and were also able to breathe spontaneously before sedation was stopped. One of the four others in the propofol group was able to obey commands when the sedation was
Nursing staff Overall management of patient Excellent Easy Adequate Poor Quality of sedation Excellent Good Adequate Poor Medical staff Excellent Good Adequate Poor
4
5 3
3
4 5 2 4
4 3
4 4
stopped, two 15 minutes after and one 2.5 hours after. One of the three who remained in the papaveretum group was able to obey commands 30 minutes after sedation was stopped, one 1.25 hours and the other 7.25 hours.
Discussion There are many factors involved in the provision of comfort for the patient in the intensive care unit and sedation may not always be beneficial." In practice, however, most patients will not tolerate artificial ventilation and the intensive care environment without some form of sedation. The agent used should ideally be free from harmful short- and long-term side effects, be easy to manage, have inactive metabolites and be noncumulative. This would allow rapid recovery for neurological assessment when required. The most commonly used regimen in
Table 5.
Number receiving steroids Mean cortisol on admission in those patients not receiving steroids mean, nmol/litre (SEM) range Synacthen test Not receiving steroids
Papaveretum
Propofol
Papaveretum
9
4
1121 (547) 547-2430
1629 (907) 548-3 110
4+ve
6+ve 1 -ve
Receiving steroids
2+ve
1 -ve
Not done
5-ve 4
4
Propofol for long-term sedation in the ICU
40c
8
~edotonlevel
.,
Fig. 4. Percentage of time spent at each sedation level excluding those patients who received neuromuscular blocking drugs. propofol; papaveretum.
m,
the United Kingdom is an infusion of opioids supplemented by a benzodiazepine,12 but this has the disadvantage of relatively prolonged recovery, respiratory depression in spontaneously breathing patients and gastrointestinal stasis. A previous study from this department? compared propofol with papaveretum and midazolam as the sedative regimens in postoperative cardiac surgical patients who required artificial ventilation and showed propofol to be the superior; these patients, however, represented a relatively homogeneous group. The present report illustrates many of the problems of comparative studies in patients in an intensive care unit. The multiple pathology and diversity of the clinical problems makes comparisons extremely difficult. All the patients were severely ill, which is reflected in the high mortality. Many of the patients required inotropic support because of their illness, so it is difficult to draw many conclusions from the measured cardiovascular data. Hypotension occurred in both groups, occasionally related to the administration of midazolam. There was a tendency for hypotension to occur more frequently in the propofol group; the one patient who was withdrawn from the study in this group for this reason was deliberately kept relatively hypovolaemic. The hypotensive effect of propofol is mainly the result of a decrease in systemic vascular resistance,” and in the present series where cardiac output was measured it was maintained. It is important that the circulating volume be maintained to minimise any decreases in arterial pressure when propofol is used to produce sedation. Similarly, respiratory variables are adjusted to maintain values as near normal as possible. Respiratory depression during weaning was not a problem in either group in the survivors. Bolus doses of propofol are associated with quite marked respiratory depression,14although this is much less when it is used by infusion to produce light sleep.i5 Six patients in the propofol group (numbers 7, 9, 11, 12, 13 and 15, Table 2) required neuromuscular blocking drugs in order to control ventilation adequately, compared to none who received papaveretum and midazolam. The reason for the use of relaxants in this group and not in the other may be related to the individual pathologies of the six patients, five of whom were immunosuppressed and all of whom had strong respiratory drives. This may also be related, in
371
retrospect, to inadequate use of papaveretum in these patients, with increased infusion rates of propofol in an attempt to deepen sedation to achieve synchronisation with the ventilator. Relatively small doses of midazolam were given in the other group, which reflects the policy in this unit to limit the use of benzodiazepines as far as possible. The mean infusion rate of propofol used in these patients (1.32 mg/kg/hour) was higher than in our previous series in cardiac surgical patient^,^ although the latter had received high dose fentanyl anaesthesia. It will not be possible to recommend a standard infusion of propofol for sedation in the intensive care unit since it will depend, not only on the level of sedation required, but particularly on the condition of the patients and the nature of their pathology.I6 Thus young, previously healthy patients who require artificial ventilation for thoracic trauma will require considerably larger doses of sedative drugs than those who require ventilation for a short time after cardiac surgery. The only incidence of adrenocortical suppression in a patient not already on steroids occurred in the control group. There is no evidence that midazolam causes depression of adrenal function.” Propofol only causes suppression of cortisol production at very high doses which are well outside the clinical range, and etomidate has been estimated to be 1500 times more potent in this respect.18 No effect on adrenocortical function was shown after 8 hours propofol infusionR and this is confirmed for the more prolonged periods of infusion described here. The objective assessment of sedation showed little difference between the two groups, although this was influenced by the number of patients who required relaxants. Nevertheless, the nursing staff and the investigators expressed a preference for propofol because it was so easy to manage, although this may reflect observer bias. Sedation was achieved with either an infusion of propofol or midazolam; analgesia was provided with morphine in a multicentre trial which involved 100 patients admitted to the intensive care unit.19 The majority of these patients were admitted after general surgery. The results were broadly similar to ours. The desired level of sedation was achieved easily in most patients in both groups. Duration of sedation was much shorter than in the present series (mean 20.2 hours in the propofol group compared to 84.5 hours) and the rate of propofol infusion slightly higher (1.77 mg/kg/hour compared to 1.32 mg/kg/hour). The authors found that propofol was a satisfactory agent for sedation in these critically ill patients. Propofol is a very useful addition to the agents that can be used to provide sedation in the intensive care unit. Some patients did present management problems and it was not possible to achieve adequate synchronisation with the ventilator with propofol alone. The possibility that drug combinations may be superior to one drug alone in order to achieve optimum sedation in the intensive care unit must always be considered. Acknowledgments
The authors thank Imperial Chemical Industries PLC for the supplies of propofol and for their help with this project; the staff in the intensive care unit for their assistance; V. Aber for advice on the statistical analysis; the Medical Illustration Department for preparation of the diagrams and Mrs S. Richens for typing the manuscript.
372
C.E. Harris et al.
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2. WAGNER RL, WHITEPF, KANPB, ROSENTHAL MH, FELDMAN D. Inhibition of adrenal steroidogenesis by the anesthetic etomidate. New England Journal of Medicine 1984; 310 14I 5-2 1. 3. DUNDEE JW, SAMUEL 10, TONER W, HOWARDPJ. Midazolam, a water soluble benzodiazepine. Studies in volunteers. Anaesthesia 1980; 35 454-8. 4. BYATT CM, LEWIS LD, DAWLINGS, COCHRANEGM. Accumulation of midazolam after repeated dosage in patients receiving mechanical ventilation in an intensive care unit. British Medical Journal 1984; 289 799-800. 5. SHELLYMP, MENDELL, PARKGR. Failure of critically ill patients to metabolise midazolam. Anaesthesia 1987; 4 2 619-26. 6 . COCKSHOTT ID. Propofol (‘Diprivan’) pharmacokinetics and metabolism-an overview. Postgraduate Medical Journal 1985; 61 (SUPPI.3): 45-50. 7. GROUNDS RM, LALORJM, LUMLEY J, ROYSTON D, MORGAN M. Propof91 infusion for sedation in the intensive care unit: preliminary, report. British Medical Journal 1987; 294 397400. 8. NEWMAN LH, MCDONALD JC, WALLACE PGM, LEDINCHAM IMcA. Propofol infusion for sedation in intensive care. Anaesthesia 1987; 4 2 929-37. 9. KNAUSWA, DRAPEREA, WAGNERDP, ZIMMERMAN JE. Apache 11: A severity of disease classification system. Critical Care Medicine 1985; 1 3 818-29. 10. RAMSAYMAE, SAVEGETM, SIMPSONBRJ, GOODWINR. Controlled sedation with alphaxolone-alphadolone. British Medical Journal 1974; ik 6 5 6 9 .
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