Respiratory and haemodynamic effects of acute postoperative pain management: evidence from published data

J. N. Cashman1,* and S. J. Dolin2

1 Department of Anaesthesia, St George's Hospital, London SW17 0QT, UK. 2 Pain Clinic, St Richard's Hospital, Chichester PO19 4E, UK

* Corresponding author. E-mail: jeremy.cashman{at}stgeorges.nhs.uk

Accepted for publication March 4, 2004.


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix 1
 Appendix 2
 Appendix 3
 Appendix 4
 Appendix 5
 References
 
Background. This study examines the evidence from published data concerning the adverse respiratory and haemodynamic effects of three analgesic techniques after major surgery; i.m. analgesia, patient-controlled analgesia (PCA), and epidural analgesia.

Methods. A MEDLINE search of the literature was conducted for publications concerned with the management of postoperative pain. Information relating to variables indicative of respiratory depression and of hypotension was extracted from these studies. Over 800 original papers and reviews were identified. Of these papers, 212 fulfilled the inclusion criteria but only 165 provided usable data on adverse effects. Pooled data obtained from these studies, which represent the experience of a total of nearly 20 000 patients, form the basis of this study.

Results. There was considerable variability between studies in the criteria used for defining respiratory depression and hypotension. The overall mean (95% CI) incidence of respiratory depression of the three analgesic techniques was: 0.3 (0.1–1.3)% using requirement for naloxone as an indicator; 1.1 (0.7–1.7)% using hypoventilation as an indicator; 3.3 (1.4–7.6)% using hypercarbia as an indicator; and 17.0 (10.2–26.9)% using oxygen desaturation as an indicator. For i.m. analgesia, the mean (95% CI) reported incidence of respiratory depression varied between 0.8 (0.2–2.5) and 37.0 (22.6–45.9)% using hypoventilation and oxygen desaturation, respectively, as indicators. For PCA, the mean (95% CI) reported incidence of respiratory depression varied between 1.2 (0.7–1.9) and 11.5 (5.6–22.0)%, using hypoventilation and oxygen desaturation, respectively, as indicators. For epidural analgesia, the mean (95% CI) reported incidence of respiratory depression varied between 1.1 (0.6–1.9) and 15.1 (5.6–34.8)%, using hypoventilation and oxygen desaturation, respectively, as indicators. The mean (95% CI) reported incidence of hypotension for i.m. analgesia was 3.8 (1.9–7.5)%, for PCA 0.4 (0.1–1.9)%, and for epidural analgesia 5.6 (3.0–10.2)%. Whereas the incidence of respiratory depression decreased over the period 1980–99, the incidence of hypotension did not.

Conclusions. Assuming a mixture of analgesic techniques, Acute Pain Services should expect an incidence of respiratory depression, as defined by a low ventilatory frequency, of less than 1%, and an incidence of hypotension related to analgesic technique of less than 5%.

Keywords: anaesthetic techniques, epidural ; analgesia, patient-controlled ; analgesic techniques, intramuscular ; complications, hypotension ; complications, respiratory depression ; pain, postoperative


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix 1
 Appendix 2
 Appendix 3
 Appendix 4
 Appendix 5
 References
 
In a previous publication, we referred to the 1997 Audit Commission report, and its recommendation that by 2002 less than 5% of patients should experience severe pain after surgery.1 In that study, we suggested that pain and pain relief were only part of the many outcome variables with which Acute Pain Services should be interested. We proposed that the safety and tolerability of the analgesic techniques used were also important aspects to be considered. Furthermore, we suggested that the incidence of respiratory depression and hypotension might be indicative of the safety of a technique. The occurrence of nausea and vomiting, sedation, itching or the need for urinary catheterization might be considered to be indicative of the tolerability of a technique.

In this, the second of three studies, we have examined the evidence from published data with regard to adverse respiratory and haemodynamic effects of i.m., patient controlled and epidural analgesic techniques. In particular, we have examined the three analgesic techniques with respect to the incidence of respiratory depression and hypotension after major surgery.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix 1
 Appendix 2
 Appendix 3
 Appendix 4
 Appendix 5
 References
 
Search strategy
Full details of the search strategy and methodology have been described in a previous publication.1 We carried out a MEDLINE search (1966 onwards) of the literature. The computerized search identified key words (analgesia, postoperative pain, pain therapy, i.v. patient controlled analgesia, epidural analgesia) in the title, abstract, and Medical Subject Headings (MESH). In addition, a cross-check of the quality of the retrieval method was made by ‘hand searching’ the full reference lists from review articles and relevant individual papers in four peer reviewed English language anaesthetic journals (Anaesthesia, British Journal of Anaesthesia, Acta Anaesthesiologica Scandinavica and Anesthesiology). All publications identified by the search strategy were categorized according to the level of evidence obtained, based on the criteria of the United States Preventive Task Force. Cohort studies, case control studies, and audit reports as well as randomized controlled clinical trials were included in the analysis. Case reports were not included, nor were authors approached for raw or unpublished data. No attempt was made to grade individual papers according to quality. All of the studies used in the analysis were given equal value, as we were interested in predetermined end points rather than the findings of individual studies. One author undertook the data extraction. Figure 1 gives a flow diagram of the review methodology.



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Fig 1 Postoperative pain management: data retrieval flow diagram.

 
Selection criteria
We included articles relating to abdominal, major gynaecological, major orthopaedic, and thoracic surgery. We excluded articles relating to paediatric, day stay and minor surgery, and where the period of observation was less than 24 h. Initial observations made in the recovery room were not included. We did not utilize any study which described a mixed or unusual analgesic technique (e.g. ketamine, clonidine), studies relating to intrathecal opioids, studies of combined spinal/epidural analgesia, nor studies relating to regional analgesic techniques such as interpleural, paravertebral, and lumbar plexus blocks. A full list of all of the studies used in the analysis is included at the end of this paper. Details of all of the excluded studies are available from the authors.

Definitions
We examined measures of safety after major surgery for each of the three analgesic techniques in common practice: patient-controlled analgesia (PCA), epidural analgesia, and i.m. injections as outlined previously. Information was extracted from published studies, which reported variables indicative of respiratory depression and of hypotension. The different measurements have been recorded and where studies involved comparison between drugs (e.g. opioids), the results have been pooled. Where the study compared analgesic techniques, results have been entered separately under each form of analgesia.

Statistical methodology
The mean percentage reporting a given level of pain was found by the method of weighted mean, with weighting by the number of subjects in the group.2 When patients were grouped by the method of analgesia, some studies contributed subjects to more than one group. This was ignored in the analysis, possibly resulting in a small loss of power.

Analysis was by estimation of the confidence interval (CI) of the log odds ratio and its CI. The standard error from which the confidence interval was estimated was adjusted for the clustering of the individual clusters within the study and treatment groups, thus allowing for the extra variation, which exists between studies. The log odds was then converted to a percentage by:

The effects of analgesic technique and year were tested using logistic regression adjusted for clustering. Analgesic technique was represented by two dummy variables, representing i.v.-PCA and epidural. Both were zero for i.m. analgesia. The significance of the modality effect was tested using the overall {chi}2 statistic. To test for analgesic technique adjusted for year, we took the difference between the {chi}2 statistics and associated degrees of freedom for the model with modality and year, and for that with year only. All analysis was done using Stata 5.0 (Stata Corporation, College Station, TX).


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix 1
 Appendix 2
 Appendix 3
 Appendix 4
 Appendix 5
 References
 
Respiratory depression
We report on 165 studies relating to respiratory indices. There were a total of 93 027 patients included in papers published between 1956 and 1999, which provided suitable data for analysis. Studies reported ventilatory frequency rate for one, two, or (rarely) all three analgesic techniques. Thus, the total number of study groups may exceed the number of studies in any particular category. A number of other studies were considered appropriate for analysis but were not used because data were not accessible.

Ventilatory frequency
104 studies reported ventilatory frequency. For studies that reported more than one ventilatory frequency, we used the higher reported ventilatory frequency in our analysis of respiratory depression. We identified 70 study groups that defined respiratory depression as a ventilatory frequency of less than 10 bpm, and 46 study groups that defined it as a ventilatory frequency of less than 8 bpm. This represents a total of 29 607 patients in 116 study groups (1590 patients i.m. analgesia; 6922 patients PCA; and 21 035 patients epidural analgesia). Another 35 studies reported respiratory depression but did not define it; these have not been included in the analysis. The overall mean (95% CI) rate of respiratory depression as defined by a specific ventilatory frequency, whatever the ventilatory frequency the authors of the various studies chose (less than 10 or less than 8 bpm), was 1.1 (0.7–1.7)%. There was no difference in respiratory depression between the three analgesic techniques (P=0.7; Table 1).


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Table 1 Reported incidence of respiratory depression as indicated by ventilatory frequency lower than predetermined value

 
Oxygen saturation
A total of 24 studies presented data on the number of patients with oxygen saturation below a particular value. As with ventilatory frequency, where more than one oxygen saturation reading was recorded (oxygen saturation less than 90%, less than 85%, or less than 80%), we used the higher reported oxygen saturation in our analysis of respiratory depression. There were 24 study groups that defined respiratory depression as an oxygen saturation of less than 90%, and eight study groups that defined respiratory depression as an oxygen saturation of less than 85% (six studies, which were not included in the analysis, defined it as an oxygen saturation of less than 80%). This represents a total of 1511 patients (246 patients i.m. analgesia; 707 patients PCA; and 563 patients epidural analgesia). The overall mean (95% CI) rate of respiratory depression as indicated by a specific oxygen saturation, as defined by the authors of the various studies, was 17.0 (10.2–26.9)%. The effect of analgesic technique was statistically significant (P<0.01) and persisted after controlling for year of publication (P=0.007), with i.m. analgesia associated with the highest incidence of oxygen desaturation (Table 2).


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Table 2 Reported incidence of respiratory depression as indicated by oxygen saturation below predetermined value

 
Arterial partial pressure of carbon dioxide
Arterial blood gas analysis was reported in 17 studies. This represents a total of 3166 patients (1508 patients i.m. analgesia; 301 patients PCA; and 1361 patients epidural analgesia). An arterial in excess of 6.5 kPa or in excess of 50 mm Hg was reported as indicating respiratory depression in nine and six studies, respectively. A further two studies did not record the specific level of arterial that had been used. The overall incidence of hypercarbia was 3.3 (0.5–6.0)%. The effect of analgesic technique was significant (P=0.03), and persisted after controlling for year of publication (P<0.0001); respiratory depression as indicated by hypercarbia was highest with epidural analgesia (Table 3).


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Table 3 Reported incidence of respiratory depression as indicated by above predetermined value

 
Naloxone
The use of naloxone as an indication of an attempt to treat was reported in 10 studies, representing a total of 55 404 patients (71 patients i.m. analgesia; 4691 patients PCA; and 50 642 patients epidural analgesia). However, in both the PCA and epidural groups, there is one overwhelmingly large study, resulting in very narrow CIs. There will be a large non-sampling error, which we cannot estimate and which is not represented in the CI. Overall mean (95% CI) rate of respiratory depression as defined by use of naloxone was 0.3 (–0.1 to 0.6)%. The effect of analgesic technique was highly significant (P=0.0001), being lowest with epidural analgesia (Table 4) and persisted after controlling for year of publication (P<0.0001).


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Table 4 Reported incidence of respiratory depression as indicated by naloxone use

 
Change in respiratory depression over time
As part of the analysis, we looked at how the incidence of respiratory depression altered over the time period of the analysis (1980–99). We have reported previously that the analgesic technique varied by year of publication, with i.m. analgesia being the most frequently reported technique in the early part of the period of the analysis, whilst latterly PCA and epidural analgesia have been the most frequently reported techniques.1 The results of the analysis of ventilatory frequency, and naloxone use indicated that there was a significant decrease in the odds of respiratory depression over time (P=0.01, P=0.0002, and P=0.002, respectively). The relationship between year of publication and respiratory depression persisted after controlling for changes in analgesic technique (P=0.08, P<0.0001 and P<0.0001, respectively), and so was not explained by a change in analgesic technique over time. The results of the analysis of oxygen saturation showed no significant change over time (P=0.8).

Cardiovascular depression
We report on 81 studies relating to haemodynamic indices. There were a total of 24 955 patients included in papers published between 1956 and 1999, which provided suitable data for analysis.

Hypotension
Studies varied in their definition of hypotension, commonly tending to present the number of patients with arterial pressure below a threshold level recorded at a particular time. A total of 54 studies presented data on the number of patients with arterial pressure below a pre-defined level, or alternatively data on the number of patients with a decrease of arterial pressure greater than a pre-defined amount. For all of these studies, which reported more than one haemodynamic parameter, we used the first reported arterial pressure in our analysis of hypotension. Thus, there were 27 study groups in which hypotension was defined as a systolic arterial pressure of less than 100 mm Hg and/or a greater than 20% decrease in arterial pressure; 24 study groups in which hypotension was defined as a systolic arterial pressure of less than 90 mm Hg; and a further 23 study groups in which hypotension was defined as a systolic arterial pressure of less than 80 mm Hg and/or a greater than 30% decrease in arterial pressure. Another 27 studies reported haemodynamic depression but did not strictly define hypotension. This represents a total of 22 573 patients (631 patients i.m. analgesia; 3954 patients PCA; and 20 370 patients epidural analgesia). If all definitions of hypotension from the 81 papers are included, the overall rate of hypotension (mean (95% CI)) was 4.7 (2.8–7.7)%. The results were remarkably similar when a definition based on a predetermined level of arterial pressure was used 4.9 (2.7–8.8)%. The effect of analgesic technique was significant, being lowest with PCA and highest with epidural analgesia (P=0.01, P=0.007; all and strict definitions, respectively). The effect of analgesic technique persisted after controlling for year of publication (P=0.027, P=0.018; all and strict definitions, respectively). The rates of hypotension are shown in Tables 5 and 6.


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Table 5 Reported incidence of haemodynamic depression (all definitions)

 

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Table 6 Reported incidence of haemodynamic depression as indicated by all arterial pressure recordings below predetermined level

 
Change in hypotension over time
Over the time period of analysis, there has not been a significant decrease in the incidence of hypotension (P=0.95 and P=0.99; all definitions and strict definition).


    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix 1
 Appendix 2
 Appendix 3
 Appendix 4
 Appendix 5
 References
 
Respiratory depression is thought to be the most important adverse effect when considering analgesic techniques. A number of criteria have been used to define respiratory depression including ventilatory frequency, percutaneous oxygen saturation, arterial blood gas analysis, and the need to administer respiratory stimulants. Of these, ventilatory frequency is the most frequently used criterion. In a Europe-wide survey of acute pain services, ventilatory frequency was routinely measured in 81% of hospitals, while oxygen saturation was measured in only 41%.3 A ventilatory frequency of less than 10 bpm is the commonest cut off figure, although a ventilatory frequency of less than 8 bpm is occasionally used. When pulse oximetry is used to identify respiratory depression, an oxygen saturation of less than 90% is most commonly reported, although other endpoints such as saturations of less than 95%, 85% or even 80% have also been used. Occasionally, ventilatory frequency is used in conjunction with pulse oximetry, but not all cases of respiratory depression have both low ventilatory frequency and low oxygen saturation. In a large audit of postoperative analgesia after major surgical procedures, 39 cases of respiratory depression were reported of which only six had a ventilatory frequency of less than 10 bpm, while 23 had an oxygen saturation of less than 90%.4 In contrast, arterial blood gas analysis, being relatively invasive, is probably not suitable as a routine practical clinical technique and consequently is much less frequently used. When blood gas analysis is used, a partial pressure of carbon dioxide greater than 6.5 kPa (50 mm Hg) is the most frequently used endpoint. Finally, the need for therapeutic intervention such as the administration of naloxone is a potentially useful criterion, but it is indirect and the decision to use naloxone often will depend on one of the above criteria for respiratory depression being fulfilled.

There is a relative lack of studies assessing the incidence of respiratory depression after intermittent, as required, opioid analgesia. This may be due partly to the fact that oxygen saturation monitoring did not become routine until the mid 1980s, yet most studies of i.m. analgesia were conducted before this date. In one of the few studies that reported oxygen saturations following i.m. opioid analgesia, Jayr and colleagues reported a 13% incidence of desaturation,5 which is very similar to the figure of 12.5% reported by Tsui and colleagues,6 whilst a 20% incidence of prolonged desaturation was reported in another much smaller study.7 Using strict criteria for drug administration, Rawal and colleagues suggested that intermittent opioid analgesia was a safe technique on the basis that no patients required ventilatory support.8 These studies, although less comprehensive than comparable studies of epidural or PCA, suggest a somewhat higher incidence of respiratory depression using intermittent i.m. opioid analgesia, an observation borne out by our analysis.

When PCA is used postoperatively, our analysis suggests that low ventilatory frequencies occur in 1.2% of patients, although at least one large study suggests a slightly higher figure.9 Arterial desaturation occurred in 11.5% of patients, yet paradoxically, larger studies seem to indicate a lower rate. In one large series of 3016 patients, Schug and Torrie reported an overall respiratory depression rate of 0.56% for i.v. opioids, but many of these were administered by a continuous infusion.10 Furthermore, respiratory depression in this study was defined by the decision to give naloxone. As has been pointed out previously, there are no clear protocols to dictate when to give naloxone, which at present is by clinician preference. In comparison, our analysis suggests a higher respiratory depression rate of 1.9% based on naloxone administration.

When epidurals are used for postoperative analgesia, the incidence of respiratory depression depends to some extent on whether or not an opiate has been used in addition to the local anaesthetic. Several large prospective studies indicate that the incidence of respiratory depression varies between 0.2 and 1.2% of patients.1113 This may be lower than the incidence with PCA, although the two have not been formally compared in the same study. One large retrospective survey of epidural analgesia reported an incidence of respiratory depression requiring naloxone administration of 0.4%, but did not define any criteria for the administration of naloxone.14 In a multi-hospital follow-up survey, Rawal and colleagues found the incidence of delayed respiratory depression to be 0.09%.15 However, because the survey was conducted over a number of hospitals, it is unclear if they were all using the same criteria to define respiratory depression.

Hypotension has been defined in a number of ways: a decrease in systolic arterial pressure of greater than 20% of a stable preoperative value has been used;16 as has a greater than 30% decrease,17 18 absolute values of systolic arterial pressure of less than 100 mm Hg,16 or less than 80 mm Hg;5 17 and systolic/diastolic arterial pressure of less than 90/60 mm Hg.18 In a number of studies, hypotension was not defined other than by the need for an intervention. Morphine administration can result in a reduction in arterial pressure, and thus hypotension may be a problem with both PCA and i.m. analgesia as well as with epidural analgesia. However, hypotension may be the result of factors other than the analgesic technique. In a large survey, Tsui and colleagues recorded a 1.9% incidence of hypotension, of which the majority were a result of surgical factors resulting in haemorrhage.4 These authors were able to implicate the analgesic technique as the cause of hypotension in only six out of 2509 cases, giving an incidence of 0.2%.4 In one of the few reasonably sized reviews of i.m. opioid analgesia that also provided details of arterial pressures, Slack and colleagues recorded a 4% incidence of hypotension.19 The results of our analysis produced a very similar figure. A slightly higher incidence of 8% has been reported with s.c. morphine.5 In contrast, the incidence of hypotension associated with PCA was 0% in two other large studies.20 21 There is much more published data on the hypotensive effect of epidural analgesia, with a number of large retrospective surveys suggesting that the incidence of hypotension lies between 2 and 4%.18 2224

This analysis differs from a formal systematic review with meta-analysis in a number of respects. We did not confine ourselves to randomized controlled trials and no attempt was made to grade individual papers according to quality. All of the studies used in the analysis were given equal value as we were not concerned with the conclusion of the individual study, merely the incidences of respiratory depression and hypotension. We feel that this approach is justified as we were not considering the results of published studies but were concerned with extracting the data from them. It is inevitable in a study of this type that there will be a degree of variability in the analgesic regimens, surgical procedures, and indeed in the data presented. Therefore, a degree of heterogeneity is unavoidable in this analysis. However, we feel that the large numbers of studies included and the small number of differences sought will reduce the likelihood of statistical heterogeneity. Also, we were mindful of the dangers of over interpretation inherent in searching for causes of heterogeneity. With respect to clinical heterogeneity, we found that the surgical case mix of the studies used was very similar between the three analgesic techniques and we feel confident that the groups mirror ‘clinical practice’. Furthermore, at least one subsequent large study has reported incidences of respiratory depression and hypotension with epidural and i.v. opiate analgesia not dissimilar to our own findings.25 The rapid evolution of Acute Pain Services is another source of variability of the data. Many of the studies analysed were reports of the initial experiences of individual centres' Pain Service. It is likely that these services have evolved, and this may well explain the decrease in the odds ratio for respiratory depression over the time period of the analysis. However, this fails to explain why the incidence of hypotension has not changed.

In summary, we present an analysis of published data on the adverse respiratory and haemodynamic effects of acute postoperative pain management. Most Acute Pain Services will use a mixture of techniques, and even when PCA and epidural analgesia are freely available, intermittent administration of opioids will still be used in up to 30% of cases after major surgery.26 Allowing for the variety of definitions, as well as the heterogeneity of the data, the following suggestions for clinical practice can be made. Acute Pain Services should expect respiratory depression related to analgesic technique to occur no more frequently than in 1% of cases as defined by a low ventilatory frequency. If oxygen desaturation is used to indicate respiratory depression, a much higher figure should be expected. I.M. opioid analgesia is associated with a similar incidence of respiratory depression to PCA or epidural analgesia, although naloxone use is greatest in association with PCA. There has been a significant decrease in the incidence of respiratory depression over the course of the last two decades. Acute Pain Services should expect an incidence of hypotension related to analgesic technique of less than 5%. Hypotension occurs most frequently with epidural analgesia and least often in association with PCA. These figures may be helpful to Acute Pain Services in setting standards of care.


    Appendix 1
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix 1
 Appendix 2
 Appendix 3
 Appendix 4
 Appendix 5
 References
 
References used to obtain incidences of respiratory depression—hypopnoea
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Badner NH, Doyle JA, Smith MH, Herrick IA. Effect of varying intravenous patient-controlled analgesia dose and lockout interval while maintaining a constant hourly maximum dose. J Clin Anesthesia 1996; 8: 382–5

Banning AM, Schmidt JF, Chraemmer-Jorgensen B, Risbo A. Comparison of oral controlled release morphine and epidural morphine in the management of postoperative pain. Anesth Analg 1986; 65: 385–8

Baron CM, Kowalski SE, Greengrass R, Horan TA, Unruh HW, Baron CL. Epinephrine decreases postoperative requirements for continuous thoracic epidural fentanyl infusions. Anesth Analg 1996; 82: 760–5

el-Baz N, Goldin M. Continuous epidural infusion of morphine for pain relief after cardiac operations. J Thorac Cardiovasc Surg 1987; 93: 878–83

Beaulieu P, Cyrenne L, Mathews S, Villeneuve E, Vischoff D. Patient-controlled analgesia after spinal fusion for idiopathic scoliosis. Internat Orthop 1996; 20: 295–9

Blanco J, Blanco E, Rodriguez G, Castro A, Alvarez J. One year's experience with an acute pain service in a Spanish University Clinic hospital. Eur J Anaesthesiol 1994; 11: 417–21

Boudreault D, Brasseur L, Samii K, Lemoing JP. Comparison of continuous epidural bupivacaine infusion plus either continuous epidural infusion or patient-controlled epidural injection of fentanyl for postoperative analgesia. Anesth Analg 1991; 73: 132–7

Bourke DL, Spatz E, Motara R, Ordia JI, Reed J, Hlavacek JM. Epidural opioids during laminectomy surgery for postoperative pain. J Clin Anesth 1992; 4: 277–81

Brodner G, Mertes N, van Aken H, et al. Epidural analgesia with local anesthetics after abdominal surgery: earlier motor recovery with 0.2% ropivacaine than 0.175% bupivacaine. Anesth Analg 1999; 88: 128–33

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Burgess FW, Anderson DM, Colonna D, Cavanaugh DG. Thoracic epidural analgesia with bupivacaine and fentanyl for postoperative thoracotomy pain. J Cardiothorac Vasc Anesth 1994; 8: 420–4

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Chien B, Burke R, Hunter D. An extensive experience with postoperative pain relief using postoperative fentanyl infusion. Arch Surg 1991; 126: 692–4

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Cooper DW, Turner G. Patient-controlled extradural analgesia to compare bupivacaine, fentanyl and bupivacaine with fentanyl in the treatment of postoperative pain. Br J Anaesth 1993; 70: 503–7

Cox CR, Serpell MG, Bannister J, Coventry DM, Williams DR. A comparison of epidural infusions of fentanyl or pethidine with bupivacaine in the management of postoperative pain. Anaesthesia 1996; 51: 695–8

Davies P, Warwick P, O'Connor M. Antiemetic efficacy of ondansetron with patient controlled analgesia. Anaesthesia 1996; 51: 880–2

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Etches RC, Sandler AN, Lawson SL. A comparison of the analgesic and respiratory effects of epidural nalbuphine or morphine in post-thoracotomy patients. Anesthesiology 1991; 75: 9–14

Gan TJ, Ginsberg B, Glass PS, Fortney J, Jhaveri R, Perno R. Opioid-sparing effects of a low-dose infusion of naloxone in patient-administered morphine sulfate. Anesthesiology 1997; 87: 1075–81

George KA, Chisakuta AM, Gamble JA, Browne GA. Thoracic epidural infusion for postoperative pain relief following abdominal aortic surgery. Anaesthesia 1992; 47: 388–94

Gillies GW, Kenny GN, Bullingham RE, McArdle CS. The morphine sparing effect of ketorolac tromethamine. A study of a new, parenteral non-steroidal anti-inflammatory agent after abdominal surgery. Anaesthesia 1987; 42: 727–31

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Laitinen J, Nuutinen L. Intravenous diclofenac coupled to PCA fentanyl for pain relief after hip replacement. Anesthesiology 1992; 76: 194–8

Larsen VH, Iversen AD, Christensen P, Andersen PK. Postoperative pain treatments after upper abdominal surgery with epidural morphine at thoracic or lumbar level. Acta Anaesthesiol Scand 1985; 29: 566–71

Laveaux MM, Hasenbos MA, Harbers JB, Liem T. Thoracic epidural bupivacaine plus sufentanil: high concentration/low volume versus low concentration/high volume. Reg Anaesth 1993; 18: 39–43

Lee A, Simpson D, Whifield A, Scott DB. Postoperative analgesia by continuous extradural infusion of bupivacaine and diamorphine. Br J Anaesth 1988; 60: 845–50

Lehmann KA, Gerhard A, Horrichs-Haermeyer G, Grond S, Zech D. Postoperative PCA with sufentanil: analgesic efficacy and minimum effective concentrations. Acta Anaesthesiol Scand 1991; 35; 221–6

Leith S, Wheatley RG, Jackson IJ, Madej TH, Hunter D. Extradural infusion analgesia for postoperative pain relief. Br J Anaesth 1994; 73: 552–8

Liu SS, Allen HW, Olsson GL. Patient controlled epidural analgesia with bupivacaine and fentanyl on hospital wards. Anesthesiology 1998; 88: 688–95

Loper KA, Ready LB, Downey M, et al. Epidural and intravenous fentanyl infusions are clinically equivalent after knee surgery. Anesth Analg 1990; 70: 72–5

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    Appendix 2
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix 1
 Appendix 2
 Appendix 3
 Appendix 4
 Appendix 5
 References
 
References used to obtain incidences of respiratory depression—desaturation
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Brose WG, Cohen SE. Oxyhemoglobin saturation following cesarean section in patients receiving epidural morphine, patient-controlled analgesia, or intramuscular meperidine analgesia. Anesthesiology 1989; 70: 948–53

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Chauvin M, Hongnat JM, Mourgeon E, Lebrault C, Bellenfait F, Alfonsi P. Equivalence of postoperative analgesia with patient controlled intravenous or epidural alfentanil. Anesth Analg 1993; 76: 1251–8

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Jayr C, Thomas H, Rey A, Farhat F, Lasser P, Bourgain J. Postoperative pulmonary complications: epidural analgesia using bupivacaine and opioids versus parenteral opioids. Anesthesiology 1993; 78: 666–76

Jayr C, Beaussier M, Gustafsson U, et al. Continuous epidural infusion of ropivacaine for postoperative analgesia after abdominal surgery. Br J Anaesth 1998; 81: 887–92

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Madej TH, Wheatley RG, Jackson IT, Hunter D. Hypoxaemia and pain relief after lower abdominal surgery: comparison of extradural and patient controlled analgesia. Br J Anaesth 1992; 69: 554–7

Nozaki-Taguchi N, Oka T, Kochi T, Taguchi N, Mizaguchi T. Apnoea and oximetric desaturation in patients receiving epidural morphine after gastrectomy. Anaesth Intens Care 1993; 21: 292–7

Parker RK, Holtmann B, White PF. Effects of a nighttime opioid infusion with patient-controlled analgesia therapy on patient comfort and analgesic requirements after abdominal hysterectomy. Anesthesiology 1992; 76: 362–7

Patrick J, Meyer-Witting M, Reynolds F. Lumbar epidural diamorphine following thoracic surgery. Anaesthesia 1991; 46: 85–9

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Rosenberg J, Rasmussen V, von Jessen F, Ullstad T, Kehlet H. Late postoperative episodic and constant hypoxaemia and associated ECG abnormalities. Br J Anaesth 1990; 65: 684–91

Saito Y, Uchita H, Kaneko M, Nakatani T, Kosaka Y. Comparison of continuous epidural infusion of morphine/bupivacaine with fentanyl/bupivacaine for postoperative pain. Acta Anaesthesiol Scand 1994; 38: 398–401

Salomaki TE, Laitinen JO, Vainionpaa V, Nuutinen LS. 0.1% bupivacaine does not reduce the requirement for epidural fentanyl infusion after major abdominal surgery. Reg Anesth 1995; 20: 435–43

Schug S, Fry R. Continuous regional analgesia in comparison with intravenous opioid administration for routine postoperative pain control. Anaesthesia 1994; 49: 528–32

Sidebotham D, Dijkhuizen MR, Schug SA. The safety and utilization of patient controlled analgesia. J Pain Symptom Manage 1997; 14: 202–9

Sidebotham DA, Russell K, Dijkhuizen M, Tester P, Schug SA. Low dose fentanyl improves continuous bupivacaine epidural analgesia following orthopaedic, urological or general surgery. Acute Pain 1997; 1: 27–32

Tsui SL, Chan CS, Chan AS, Wong SJ, Lam CS, Jones RD. Postoperative analgesia for oesophageal surgery: a comparison of three analgesic regimens. Anaesth Intens Care 1991; 19: 329–37

Tsui SL, Lo RJ, Tong WN, et al. A clinical audit for postoperative pain control on 1443 surgical patients. Acta Anaesthesiol Sin 1995; 33: 137–48

Tsui SL, Tong WN, Irwin M, et al. The efficacy, applicability and side effects of postoperative intravenous patient controlled morphine analgesia: an audit of 1233 Chinese patients. Anaesth Intens Care 1996; 24: 658–64

Vercauteren M, Lauwers E, Meert T, DeHert S, Adriaensen H. Comparison of epidural sufentanil plus clonidine with sufentanil alone for postoperative pain relief. Anaesthesia 1990; 45: 531–4

Wheatley RG, Shepherd D, Jackson IJ, Madej TH, Hunter D. Hypoxaemia and pain relief after upper abdominal surgery: comparison of intramuscular and patient controlled analgesia. Br J Anaesth 1992; 69: 558–61


    Appendix 3
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix 1
 Appendix 2
 Appendix 3
 Appendix 4
 Appendix 5
 References
 
References used to obtain incidences of respiratory depression—hypercarbia
Brodsky JB, Chaplan SR, Brose WG, Marks JB. Continuous epidural hydromorphone for postthoracotomy pain relief. Ann Thorac Surg 1990; 50: 888–93

Guinard JP, Mavrocordatos P, Chiolero R, Carpenter RL. A randomized comparison of intravenous versus lumbar and thoracic epidural fentanyl for analgesia after thoracotomy. Anesthesiology 1992; 77: 1108–15

Hansdottir V, Bake B, Nordberg G. The analgesic efficacy and adverse effects of continuous epidural sufentanil and bupivacaine infusion after thoracotomy. Anesth Analg 1996; 83: 394–400

Laveaux MM, Hasenbos MA, Harbers JB, Liem T. Thoracic epidural bupivacaine plus sufentanil: high concentration/low volume versus low concentration/high volume. Reg Anesth 1993; 18: 39–43

Nimmo WS, Todd JG. Fentanyl by constant rate intravenous infusion for postoperative analgesia. Br J Anaesth 1985; 57: 250–4

Pelton JJ, Fish DJ, Keller SM. Epidural narcotic analgesia after thoracotomy. South Med J 1993; 86: 1106–9

Rapp S, Ready L, Greer B. Postoperative pain management in gynecologic oncology patients utilizing epidural opiate analgesia and patient-controlled analgesia. Gynecol Oncol 1989; 35: 341–4

Ready LB, Oden R, Chadwick HS, et al. Development of an anesthesiology-based postoperative pain management service. Anesthesiology 1988; 68: 100–6

Rosenberg PH, Heino A, Scheinin B. Comparison of intramuscular analgesia, intercostal block, epidural morphine and on-demand intravenous fentanyl in the control of pain after upper abdominal surgery. Acta Anaesthesiol Scand 1984; 28: 603–7

Salomaki TE, Laitinen JO, Nuutinen LS. A randomized double blind comparison of epidural versus intravenous fentanyl infusion for analgesia after thoracotomy. Anesthesiology 1991; 75: 790–5

Salomaki TE, Laitinen JO, Vainionpaa V, Nuutinen LS. 0.1% bupivacaine does not reduce the requirement for epidural fentanyl infusion after major abdominal surgery. Reg Anesth 1995; 20: 435–43

Scheinin B, Asantila R, Orko R. The effect of bupivacaine and morphine on pain and bowel function after colonic surgery. Acta Anaesthesiol Scand 1987; 31: 161–4

Shulman M, Sandler AN, Bradley JW, Young PS, Brebner J. Post-thoracotomy pain and pulmonary function following epidural and systemic morphine. Anesthesiology 1984; 61: 569–75

Snijdelaar DG, Hasenbos MA, van Egmond J, Wolff AP, Liem TH. High thoracic epidural sufentanil with bupivacaine: continuous infusion of high volume versus low volume. Anesth Analg 1994; 78: 490–4

Tamsen A, Hartvig P, Faherlund G, Dahlstrom B, Bondessen U. Patient controlled analgesic therapy: clinical experience. Acta Anaesthesiol Scand 1982; 74 (Suppl.): 157–60

Tsui SL, Chan CS, Chan AS, Wong SJ, Lam CS, Jones RD. Postoperative analgesia for oesophageal surgery: a comparison of three analgesic regimens. Anaesth Intens Care 1991; 19: 329–37

Tsui SL, Lo RJ, Tong WN, et al. A clinical audit for postoperative pain control on 1443 surgical patients. Acta Anaesthesiol Sin 1995; 33: 137–48


    Appendix 4
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix 1
 Appendix 2
 Appendix 3
 Appendix 4
 Appendix 5
 References
 
References used to obtain incidences of respiratory depression-use of naloxone
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Liu SS, Allen HW, Olsson GL. Patient controlled epidural analgesia with bupivacaine and fentanyl on hospital wards. Anesthesiology 1998; 88: 688–95

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    Appendix 5
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix 1
 Appendix 2
 Appendix 3
 Appendix 4
 Appendix 5
 References
 
References used to obtain incidences of cardiovascular depression-hypotension
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Burgess FW, Anderson DM, Colonna D, Cavanaugh DG. Thoracic epidural analgesia with bupivacaine and fentanyl for postoperative thoracotomy pain. J Cardiothorac Vasc Anesth 1994; 8: 420–4

Burstal R, Wegener F, Hayes C, Lantry G. Epidural analgesia: prospective audit of 1062 patients. Anaesth Intens Care 1998; 26: 165–72

Capdevila X, Barthelet Y, Biboulet P, Ryckwaert Y, Rubenovitch J, d'Athis F. Effects of perioperative analgesic technique on the surgical outcome and duration of rehabilitation after major knee surgery. Anesthesiology 1999; 91: 8–15

Chisakuta AM, George KA, Hawthorne CT. Postoperative epidural infusion of a mixture of bupivacaine with fentanyl for upper abdominal surgery. Anaesthesia 1995; 50: 72–5

Coleman S, Brooker-Milburn J. Audit of postoperative pain control. Anaesthesia 1996; 51: 1093–6

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Cooper DW, Turner G. Patient-controlled extradural analgesia to compare bupivacaine, fentanyl and bupivacaine with fentanyl in the treatment of postoperative pain. Br J Anaesth 1993; 70: 503–7

Cox CR, Serpell MG, Bannister J, Coventry DM, Williams DR. A comparison of epidural infusions of fentanyl or pethidine with bupivacaine in the management of postoperative pain. Anaesthesia 1996; 51: 695–8

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Dahl JB, Hjortso NC, Stage JG, et al. Effects of combined perioperative epidural bupivacaine and morphine, ibuprofen, and incisional bupivacaine on postoperative pain, pulmonary and endocrine-metabolic function after minilaparotomy cholecystectomy. Reg Anesth 1994; 19: 199–205

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George KA, Wright PM, Chisakuta AM, Rao NV. Thoracic epidural analgesia compared with patient controlled intravenous morphine after upper abdominal surgery. Acta Anaesthesiol Scand 1994; 38: 808–12

Hansdottir V, Bake B, Nordberg G. The analgesic efficacy and adverse effects of continuous epidural sufentanil and bupivacaine infusion after thoracotomy. Anesth Analg 1996; 83: 394–400

Hasenbos M, van Egmond J, Gielen M, Crul JF. Postoperative analgesia by epidural versus intramuscular nicomorphine after thoracotomy. Part II. Acta Anaesthesiol Scand 1985; 29: 577–82

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Jayr C, Thomas H, Rey A, Farhat F, Lasser P, Bourgain J. Postoperative pulmonary complications: epidural analgesia using bupivacaine and opioids versus parenteral opioids. Anesthesiology 1993; 78: 666–76

Knapp M, Beecher H. Postanaesthetic nausea, vomiting and retching. JAMA 1956; 160: 376–85

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Laveaux MM, Hasenbos MA, Harbers JB, Liem T. Thoracic epidural bupivacaine plus sufentanil: high concentration/low volume versus low concentration/high volume. Reg Anesth 1993; 18: 39–43

Leith S, Wheatley RG, Jackson IJ, Madej TH, Hunter D. Extradural infusion analgesia for postoperative pain relief. Br J Anaesth 1994; 73: 552–8

de Leon-Casasola OA, Parker B, Lema MJ, Harrison P, Masey J. Postoperative epidural bupivacaine-morphine therapy. Anesthesiology 1994; 81: 368–75

de Leon-Casasola OA, Lema MJ, Karabella D, Harrison P. Postoperative myocardial ischaemia: epidural versus intravenous patient-controlled analgesia. Reg Anesth 1995; 20: 105–12

Liu S, Angel JM, Owens BD, Carpenter RL, Isabel L. Effects of epidural bupivacaine after thoracotomy. Reg Anesth 1995; 20: 303–10

Liu SS, Carpenter RL, Mackey DC, et al. Effects of perioperative analgesic technique on rate of recovery after colon surgery. Anesthesiology 1995; 83:757–65

Liu SS, Allen HW, Olsson GL. Patient controlled epidural analgesia with bupivacaine and fentanyl on hospital wards. Anesthesiology 1998; 88: 688–95

Liu SS, Moore JM, Luo AM, Trautman WJ, Carpenter RL. Comparison of three solutions of ropivacaine/fentanyl for postoperative patient-controlled epidural analgesia. Anesthesiology 1999; 90: 727–33

MacIntyre PE. An acute pain service in an Australian teaching hospital: the first year. Med J Aust 1990; 153: 417–21

Matthews PJ, Govenden V. Comparison of continuous paravertebral and extradural infusions of bupivacaine for pain relief after thoracotomy. Br J Anaesth 1989; 62: 204–5

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    Acknowledgments
 
We wish to thank Professor J. M. Bland, Department of Public Health Sciences, St George's Hospital Medical School, London for his invaluable advice and assistance in the statistical analysis of the data.


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix 1
 Appendix 2
 Appendix 3
 Appendix 4
 Appendix 5
 References
 
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