Abstract
A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was ‘is the addition of ketamine to morphine patient-controlled analgesia (PCA) following thoracic surgery superior to morphine alone’. Altogether 201 papers were found using the reported search, of which nine represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. This consisted of one systematic review of PCA morphine with ketamine (PCA-MK) trials, one meta-analysis of PCA-MK trials, four randomized controlled trials of PCA-MK, one meta-analysis of trials using a variety of peri-operative ketamine regimes and two cohort studies of PCA-MK. Main outcomes measured included pain score rated on visual analogue scale, morphine consumption and incidence of psychotomimetic side effects/hallucination. Two papers reported the measurements of respiratory function. This evidence shows that adding ketamine to morphine PCA is safe, with a reported incidence of hallucination requiring intervention of 2.9%, and a meta-analysis finding an incidence of all central nervous system side effects of 18% compared with 15% with morphine alone, P = 0.31, RR 1.27 with 95% CI (0.8–2.01). All randomized controlled trials of its use following thoracic surgery found no hallucination or psychological side effect. All five studies in thoracic surgery (n = 243) found reduced morphine requirements with PCA-MK. Pain scores were significantly lower in PCA-MK patients in thoracic surgery papers, with one paper additionally reporting increased patient satisfaction. However, no significant improvement was found in a meta-analysis of five papers studying PCA-MK in a variety of surgical settings. Both papers reporting respiratory outcomes found improved oxygen saturations and PaCO2 levels in PCA-MK patients following thoracic surgery. We conclude that adding low-dose ketamine to morphine PCA is safe and post-thoracotomy may provide better pain control than PCA with morphine alone (PCA-MO), with reduced morphine consumption and possible improvement in respiratory function. These studies thus support the routine use of PCA-MK instead of PCA-MO to improve post-thoracotomy pain control.
Keywords: Review, Ketamine, Morphine, Analgesia, Patient-controlled
INTRODUCTION
A best evidence topic was constructed according to a structured protocol. This is fully described in the ICVTS [1].
THREE-PART QUESTION
In [patients undergoing thoracic surgery] is a patient-controlled analgesia (PCA) [consisting of ketamine with morphine] or [morphine alone] the best for [post-operative analgesia].
CLINICAL SCENARIO
You have just started a video-assisted thoracoscopic surgery lobectomy programme and have been impressed by their lack of pain. Unfortunately, your thoracotomy patients are still in pain despite paravertebrals, PCAs, nefopam, paracetamol and non-steroidal anti-inflammatory drugs. You talk to an anaesthetist who has just come from the pain service, who suggests adding ketamine to the morphine PCA. You are anxious about episodes of psychosis so you resolve to check the literature for this new method of analgesia.
SEARCH STRATEGY
Medline was searched from 1948 to June week 5 2011 using the OVIDSP interface.
(ketamine.mp. OR exp Ketamine/)AND(morphine.mp. or exp Morphine/OR exp Morphine Derivatives/)AND(exp Post-operative Complications/OR post-operative.mp. OR patient controlled analgesia.mp. OR exp Analgesia, Patient-Controlled/ OR PCA.mp).
Studies were included if they compared morphine PCA (PCA-MO) with morphine and Ketamine PCA (PCA-MK) in any specialty. We also added any studies on ketamine in thoracotomy wounds.
SEARCH OUTCOME
Two hundred and one papers were found using the reported search. From these, nine papers were identified that provided the best evidence to answer the question. These are presented in Table 1.
Table 1:
Best evidence papers
| Author, date and country, study type (level of evidence) | Patient group | Outcomes | Key results | Comments |
|---|---|---|---|---|
| Subramaniam et al., 2004, USA [2] Meta-analysis of RCTs (level 1a) |
|
Mean resting pain scores (VAS) for the first 24 h was analysed with available data from five PCA studies | Overall WMD of −5.4 mm (95% CI: −1.25, 0.18). No significant difference | A discrepancy was noted between the total number of patients in IV PCA-MK trials and the data given in analysis of CNS side effects without clear explanation in the paper |
|
CNS side effects (dizziness, disorientation, dysphoria, confusion, excess sedation, bad dreams, strange feelings and hallucinations) were analysed from all six PCA studies |
|
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| Sveticic G et al., 2005, Switzerland [3] Prospective cohort study (level 2b) | 1026 patients undergoing various elective surgical procedures under general anaesthetic received post-operative PCA consisting of morphine and ketamine in the 1:1 ratio, initially given as 1.5 mg of bolus of each drug and increased as needed in 0.5 mg increments to the maximum of 2.5 mg | Incidence of vivid dreams or hallucinations (%) |
|
In all cases of vivid dreams/ hallucinations requiring discontinuation of the therapy, symptoms fully resolved in 1–2 h |
| Incidence of respiratory depression (%) | Total = 1.2 | |||
| Nausea (%) | Total = 23.5 | |||
| Sedation (%) | Total = 21.4 | |||
| Pruritus (%) | Total = 10.3 | |||
| Carstensen and Moller, 2010, Denmark [4] Systematic review of RCTs (level 1a) |
|
Pain score measured by patient self-reporting using VAS or verbal rating scale | Six studies (n = 333, average quality score = 4.8) showed a statistically significant decrease in pain intensity with ketamine compared with morphine alone. Four studies found no improvement in pain when adding ketamine to morphine (n = 512, average quality score = 4.3). All three studies with patients undergoing thoracic surgery found a significantly improved pain score with the addition of ketamine (n = 148, average quality score = 5) |
|
| Total consumption of opioid | Six studies (n = 305, average quality score = 4.5) found a statistically significant decrease in morphine consumption in the ketamine group, and five studies (n = 582, average quality score = 4.4) did not. The morphine sparing effect ranged from 45 to 60%. | |||
| Psychotomimetic adverse effects | Nine studies (n = 746, average quality score 4.6) found no significant increase with ketamine, and two studies (n = 141, average quality score 4) did. | |||
| Chazan et al., 2010, Israel [5] Double blind RCT (level 1b) | 46 patients undergoing various transthoracic surgical procedures (minimally invasive direct coronary artery bypass, off-pump coronary artery bypass or thoracotomy) were randomized to receive post-operative IV PCA with either 2 mg of morphine bolus alone (group MO) or 1 mg/5 mg of morphine + ketamine bolus, respectively (MK) | Cumulative morphine usage (mg) | MO = 78, SD 48; MK = 48, SD 34; P = 0.01 |
|
| Patients pain POD3 (VAS) | MO = 2.4, SD 1.8; MK = 1.8, SD 1.1; P = 0.1 (given as P = 0.0001 in graph) | |||
| Patients' satisfaction POD1–3 (VAS) | MO = 7.1, SD 1.7; MK = 8.3, SD 1.4; P = 0.012 | |||
| Family's satisfaction (VAS) |
|
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| Patients wakefulness POD1–3 (VAS) | MO = 7.7, SD 0.3; MK = 7.9, SD 0.3; P = 0.028 | |||
| Post-operative nausea and vomiting (n) | MO = 15; MK = 10; P = 0.98 | |||
| Nesher et al., 2009, Israel [6] Double blind RCT (level 1b) | 41 patients undergoing unspecified thoracotomy for elective MIDCAB or lung resection were randomized to receive post-operative IV PCA of boluses of either 1 mg of morphine plus saline (group MO) or 1 mg of morphine + 5 mg of ketamine (MK) | Morphine consumption (mg) |
|
One MK patient reported episode of light-headedness that resolved spontaneously in <4 min. No MK patients reported hallucinations or post-operative confusion. Incidence of post-operative nausea and vomiting similar between two groups |
| Maximal pain over 4 h post-operatively (VAS) | MO = 5.6, SD 1.0; MK = 3.7, SD 0.7; P = 0.0001 | |||
| 90 min PaCO2 (mmHg) | MO = 40, SD 6; MK = 33, SD 5; P = 0.0003 | |||
| Post-operative SpO2 increase, % difference between baseline and 90 min value |
|
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| Respiratory rate (breaths/min) at 4 h post-operatively | MO = 19, SD 1; MK = 13, SD 1; P = 0.0001 | |||
| Wakefulness score (VAS) at 4 h post-operatively | MO = 3.2, SD 1.3; MK = 5.5, SD 1.2; P = 0.0001 | |||
| Nesher et al., 2008, Israel [7] Double blind RCT (level 1b) | 58 patients undergoing anterolateral thoracotomy for MIDCAB, lung tumour resection or median sternotomy for OPCAB were randomized to receive post-operative IV PCA boluses of 1.5 mg of morphine alone (group MO) or 1 mg of morphine + 5 mg of ketamine (group MK), both with lockout time of 7 min | Morphine consumption (mg/patient/h) over 24 h | MO = 2.0, SD 2.3; MK = 1.0, SD 1.4; P < 0.05 | No ketamine-specific side effects observed |
| Pain intensity over 72 h period (VAS) | Consistently and significantly lower in the MK group than the MO group (P = 0.03) | |||
| Requirement for IV PCA at 36 h (n) | MO = 10; MK = 5; P = 0.008 | |||
| Respiratory rate | Higher in the MK group than the MO group (P = 0.001) | |||
| SpO2 |
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| Michelet et al., 2007, France [8] Double blind RCT (level 1b) | 48 patients undergoing posterolateral thoracotomy for lobectomy were randomized to receive post-operative PCA consisting of either morphine 1 mg/ml (group MO) or morphine with ketamine 1 mg/ml of each (MK), bolus dose of 0.015 ml/kg with 10 min lockout time | Cumulative morphine consumption (mg) |
|
No psychological alteration or side effect related to ketamine use was noted |
| Nocturnal desaturation (% of time with SpO2 < 90%) |
|
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| FEV1 |
|
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| Pain score (VAS) |
|
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| Bell et al., 2005, Norway, Denmark, UK, Finland [9] Meta-analysis of RCTs (level 1a) | This was a qualitative and quantitative systematic review of RCTs of peri-operative administration of ketamine. Thirty-seven trials with a total of 2137 patients were included, with various methodologies of administration of ketamine peri-operatively for various surgical procedures. Post-operative PCA ketamine was used in four studies (n = 212, average quality score 3.5). Due to the heterogenicity of the trials, quantitative analysis was only performed on data on 24 h cumulative IV PCA morphine consumption (10 trials, n = 432) and post-operative nausea and vomiting (26 trials, n = 1261) | Cumulative PCA morphine consumption in first 24 h after surgery. | Treatment with ketamine reduced morphine consumption, WMD −15.98 mg with 95% CI (−19.70, −12.26) | The results of this meta-analysis should be interpreted with caution, as the timing and methodology of ketamine administration varied between trials used |
| Post-operative nausea and vomiting | Ketamine significantly reduced post-operative nausea and vomiting (P = 0.001) | |||
| Atangana et al., 2007, Republic of Cameroon [10] Cohort study (level 3) | 50 patients undergoing thoracic surgery [unspecified thoracotomy for intrathoracic tumours (n = 21), pleural decortications (n = 22) and thoracic trauma associated with multiple rib fractures or sternal fractures needing osteosynthesis (n = 7)] were allocated to receive post-operative PCA consisting of either 0.5 mg/ml of morphine with placebo (MO) or 0.5 mg/ml of morphine with 0.5 mg/ml of ketamine(MK), in boluses of 2 ml, with lockout time of 5 min | Pain on coughing (VAS) |
|
|
| Total morphine consumption (mg) | MO = 52, SD 12; MK = 31.5, SD 16; P < 0.05 |
RESULTS
Safety
Subramaniam et al. [2] performed a meta-analysis of six trials (n = 330) comparing PCA-MK with PCA-MO. 18% of PCA-MK patients reported central nervous system (CNS) side effects compared with 15% of PCA-MO patients, P = 0.31, seven trials (n = 289) using IV-ketamine infusion were identified, with 149 patients receiving ketamine. No significant increase in CNS side effects was noted in this group (15 of 149, vs 9 of 140, P = 0.09).
Sveticic et al. [3] reported an incidence of hallucination/vivid dreams requiring the intervention of 2.9%, and incidence requiring no intervention of 3.3% in a prospective cohort study of 1026 patients receiving PCA-MK post-operatively in a variety of surgical settings.
In Carstensen and Moller's [4] qualitative systematic review of 11 randomized controlled trials (RCTs) looking at PCA-MK in a range of different surgical settings (n = 887 of whom 448 received ketamine), nine studies (n = 746) found no significant increase in psychotomimetic side effects with PCA-MK and two (n = 141) did.
All four RCTs of PCA-MK in thoracic surgery [5–8] reported no hallucinations or psychological side effect in the MK group.
Morphine consumption
Carstensen and Moller's [4] qualitative review found six studies (n = 305) showed significantly reduced morphine consumption in the PCA-MK group compared with the PCA-MO group, and five studies (n = 582) did not.
Bell et al. [9] performed meta-analysis on 24 h IV-PCA morphine consumption from 10 trials (n = 432) using a variety of methods of ketamine administration peri-operatively. They found that treatment with ketamine reduced morphine consumption.
Chazan et al. [5] reported the reduced cumulative morphine usage in the PCA-MK group following various transthoracic procedures.
Nesher et al. [6] reported reduced morphine consumption over hours 1 and 2 post-thoracotomy in PCA-MK patients (P = 0.0001 and P = 0.008 respectively). This was repeated in their further study [7] which found reduced morphine consumption over 24 h in PCA-MK patients following thoracotomy (P < 0.05).
Michelet et al. [8] found no significant difference in morphine consumption with PCA-MK in the first 24 h post-thoracotomy. Reduced morphine consumption was found, however, at 36 h (P = 0.029), 48 h (P = 0.007) and 60 h (P = 0.006).
Atangana et al. [10] found reduced total morphine consumption with PCA-MK following thoracic surgery (MO = 52, SD 12; MK = 31.5, SD 16, P < 0.05).
Pain control
Carstensen and Moller's [4] qualitative systematic review of RCTs reported six studies (n = 333) showed significantly lower pain scores with PCA-MK compared with MO. Four studies (n = 512) showed no significant difference. All three thoracic surgery studies (n = 148) showed significantly lower pain scores with PCA-MK. Subramaniam et al. [2] performed meta-analysis on six trials (n = 330) comparing PCA-MK and PCA-MO in a variety of surgical settings. They found a weighted mean difference (WMD) of −5.4 mm visual analogue scale (VAS) with ketamine (95% CI, −1.25, 0.18), this difference was not significant.
Chazan et al. [5] found lower pain scores following various transthoracic procedures in the PCA-MK group over days 1–3, but this difference was not significant until day 3 (P = 0.0001). They found significantly increased patient satisfaction in the MK group over days 1–3 (P = 0.012). Similarly, Michelet et al. [8] found no significant difference in pain scores between PCA-MK and PCA-MO patients until 48 h and 60 h post-thoracotomy (P < 0.05).
Nesher et al. [6] found reduced maximal pain scores over 4 h post-thoracotomy in PCA-MK patients compared with MO (MO = 5.6, SD 1.0; MK = 3.7, SD 0.7; P = 0.0001). This was followed up by a further RCT by Nesher et al. [7], which found consistently significantly reduced pain scores in the PCA-MK group following thoracotomy (P = 0.03). They also reported a reduced requirement for IV-PCA at 36 h in the MK group (P = 0.008).
Atangana et al.'s [10] cohort study of thoracic patients found reduced pain scores on coughing at 12 h and 24 h post-operatively with PCA-MK compared with PCA-MO (P < 0.05).
Respiratory function
Nesher et al. [6] reported reduced PaCO2 at 90 min post-thoracotomy with PCA-MK compared with PCA-MO (MO = 40 mmHg, SD 6; MK = 33 mmHg, SD 5; P = 0.0003) and a greater percentage increase in SpO2 over 90 min post-operatively (MO = 1.0, SD 1.0; MK = 4.5, SD 1.0; P = 0.0001). The respiratory rate was higher at 4 h post-operatively in MO compared with MK patients (P = 0.0001). In their follow-up study, Nesher et al. [7] found no PCA-MK patients desaturated below SpO2 of 94% with 40% oxygen facemask following thoracotomy, whereas seven MO patients did (P < 0.001).
Michelet et al. [8] found the reduced incidence of nocturnal desaturation over the first three nights post-thoracotomy with PCA-MK compared with PCA-MO (P < 0.001, P = 0.021 and P = 0.0019). They also found a greater decrease in FEV1 in the MO group on post-operative day 1 (P = 0.039), this difference was lost by day 2.
CLINICAL BOTTOM LINE
Adding ketamine to morphine PCA is safe, with reported incidence of hallucination requiring intervention of 2.9% [3], and a meta-analysis [2] finding an incidence of all CNS side effects of 18% compared with 15% with morphine alone. All trials of its use following thoracic surgery found no hallucination or psychological side effect. All five thoracic surgery studies (n = 243) found reduced morphine requirements with PCA-MK, with a trend towards decreased morphine consumption in other trials. Pain scores were significantly lower in PCA-MK patients in all thoracic surgery papers, with one paper additionally reporting increased patient satisfaction. Two papers reported respiratory outcomes and found improved oxygen saturations and PaCO2 levels in PCA-MK patients following thoracic surgery. These studies thus support the routine use of PCA-MK instead of PCA-MO to improve post-thoracotomy pain control.
Conflict of interest: none declared.
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