Explanations - Lippincott Williams & Wilkins
Supplemental Table 3. Pain Group Evidence Summaries and Evidence to Decision TablesQuestion: Adjunctive nefopam compared to no adjunctive nefopam for ICU pain management (5.2) Quality assessment№ of patientsEffectQualityImportance№ of studiesStudy designRisk of biasInconsistencyIndirectnessImprecisionOther considerationsadjunctive nefopamno adjunctive nefopamRelative(95% CI)Absolute(95% CI)VAS Score with movement1 randomised trials serious anot serious serious bserious cnone Overall no difference in Pain assessment with or without nefopam: at rest and during movement at 12, 24, 36, 48 and 72 h after surgery using a visual analogue scale (VAS) Pain with movement at 48h was the only time point for which the difference was statistically significant. All others were non-significant. ????VERY LOW CRITICAL CI: Confidence interval; MD: Mean differenceExplanationsa. Randomization method not described, no intention to treat with 24/300 loss to follow-up, blinding described b. Only included CVICU patients in this study, however analgesic efficacy may be broadly applicable to all ICU patients c. Confidence Intervals do not cross z ero (no effect) - however small sample siz e hard to draw conclusion on nefopam effects QuestionShould adjunctive nefopam vs. no adjunctive nefopam be used for ICU pain management (5.2)?Population:ICU pain management (5.2)Background:Intervention:adjunctive nefopamComparison:no adjunctive nefopamMain outcomes:VAS Score with movement;Setting:Perspective:JudgementResearch evidenceAdditional considerationsProblemIs the problem a priority?○ No○ Probably no○ Probably yes● Yes○ Varies○ Don't knowIt is top priority to investigate the effectiveness/side effects of Adjunctive Non opioid analgesics to opioids compared to opioids alone in order to decrease opioids related side effects that are especially at risk in ICU patients: - respiratory depression- neurological impairment (decreased vigilance, delirium)- ileus, nausea vomiting, etc... Kim et al. 2014 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaW08L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA [1]n=276 patients scheduled to undergo cardiac surgery were randomly assigned between threePCA groups (92 patients per group): nefopam, fentanyl or nefopam + fentanyl.Each drug was given continuously + in PCA mode. NB (1): For Question 5.2, we only take into consideration nefopam+fentanyl group versus fentanyl group.Pain assessment:at rest and during movementat 12, 24, 36, 48 and 72 h after surgery using a visual analogue scale (VAS)NB (2): The evidence table reported only pain at H48 which was the only time point for which the difference was statistically significant. Doses:nefopam group:nefopam 4 mg/hbolus: nefopam 2 mg (lock out ime = 15 min) fentanyl group:fentanyl 20 ?g/hbolus: fentanyl 10 ?g (lock out ime = 15 min)nefopam+fentanyl group:nefopam 1.86 mg/h + fentanyl 9.4 ?g/hbolus: nefopam 0.93 mg + fentanyl 4.7 ?g(lock out ime = 15 min in every group) Desirable EffectsHow substantial are the desirable anticipated effects?○ Trivial● Small○ Moderate○ Large○ Varies○ Don't knowThis study has a "Non inferiority design"According to the study design, there was no inferiority of nefopam (adjunctive or not) compared to fentanyl (VAS non significant at H24 at rest and during movement).Note that fentanyl dose changes according to the group from 0 (no fentanyl, nefopam only) to 9.4 ?g/h (nefopam+fentanyl group) to 20 ?g/h (fentanyl only)VAS also non significant at H12, 24, 36, 48, 72 at rest, as well as during movement at H12, 24, 36, 72.The VAS difference between group is only significant during movement at H48:MD 0.34 higher (0.01 higher to 0.67 higher)i.e. VAS higher in nefopam+fentanyl group compared to fentanyl alone group"large" desirable anticipated effects because nefopam did as well as fentanyl, a good point for nefopam if we would like to spare opioids. Undesirable EffectsHow substantial are the undesirable anticipated effects?○ Large○ Moderate● Small○ Trivial○ Varies○ Don't know"small" undesirable anticipated effects beucause on the contrary, nausea was less frequent in the nefopam+fentanyl group (13%) compared to the fentanyl group (27%), p<0.01 taking into account the three groups (nefopam, nefopam+fentanyl, fentanyl).No significant difference between groups for: tachycardia, sweating, sedation, dyspnoa, prutirus, vomiting.(All adverse events were reported during the first 48 hours).No post-hoc tests comparing groups in pairs.Certainty of evidenceWhat is the overall certainty of the evidence of effects?○ Very low● Low○ Moderate○ High○ No included studiesn=92 patients per group is a small group for John Centofanti.There was an important ROB:Randomization method not described, no intention to treat with 24/300 loss to follow-upReasons for non completion of the study:-duration of intubation > or = 48h: n=11 (it is not precised the timing of begining of the PCA with continuous mode, only that ot was "initiated postoperatively")-repeat surgery within 72h: n=5-reintubation in ICU: n=4-malfunctionning PCA device: n=4"low" certainty of the evidence of effects because of: - a moderate to important size (almost 100!)- a double blinded designbut- only one study- with an important ROBValuesIs there important uncertainty about or variability in how much people value the main outcomes?○ Important uncertainty or variability○ Possibly important uncertainty or variability○ Probably no important uncertainty or variability● No important uncertainty or variability○ No known undesirable outcomesExcept for nausea, other classical opioid related side effects were not decreased nor investigated (respiratory rate, ileus, delirium...). "Possibly" important uncertainty or variabilityBalance of effectsDoes the balance between desirable and undesirable effects favor the intervention or the comparison?○ Favors the comparison○ Probably favors the comparison○ Does not favor either the intervention or the comparison● Probably favors the intervention○ Favors the intervention○ Varies○ Don't knowGlobally no statistical difference (or small difference) of pain intensity but less nausea in nefopam+fentanyl group (intervention) compared to fentanyl alone group (comparison). Also, there is at least a 50% reduction in fentanyl dose in the nefopam+fentanyl group (see dosing above, no difference in PCA volume between groups)."the balance between desirable and undesirable effects favors the intervention"Resources requiredHow large are the resource requirements (costs)?○ Large costs● Moderate costs○ Negligible costs and savings○ Moderate savings○ Large savings○ Varies○ Don't knowNefopam costs are very small in France (20 mg = $0.39; between $1.56 and $2.34 per day usually, 2016 prices in Montpellier Hospitals) but must probably depend on the country.Not available in the US and Canada.Countries where nefopam was available in 2010:BAHRAIN - TABLETS ONLYBELGIUMCHILEDOMINICAN REPUBLICEGYPTEQUATOR - TABLETS ONLYFRANCEGERMANY - TABLETS ONLYHAITIHONG KONG - TABLETS ONLYIRLANDLUXEMBOURGMALAISIAMALTAMAURITIUSMEXICONEW ZEALAND - TABLETS ONLYOMANPAKISTANPANANAQATARSALVADORSINGAPOUR - TABLETS ONLYSWITZERLANDTHE BARBADOS - TABLETS ONLYUNITED ARAB EMIRATESUNITED KINGDOM"moderate costs"because this study used a PCA device but not the drug costsCertainty of evidence of required resourcesWhat is the certainty of the evidence of resource requirements (costs)?○ Very low● Low○ Moderate○ HighCost and availability not known in every countrySee above.Cost effectivenessDoes the cost-effectiveness of the intervention favor the intervention or the comparison?○ Favors the comparison○ Probably favors the comparison○ Does not favor either the intervention or the comparison● Probably favors the intervention○ Favors the intervention○ Varies○ No included studiesPCA was used in the two groups (no increased costs related to the PCA that was used in the two groups).Regarding the drug: nefopam might be less or more expensive than fentanyl (depends on local costs). Also to take into consideration, if nausea is less frequent, antiemetic drugs should be less required for rescue (this should decrease the averall cost of the drugs).NB: ramosetron was systematically given in both groups to reduce nausea. cost-effectiveness "probably" favors the interventionEquityWhat would be the impact on health equity?○ Reduced○ Probably reduced● Probably no impact○ Probably increased○ IncreasedAcceptabilityIs the intervention acceptable to key stakeholders?○ No○ Probably no○ Probably yes○ Yes● Variesthe intervention is acceptable to key stakeholders "Probably YES" However, this requires patient's acceptation based on her/his preference:- some patients prefer avoiding opioids because of a past experience of nausea- some patients prefer, or do not prefer, using a PCA device FeasibilityIs the intervention feasible to implement?○ No○ Probably no○ Probably yes○ Yes● Varies○ Don't knowNefopam is widely available but not in all countries(please, see the countries where nefopam is available above)."Varies"Summary of judgementsJudgementImplicationsProblemNoProbably noProbably yesYesVariesDon't knowDesirable EffectsTrivialSmallModerateLargeVariesDon't knowUndesirable EffectsLargeModerateSmallTrivialVariesDon't knowCertainty of evidenceVery lowLowModerateHighNo included studiesValuesImportant uncertainty or variabilityPossibly important uncertainty or variabilityProbably no important uncertainty or variabilityNo important uncertainty or variabilityNo known undesirable outcomesBalance of effectsFavors the comparisonProbably favors the comparisonDoes not favor either the intervention or the comparisonProbably favors the interventionFavors the interventionVariesDon't knowResources requiredLarge costsModerate costsNegligible costs and savingsModerate savingsLarge savingsVariesDon't knowCertainty of evidence of required resourcesVery lowLowModerateHighNo included studiesCost effectivenessFavors the comparisonProbably favors the comparisonDoes not favor either the intervention or the comparisonProbably favors the interventionFavors the interventionVariesNo included studiesEquityReducedProbably reducedProbably no impactProbably increasedIncreasedVariesDon't knowAcceptabilityNoProbably noProbably yesYesVariesDon't knowFeasibilityNoProbably noProbably yesYesVariesDon't knowShould adjunctive nefopam vs. no adjunctive nefopam be used for ICU pain management (5.2)?Type of recommendationStrong recommendation against the interventionConditional recommendation against the interventionConditional recommendation for either the intervention or the comparisonConditional recommendation for the interventionStrong recommendation for the intervention○ ○ ○ ● ○ RecommendationWe suggest that adjunctive nefopam (if available) can be used to decrease opioid dose and nausea while treating pain in ICU patients (at risk of opioid side effects) (+2C). no recommendationnausea considered in previous recommendation comparing nefopam vs fentanyl groups; no clinical outcomes difference, reduction in side effectsJustificationOverall justificationOnly one moderate size, moderate quality (8% of excluded patients, no intent to treat analysis) doube blind RCT in 184 postcardiac SICU patients able to use a PCA device.-> Level B of evidence because the RCT is downgraded.Detailed justificationProblemVery selected ICU population. However, generalization of the results to another kind of population is likely because pain is frequent in postcardiac SICU patients.FeasibilityPatients able to use a PCA device. These promising results need to be also found in patients unable to use a PCA device (non communicant patients). However, 62% of nefopam +fentanyl infusion was provided continuously (not by PCA) at H12, and 77% at H48.Subgroup considerationsImplementation considerationsAvailability of nefopam in some countries, availability of a PCA device in some ICUs. Monitoring and evaluationAnalgesic related side effects or outcomes should be assessed more largely including:-delirium-ileus-duration of MV weaning-LOS in ICU and hospitalResearch prioritiesThis is top priority to investigate adjunctive analgesics that could decrease opioids dose to treat pain in ICU patients.These promising results require that this study be replicated:- in medical ICU and noncardiac SICU patients- non communicant patients- using a more common mode of drug administration in ICU patients who are sometimes non communicant (a continuous infusion with boli and/or an intermittent administration, but provided by the nurse based on behavioral pain tools, instead of a PCA device needing the participation of the patient)comments during electronic Voting by Entire panelAdding nefopam did not appear to change pain over time; do lower fentanyl doses translate into clinical benefit?Nausea (side effect) has a risk of bias in this specific population; Inexperience using this medication mitigates enthusiasmRephrazing to consider nefopam alone vs opioid alone: should adjunctive nefopam or nefopam alone (vs. an opioid alone) be used…? Very low quality of evidence, how can a decision be stated? Question: Nefopam compared to Opioids for ICU Patients (5.1) Setting: Post-operative Cardiac Surgery Patients Bibliography: Kim K., Kim WJ., Choi DK., Lee YK, Choi I., Sim J. The analgesic efficacy and safety of nefopam in patient-controlled analgesia after cardiac surgery: A randomized, double-blind, prospective study. Journal of International Medical Research: 42(3), 684-692. Quality assessment№ of patientsEffectQualityImportance№ of studiesStudy designRisk of biasInconsistencyIndirectnessImprecisionOther considerationsNefopamOpioidsRelative(95% CI)Absolute(95% CI)Pain at rest at 24 hours (follow up: mean 24 Hours; assessed with: Visual Analogue Scale; Scale from: 0 to 10)1 randomised trials serious anot serious not serious bserious cnone 92 92 - mean 0.23 mean higher(0.21 lower to 0.68 higher) ????LOW IMPORTANT Pain with movement at 24 hours (follow up: mean 24 hours; assessed with: Visual Analogue Scale; Scale from: 0 to 10)1 randomised trials serious anot serious not serious bserious cnone 92 92 - mean 0.14 mean higher(0.28 lower to 0.56 higher) ????LOW IMPORTANT Pain at rest at 48 hours (assessed with: Visual Analogue Scale)1 randomised trials serious anot serious not serious bserious cnone 92 92 - MD 0.25 higher(0.553 lower to 0.053 higher) ????LOW IMPORTANT Pain with movement at 48 hours (follow up: mean 24 hours; assessed with: Visual Analogue Scale; Scale from: 0 to 10)1 randomised trials serious anot serious not serious bserious c,dnone 92 92 - MD 0.41 higher(0.081 higher to 0.739 higher) ????LOW IMPORTANT CI: Confidence interval; MD: Mean differenceExplanationsa. Randomization method not described, no intention to treat with 24/300 loss to follow-up, blinding described b. Only included CVICU patients in this study, however analgesic efficacy may be broadly applicable to all ICU patients c. Large confidence intervals, cannot determine if value of nefopam independently d. Confidence Intervals do not cross zero (no effect) - however small sample size hard to draw conclusion on nefopam effects QuestionShould Nefopam vs. Opioids be used for ICU Patients (5.1)?Population:ICU Patients (5.1)Background:Intervention:NefopamComparison:OpioidsMain outcomes:Pain at rest at 24 hours; Pain with movement at 24 hours; Pain at rest at 48 hours; Pain with movement at 48 hours;Setting:Post-operative Cardiac Surgery PatientsPerspective:AssessmentJudgementResearch evidenceAdditional considerationsProblemIs the problem a priority?○ No○ Probably no○ Probably yes● Yes○ Varies○ Don't knowIt is top priority to investigate the effectiveness/side effects of Non opioid analgesics compared to opioids in order to decrease opioids related side effects that are especially at risk in ICU patients:- respiratory depression- neurological impairment (decreased vigilance, delirium)- ileus, nausea vomiting, etc...Kim et al. 2014PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaW08L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA [1]n=276 patients scheduled to undergo cardiac surgery were randomly assigned between threePCA groups (92 patients per group): nefopam, fentanyl or nefopam + fentanyl.Each drug was given continuously + in PCA mode. NB (1): For Question 5.1, we only take into consideration nefopam group versus fentanyl group.Pain assessment:at rest and during movementat 12, 24, 36, 48 and 72 h after surgery using a visual analogue scale (VAS)NB (2): The evidence table reported only pain at rest and with movement at H24 and H48.Doses:nefopam group:nefopam 4 mg/hbolus: nefopam 2 mg (lock out ime = 15 min) fentanyl group:fentanyl 20 ?g/hbolus: fentanyl 10 ?g (lock out ime = 15 min)nefopam+fentanyl group:nefopam 1.86 mg/h + fentanyl 9.4 ?g/hbolus: nefopam 0.93 mg + fentanyl 4.7 ?g(lock out ime = 15 min for every group) Desirable EffectsHow substantial are the desirable anticipated effects?○ Trivial● Small○ Moderate○ Large○ Varies○ Don't knowThis study has a "Non inferiority design"According to the study design, there was no inferiority of nefopam compared to fentanyl(VAS non significant at H24 at rest and during movement).VAS also non significant at H12, 24, 36, 48, 72 at rest, as well as during movement at H12, 24, 36, 72.The VAS difference between group is only significant during movement at H48: MD 0.41 higher (0.081 higher to 0.739 higher)i.e. VAS higher in nefopam group compared to fentanyl group "large" desirable anticipated effects because nefopam did as well as fentanyl, a good point for nefopam if we would like to spare opioids.Is nefopan better than opioids? Different approach from the one we used in previous questions. Small effect.-agrees; large would mean that nefopam is better than opioids; small-agrees with smallGroup consensus for "small effects"Undesirable EffectsHow substantial are the undesirable anticipated effects?○ Large○ Moderate● Small○ Trivial○ Varies○ Don't know"small" undesirable anticipated effects because on the contrary,nausea was less frequent in the nefopam group (11%) compared to the fentanyl group (27%), p<0.05.-No significant difference between groups for:tachycardia, sweating, sedation, dyspnea, prutirus, vomiting. (All adverse events were reported during the first 48 hours).-could be moved to moderate conisdeing that they were fewer side effects with nefopam; are their adverse effects of nefopam that could be detrimental?-delirium (but not reported)-curious to know how they found out about nausea in MV patients: moderate or small would be fine -small because the difference is not large between the 2 groupsnefopam has small undesirable effects compare to opioidsCertainty of evidenceWhat is the overall certainty of the evidence of effects?○ Very low● Low○ Moderate○ High○ No included studiesn=92 patients per group is a small group for John Centofanti. There was an important ROB:Randomization method not described, no intention to treat with 24/300 loss to follow-up Reasons for non completion of the study:-duration of intubation > or = 48h: n=11 (it is not precised the timing of begining of the PCA with continuous mode, only that ot was "initiated postoperatively")-repeat surgery within 72h: n=5-reintubation in ICU: n=4-malfunctionning PCA device: n=4 "moderate" certainty of the evidence of effects because of:- a moderate to important size (almost 100!)- a double blinded designbut- only one study- with an important ROB- imprecision noted (CI) + ROB assessment- Low because only one study; power analysis missing; non-significant resultsGroup: keep "low"ValuesIs there important uncertainty about or variability in how much people value the main outcomes?○ Important uncertainty or variability○ Possibly important uncertainty or variability○ Probably no important uncertainty or variability● No important uncertainty or variability○ No known undesirable outcomesExcept for nausea, other classical opioid related side effects were not decreased nor investigated (respiratory rate, ileus, delirium...). "Possibly" important uncertainty or variabilityIn previous questions, we referred to pain scores as the main outcome. VAS is a valid and accepted measure.Balance of effectsDoes the balance between desirable and undesirable effects favor the intervention or the comparison?○ Favors the comparison○ Probably favors the comparison○ Does not favor either the intervention or the comparison● Probably favors the intervention○ Favors the intervention○ Varies○ Don't knowGlobaly no statistical difference (or small difference) of pain intensity but less nausea in nefopam group (intervention) compared to fentanyl group (comparison).Gerald: "the balance between desirable and undesirable effects favors the intervention" because:-Probably favors because the only difference was for nausea; only one study too- balancing between nefopam and opioids-also consider the possibility to reduce exposure to opioids Resources requiredHow large are the resource requirements (costs)?○ Large costs● Moderate costs○ Negligible costs and savings○ Moderate savings○ Large savings○ Varies○ Don't knowNefopam costs are very small in France (20 mg = $0.39; between $1.56 and $2.34 per day usually, 2016 prices in Montpellier Hospitals) but must probably depend on the country.Not available in the US and Canada.Countries where nefopam was available in 2010:See above for list of countries where marketed"moderate costs" because this study used a PCA device but not regarding the drug costsCertainty of evidence of required resourcesWhat is the certainty of the evidence of resource requirements (costs)?○ Very low● Low○ Moderate○ Higg○ No included studiesSee above.Cost effectivenessDoes the cost-effectiveness of the intervention favor the intervention or the comparison?○ Favors the comparison○ Probably favors the comparison○ Does not favor either the intervention or the comparison● Probably favors the intervention○ Favors the intervention○ Varies○ No included studiesPCA was used in the two groups (no increased costs related to the PCA that was used in the two groups).Regarding the drug: nefopam might be less or more expensive than fentanyl (depends on local costs).Also to take into consideration, if nausea is less frequent, antiemetic drugs should be less required for rescue (this should decrease the averall cost of the drugs).NB: ramostron was systematically given in both groups to reduce nausea.cost-effectiveness "probably" favors the interventionEquityWhat would be the impact on health equity?○ Reduced○ Probably reduced● Probably no impact○ Probably increased○ Increased○ Varies○ Don't knowAcceptabilityIs the intervention acceptable to key stakeholders?○ No○ Probably no○ Probably yes○ Yes● Varies○ Don't knowintervention is acceptable to key stakeholders "Probably YES"because this requires patient's acceptation based on her/his preference:- some patients prefer avoiding opioids because of a past experience of nausea for example- some patients prefer, or do not prefer, using a PCA device It varies because of the availability of the drug and the use of PCA.Varies because also depends on patient's preference.FeasibilityIs the intervention feasible to implement?○ No○ Probably no○ Probably yes○ Yes● Varies○ Don't knowNefopam is widely available but not in all countries (Canada and the US for example... but these guidelines are international :) "varies"Summary of judgementsJudgementImplicationsProblemNoProbably noProbably yesYesVariesDon't knowDesirable EffectsTrivialSmallModerateLargeVariesDon't knowUndesirable EffectsLargeModerateSmallTrivialVariesDon't knowCertainty of evidenceVery lowLowModerateHighNo included studiesValuesImportant uncertainty or variabilityPossibly important uncertainty or variabilityProbably no important uncertainty or variabilityNo important uncertainty or variabilityNo known undesirable outcomesBalance of effectsFavors the comparisonProbably favors the comparisonDoes not favor either the intervention or the comparisonProbably favors the interventionFavors the interventionVariesDon't knowResources requiredLarge costsModerate costsNegligible costs and savingsModerate savingsLarge savingsVariesDon't knowCertainty of evidence of required resourcesVery lowLowModerateHighNo included studiesCost effectivenessFavors the comparisonProbably favors the comparisonDoes not favor either the intervention or the comparisonProbably favors the interventionFavors the interventionVariesNo included studiesEquityReducedProbably reducedProbably no impactProbably increasedIncreasedVariesDon't knowAcceptabilityNoProbably noProbably yesYesVariesDon't knowFeasibilityNoProbably noProbably yesYesVariesDon't knowShould Nefopam vs. Opioids be used for ICU Patients (5.1)?Type of recommendationStrong recommendation against the interventionConditional recommendation against the interventionConditional recommendation for either the intervention or the comparisonConditional recommendation for the interventionStrong recommendation for the intervention○ ○ ● ○ ○ RecommendationWe suggest that nefopam (if available) can be an alternative to opioids to?treat pain in ICU patients, especially in case of?opioids contraindication (+2C).Change "might" with "can"; keep it general and specify in the justification the sub-group considerations.JustificationOverall justificationOnly one moderate size, moderate quality (8% of excluded patients, no intent to treat analysis) doube blind RCT in 184 postcardiac SICU patients able to use a PCA device.-> Level B of evidence because the RCT is downgraded.Detailed justificationProblemVery selected ICU population. However, generalization of the results to another kind of population is likely because pain is frequent in postcardiac SICU patients.FeasibilityPatients were able to use a PCA device. These promising results need to be also found in patients unable to use a PCA device (non communicant patients). However, 63% of nefopam infusion was provided continuously (not by PCA) at H12, and 83% at H48.Subgroup considerationsCardiac surgery patientsImplementation considerationsAvailability of nefopam in some countries, availability of a PCA device in some ICUs.Monitoring and evaluationAnalgesic related side effects or outcomes should be assessed more largely including:-delirium-ileus-duration of MV weaning-LOS in ICU and hospitalResearch prioritiesThis is top priority to investigate alternative analgesics?to opioids to treat pain in ICU patients.These promising results require that this study be replicated:- in medical ICU and noncardiac SICU patients/ - non-communicative patients- using a more common mode of drug administration in ICU patients who are challenged when communicating?(e.g. a continuous infusion with boluses and/or an intermittent administration, provided by the nurse based on behavioral pain tools, instead of a PCA device needing the participation of the patient)comments during electronic Voting by Entire panelNefopam of uncertain benefit for pain given no change at most time points- despite non-inferiority trial. Although fentanyl dose lower, how did that translate into a clinical benefit? Nausea finding has risk of bias (specific patient population); Limited applicability to US. Rephrazing to consider nefopam alone vs opioid alone: adjunctive nefopam or nefopam alone (vs. an opioid alone) be used…? Should we consider this opiate-sparing strategy? Very low quality of evidence, how can a decision be stated? Inexperience using this medication mitigates enthusiasmQuestion: Adjunctive paracetamol compared to no adjunctive paracetamol for ICU pain management (5.2) Setting: Intensive Care Unit Quality assessment№ of patientsEffectQualityImportance№ of studiesStudy designRisk of biasInconsistencyIndirectnessImprecisionOther conside-rationsadjunctive paracetamolno adjunctive paracetamolRelative(95% CI)Absolute(95% CI)VAS Score at 24 hours postoperatively (in cm)2 randomised trials serious anot serious not serious bnot serious none 76 77 - MD 0.46 lower(0.69 lower to 0.23 lower) ????MODERATE CRITICAL Mean BPS Pain Scores until patient extubated1 randomised trials very serious cnot serious not serious dserious enone 20 20 - MD 1.98 lower(2.98 lower to 0.98 lower) ????VERY LOW CRITICAL Pain Score at extubation1 randomised trials very serious cnot serious not serious dserious enone 20 20 - MD 1.1 lower(1.73 lower to 0.47 lower) ????VERY LOW CRITICAL Time to extubation (minutes)1 randomised trials very serious cnot serious not serious dserious enone 20 20 - MD 140.2 lower(192.7 lower to 87.7 lower) ????VERY LOW CRITICAL Rescue Doses of Morphine1 randomised trials not serious not serious not serious fserious gnone 8/56 (14.3%) 14/57 (24.6%) OR 0.51(0.20 to 1.34) 103 fewer per 1,000(from 58 more to 184 fewer) ????MODERATE CRITICAL Opioid Consumption (in Morphine equivalents)2 randomised trials serious anot serious not serious bnot serious none 76 77 - MD 4.54 lower(6.6 lower to 2.47 lower) ????MODERATE CRITICAL CI: Confidence interval; MD: Mean difference; OR: Odds ratioExplanations a. 1 study has low ROB, however the 2nd study was high ROB due to lack of blinding, no intention to treat and unclear randomization process b. Includes both postoperative cardiac surgery and abdominal surgery patients c. No blinding, unclear randomization process, no intention to treat d. Includes only abdominal surgery ICU pts. Lowered due to very small sample size f. Includes only cardiac surgery ICU patients g.OR CI cannot rule out harm at upper limit QuestionShould adjunctive paracetamol vs. no adjunctive paracetamol be used for ICU pain management (5.2)?Population:ICU pain management (5.2)Background:Intervention:adjunctive paracetamolComparison:no adjunctive paracetamolMain outcomes:VAS Score at 24 hours postoperatively (in cm); Mean BPS Pain Scores until patient extubated; Pain Score at extubation; Time to extubation (minutes); Rescue Doses of Morphine; Opioid Consumption (in Morphine equivalents);Setting:Intensive Care UnitPerspective:AssessmentJudgementResearch evidenceAdditional considerationsProblemIs the problem a priority?○ No○ Probably no○ Probably yes● Yes○ Varies○ Don't knowIt is top priority to investigate the effectiveness/side effects of Adjunctive Non opioid analgesics to opioids compared to opioids alone in order to decrease opioids related side effects that are especially at risk in ICU patients: - respiratory depression- neurological impairment (decreased vigilance, delirium)- ileus, nausea vomiting, etc... Two single center RCT in ICU patients after a scheduled surgery- Cattabriga 2007 ADDIN EN.CITE <EndNote><Cite><Author>Cattabriga</Author><Year>2007</Year><RecNum>1890</RecNum><DisplayText>[2]</DisplayText><record><rec-number>1890</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232811">1890</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cattabriga, Iolter</author><author>Pacini, Davide</author><author>Lamazza, Gaia</author><author>Talarico, Francesco</author><author>Di Bartolomeo, Roberto</author><author>Grillone, Giovanni</author><author>Bacchi-Reggiani, Letizia</author></authors></contributors><auth-address>Department of Anesthesia and Intensive Care, Sant'Orsola-Malpighi Hospital, University of Bologna, Italy. iolter.cattabriga@fastwebnet.it</auth-address><titles><title>Intravenous paracetamol as adjunctive treatment for postoperative pain after cardiac surgery: a double blind randomized controlled trial</title><secondary-title>Eur. J. Cardiothorac. Surg.</secondary-title></titles><periodical><full-title>Eur. J. Cardiothorac. Surg.</full-title></periodical><pages>527-531</pages><volume>32</volume><number>3</number><dates><year>2007</year><pub-dates><date>2007/9</date></pub-dates></dates><isbn>1010-7940</isbn><urls><related-urls><url> Papers/C/Cattabriga et al. 2007 - Intravenous paracetamol as adjunctive treatmen ... ain after cardiac surgery - a double blind randomized controlled trial.pdf</url></pdf-urls></urls><electronic-resource-num>10.1016/j.ejcts.2007.05.017</electronic-resource-num></record></Cite></EndNote>[2]: cardiac surgery, n=113, low ROB- Memis 2010 ADDIN EN.CITE <EndNote><Cite><Author>Memis</Author><Year>2010</Year><RecNum>1891</RecNum><DisplayText>[3]</DisplayText><record><rec-number>1891</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232811">1891</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Memis, Dilek</author><author>Inal, Mehmet Turan</author><author>Kavalci, Gulsum</author><author>Sezer, Atakan</author><author>Sut, Necdet</author></authors></contributors><auth-address>Medical Faculty, Department of Anesthesiology and Reanimation, Trakya University, 22030 Edirne, Turkey. dilmemis@</auth-address><titles><title>Intravenous paracetamol reduced the use of opioids, extubation time, and opioid-related adverse effects after major surgery in intensive care unit</title><secondary-title>J. Crit. Care</secondary-title></titles><periodical><full-title>J. Crit. Care</full-title></periodical><pages>458-462</pages><volume>25</volume><number>3</number><dates><year>2010</year><pub-dates><date>2010/9</date></pub-dates></dates><isbn>0883-9441</isbn><urls><related-urls><url>(10)00012-2</url><url>(10)00012-2</url></related-urls><pdf-urls><url>All Papers/M/Memis et al. 2010 - Intravenous paracetamol reduced the use of opioids, ... oid-related adverse effects after major surgery in intensive care unit.pdf</url></pdf-urls></urls><electronic-resource-num>10.1016/j.jcrc.2009.12.012</electronic-resource-num></record></Cite></EndNote>[3]: abdominal surgery, n=40, unblinded, high ROB Intervention:Adjunct IV paracetamol 1g/6hrs in both studies- Cattabriga ADDIN EN.CITE <EndNote><Cite><Author>Cattabriga</Author><Year>2007</Year><RecNum>1890</RecNum><DisplayText>[2]</DisplayText><record><rec-number>1890</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232811">1890</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cattabriga, Iolter</author><author>Pacini, Davide</author><author>Lamazza, Gaia</author><author>Talarico, Francesco</author><author>Di Bartolomeo, Roberto</author><author>Grillone, Giovanni</author><author>Bacchi-Reggiani, Letizia</author></authors></contributors><auth-address>Department of Anesthesia and Intensive Care, Sant'Orsola-Malpighi Hospital, University of Bologna, Italy. iolter.cattabriga@fastwebnet.it</auth-address><titles><title>Intravenous paracetamol as adjunctive treatment for postoperative pain after cardiac surgery: a double blind randomized controlled trial</title><secondary-title>Eur. J. Cardiothorac. Surg.</secondary-title></titles><periodical><full-title>Eur. J. Cardiothorac. Surg.</full-title></periodical><pages>527-531</pages><volume>32</volume><number>3</number><dates><year>2007</year><pub-dates><date>2007/9</date></pub-dates></dates><isbn>1010-7940</isbn><urls><related-urls><url> Papers/C/Cattabriga et al. 2007 - Intravenous paracetamol as adjunctive treatmen ... ain after cardiac surgery - a double blind randomized controlled trial.pdf</url></pdf-urls></urls><electronic-resource-num>10.1016/j.ejcts.2007.05.017</electronic-resource-num></record></Cite></EndNote>[2]: for 72 hours, opioid= tramadol + rescue morphine- Memis ADDIN EN.CITE <EndNote><Cite><Author>Memis</Author><Year>2010</Year><RecNum>1891</RecNum><DisplayText>[3]</DisplayText><record><rec-number>1891</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232811">1891</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Memis, Dilek</author><author>Inal, Mehmet Turan</author><author>Kavalci, Gulsum</author><author>Sezer, Atakan</author><author>Sut, Necdet</author></authors></contributors><auth-address>Medical Faculty, Department of Anesthesiology and Reanimation, Trakya University, 22030 Edirne, Turkey. dilmemis@</auth-address><titles><title>Intravenous paracetamol reduced the use of opioids, extubation time, and opioid-related adverse effects after major surgery in intensive care unit</title><secondary-title>J. Crit. Care</secondary-title></titles><periodical><full-title>J. Crit. Care</full-title></periodical><pages>458-462</pages><volume>25</volume><number>3</number><dates><year>2010</year><pub-dates><date>2010/9</date></pub-dates></dates><isbn>0883-9441</isbn><urls><related-urls><url>(10)00012-2</url><url>(10)00012-2</url></related-urls><pdf-urls><url>All Papers/M/Memis et al. 2010 - Intravenous paracetamol reduced the use of opioids, ... oid-related adverse effects after major surgery in intensive care unit.pdf</url></pdf-urls></urls><electronic-resource-num>10.1016/j.jcrc.2009.12.012</electronic-resource-num></record></Cite></EndNote>[3]: for 24 hours, opioid= mepiridine + rescue mepiridinePain measurement:VAS in Cattabriga ADDIN EN.CITE <EndNote><Cite><Author>Cattabriga</Author><Year>2007</Year><RecNum>1890</RecNum><DisplayText>[2]</DisplayText><record><rec-number>1890</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232811">1890</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cattabriga, Iolter</author><author>Pacini, Davide</author><author>Lamazza, Gaia</author><author>Talarico, Francesco</author><author>Di Bartolomeo, Roberto</author><author>Grillone, Giovanni</author><author>Bacchi-Reggiani, Letizia</author></authors></contributors><auth-address>Department of Anesthesia and Intensive Care, Sant'Orsola-Malpighi Hospital, University of Bologna, Italy. iolter.cattabriga@fastwebnet.it</auth-address><titles><title>Intravenous paracetamol as adjunctive treatment for postoperative pain after cardiac surgery: a double blind randomized controlled trial</title><secondary-title>Eur. J. Cardiothorac. Surg.</secondary-title></titles><periodical><full-title>Eur. J. Cardiothorac. Surg.</full-title></periodical><pages>527-531</pages><volume>32</volume><number>3</number><dates><year>2007</year><pub-dates><date>2007/9</date></pub-dates></dates><isbn>1010-7940</isbn><urls><related-urls><url> Papers/C/Cattabriga et al. 2007 - Intravenous paracetamol as adjunctive treatmen ... ain after cardiac surgery - a double blind randomized controlled trial.pdf</url></pdf-urls></urls><electronic-resource-num>10.1016/j.ejcts.2007.05.017</electronic-resource-num></record></Cite></EndNote>[2] (/6h till H72, at rest and during deep breath),mean VAS after extubation in Memis (at H24 postextubation);mean BPS before and at extubation in MemisDesirable EffectsHow substantial are the desirable anticipated effects?○ Trivial○ Small● Moderate○ Large○ Varies○ Don't knowMean BPS before extubation (Memis) ADDIN EN.CITE <EndNote><Cite><Author>Memis</Author><Year>2010</Year><RecNum>1891</RecNum><DisplayText>[3]</DisplayText><record><rec-number>1891</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232811">1891</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Memis, Dilek</author><author>Inal, Mehmet Turan</author><author>Kavalci, Gulsum</author><author>Sezer, Atakan</author><author>Sut, Necdet</author></authors></contributors><auth-address>Medical Faculty, Department of Anesthesiology and Reanimation, Trakya University, 22030 Edirne, Turkey. dilmemis@</auth-address><titles><title>Intravenous paracetamol reduced the use of opioids, extubation time, and opioid-related adverse effects after major surgery in intensive care unit</title><secondary-title>J. Crit. Care</secondary-title></titles><periodical><full-title>J. Crit. Care</full-title></periodical><pages>458-462</pages><volume>25</volume><number>3</number><dates><year>2010</year><pub-dates><date>2010/9</date></pub-dates></dates><isbn>0883-9441</isbn><urls><related-urls><url>(10)00012-2</url><url>(10)00012-2</url></related-urls><pdf-urls><url>All Papers/M/Memis et al. 2010 - Intravenous paracetamol reduced the use of opioids, ... oid-related adverse effects after major surgery in intensive care unit.pdf</url></pdf-urls></urls><electronic-resource-num>10.1016/j.jcrc.2009.12.012</electronic-resource-num></record></Cite></EndNote>[3] : MD 3 fewer (3 fewer to 1 fewer) (5.7 versus 3.7)Mean BPS at extubation (Memis) ADDIN EN.CITE <EndNote><Cite><Author>Memis</Author><Year>2010</Year><RecNum>1891</RecNum><DisplayText>[3]</DisplayText><record><rec-number>1891</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232811">1891</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Memis, Dilek</author><author>Inal, Mehmet Turan</author><author>Kavalci, Gulsum</author><author>Sezer, Atakan</author><author>Sut, Necdet</author></authors></contributors><auth-address>Medical Faculty, Department of Anesthesiology and Reanimation, Trakya University, 22030 Edirne, Turkey. dilmemis@</auth-address><titles><title>Intravenous paracetamol reduced the use of opioids, extubation time, and opioid-related adverse effects after major surgery in intensive care unit</title><secondary-title>J. Crit. Care</secondary-title></titles><periodical><full-title>J. Crit. Care</full-title></periodical><pages>458-462</pages><volume>25</volume><number>3</number><dates><year>2010</year><pub-dates><date>2010/9</date></pub-dates></dates><isbn>0883-9441</isbn><urls><related-urls><url>(10)00012-2</url><url>(10)00012-2</url></related-urls><pdf-urls><url>All Papers/M/Memis et al. 2010 - Intravenous paracetamol reduced the use of opioids, ... oid-related adverse effects after major surgery in intensive care unit.pdf</url></pdf-urls></urls><electronic-resource-num>10.1016/j.jcrc.2009.12.012</electronic-resource-num></record></Cite></EndNote>[3]: MD 1 fewer (1.7 fewer to 0.5 fewer) (3.6 versus 2.5 -> it is weird to show a result of mean BPS < 3??)Forrest plot for VAS (cm) supposed to be at rest in both studies = -0.5 [-0.7 to -0.2]In fact, Cattabriga has the highest weight (highest reduction in VAS) but no difference in opioid consumption. Inversely, there was a less important reduction of VAS in Memis ADDIN EN.CITE <EndNote><Cite><Author>Memis</Author><Year>2010</Year><RecNum>1891</RecNum><DisplayText>[3]</DisplayText><record><rec-number>1891</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232811">1891</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Memis, Dilek</author><author>Inal, Mehmet Turan</author><author>Kavalci, Gulsum</author><author>Sezer, Atakan</author><author>Sut, Necdet</author></authors></contributors><auth-address>Medical Faculty, Department of Anesthesiology and Reanimation, Trakya University, 22030 Edirne, Turkey. dilmemis@</auth-address><titles><title>Intravenous paracetamol reduced the use of opioids, extubation time, and opioid-related adverse effects after major surgery in intensive care unit</title><secondary-title>J. Crit. Care</secondary-title></titles><periodical><full-title>J. Crit. Care</full-title></periodical><pages>458-462</pages><volume>25</volume><number>3</number><dates><year>2010</year><pub-dates><date>2010/9</date></pub-dates></dates><isbn>0883-9441</isbn><urls><related-urls><url>(10)00012-2</url><url>(10)00012-2</url></related-urls><pdf-urls><url>All Papers/M/Memis et al. 2010 - Intravenous paracetamol reduced the use of opioids, ... oid-related adverse effects after major surgery in intensive care unit.pdf</url></pdf-urls></urls><electronic-resource-num>10.1016/j.jcrc.2009.12.012</electronic-resource-num></record></Cite></EndNote>[3]but a significant reduction in opioid consumption.I think is mathematical/logical. Adjunct paracetamol has "additional" analgesic effect.NB: mean VAS are low in all groups in both studies (means or medians < 3)Forrest plot for opioid consumption (mg morphine equivalents, within 24h for Memis; 72h for Cattabriga ADDIN EN.CITE <EndNote><Cite><Author>Cattabriga</Author><Year>2007</Year><RecNum>1890</RecNum><DisplayText>[2]</DisplayText><record><rec-number>1890</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232811">1890</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cattabriga, Iolter</author><author>Pacini, Davide</author><author>Lamazza, Gaia</author><author>Talarico, Francesco</author><author>Di Bartolomeo, Roberto</author><author>Grillone, Giovanni</author><author>Bacchi-Reggiani, Letizia</author></authors></contributors><auth-address>Department of Anesthesia and Intensive Care, Sant'Orsola-Malpighi Hospital, University of Bologna, Italy. iolter.cattabriga@fastwebnet.it</auth-address><titles><title>Intravenous paracetamol as adjunctive treatment for postoperative pain after cardiac surgery: a double blind randomized controlled trial</title><secondary-title>Eur. J. Cardiothorac. Surg.</secondary-title></titles><periodical><full-title>Eur. J. Cardiothorac. Surg.</full-title></periodical><pages>527-531</pages><volume>32</volume><number>3</number><dates><year>2007</year><pub-dates><date>2007/9</date></pub-dates></dates><isbn>1010-7940</isbn><urls><related-urls><url> Papers/C/Cattabriga et al. 2007 - Intravenous paracetamol as adjunctive treatmen ... ain after cardiac surgery - a double blind randomized controlled trial.pdf</url></pdf-urls></urls><electronic-resource-num>10.1016/j.ejcts.2007.05.017</electronic-resource-num></record></Cite></EndNote>[2]) = -4.5 [-6.6 to -2.5] -was the forrest plot mean the consumption per 24h or was it an "overall" forest plot taking into account the consumption within 24h in Memis and in 72h in Catabriga?Rescue dose of morphine (Cattabriga ADDIN EN.CITE <EndNote><Cite><Author>Cattabriga</Author><Year>2007</Year><RecNum>1890</RecNum><DisplayText>[2]</DisplayText><record><rec-number>1890</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232811">1890</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cattabriga, Iolter</author><author>Pacini, Davide</author><author>Lamazza, Gaia</author><author>Talarico, Francesco</author><author>Di Bartolomeo, Roberto</author><author>Grillone, Giovanni</author><author>Bacchi-Reggiani, Letizia</author></authors></contributors><auth-address>Department of Anesthesia and Intensive Care, Sant'Orsola-Malpighi Hospital, University of Bologna, Italy. iolter.cattabriga@fastwebnet.it</auth-address><titles><title>Intravenous paracetamol as adjunctive treatment for postoperative pain after cardiac surgery: a double blind randomized controlled trial</title><secondary-title>Eur. J. Cardiothorac. Surg.</secondary-title></titles><periodical><full-title>Eur. J. Cardiothorac. Surg.</full-title></periodical><pages>527-531</pages><volume>32</volume><number>3</number><dates><year>2007</year><pub-dates><date>2007/9</date></pub-dates></dates><isbn>1010-7940</isbn><urls><related-urls><url> Papers/C/Cattabriga et al. 2007 - Intravenous paracetamol as adjunctive treatmen ... ain after cardiac surgery - a double blind randomized controlled trial.pdf</url></pdf-urls></urls><electronic-resource-num>10.1016/j.ejcts.2007.05.017</electronic-resource-num></record></Cite></EndNote>[2]) : OR 0.51 (0.20 to 1.34)Other outcomes:Time to extubation in minutes (Memis ADDIN EN.CITE <EndNote><Cite><Author>Memis</Author><Year>2010</Year><RecNum>1891</RecNum><DisplayText>[3]</DisplayText><record><rec-number>1891</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232811">1891</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Memis, Dilek</author><author>Inal, Mehmet Turan</author><author>Kavalci, Gulsum</author><author>Sezer, Atakan</author><author>Sut, Necdet</author></authors></contributors><auth-address>Medical Faculty, Department of Anesthesiology and Reanimation, Trakya University, 22030 Edirne, Turkey. dilmemis@</auth-address><titles><title>Intravenous paracetamol reduced the use of opioids, extubation time, and opioid-related adverse effects after major surgery in intensive care unit</title><secondary-title>J. Crit. Care</secondary-title></titles><periodical><full-title>J. Crit. Care</full-title></periodical><pages>458-462</pages><volume>25</volume><number>3</number><dates><year>2010</year><pub-dates><date>2010/9</date></pub-dates></dates><isbn>0883-9441</isbn><urls><related-urls><url>(10)00012-2</url><url>(10)00012-2</url></related-urls><pdf-urls><url>All Papers/M/Memis et al. 2010 - Intravenous paracetamol reduced the use of opioids, ... oid-related adverse effects after major surgery in intensive care unit.pdf</url></pdf-urls></urls><electronic-resource-num>10.1016/j.jcrc.2009.12.012</electronic-resource-num></record></Cite></EndNote>[3]): MD 140 fewer (193 fewer to 88 fewer)Sedation score (1 to 5 points scale) significantly lower in Memis (= less sedated)Nausea lower in Memis ADDIN EN.CITE <EndNote><Cite><Author>Memis</Author><Year>2010</Year><RecNum>1891</RecNum><DisplayText>[3]</DisplayText><record><rec-number>1891</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232811">1891</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Memis, Dilek</author><author>Inal, Mehmet Turan</author><author>Kavalci, Gulsum</author><author>Sezer, Atakan</author><author>Sut, Necdet</author></authors></contributors><auth-address>Medical Faculty, Department of Anesthesiology and Reanimation, Trakya University, 22030 Edirne, Turkey. dilmemis@</auth-address><titles><title>Intravenous paracetamol reduced the use of opioids, extubation time, and opioid-related adverse effects after major surgery in intensive care unit</title><secondary-title>J. Crit. Care</secondary-title></titles><periodical><full-title>J. Crit. Care</full-title></periodical><pages>458-462</pages><volume>25</volume><number>3</number><dates><year>2010</year><pub-dates><date>2010/9</date></pub-dates></dates><isbn>0883-9441</isbn><urls><related-urls><url>(10)00012-2</url><url>(10)00012-2</url></related-urls><pdf-urls><url>All Papers/M/Memis et al. 2010 - Intravenous paracetamol reduced the use of opioids, ... oid-related adverse effects after major surgery in intensive care unit.pdf</url></pdf-urls></urls><electronic-resource-num>10.1016/j.jcrc.2009.12.012</electronic-resource-num></record></Cite></EndNote>[3], Nausea NS in Cattabriga ADDIN EN.CITE <EndNote><Cite><Author>Cattabriga</Author><Year>2007</Year><RecNum>1890</RecNum><DisplayText>[2]</DisplayText><record><rec-number>1890</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232811">1890</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cattabriga, Iolter</author><author>Pacini, Davide</author><author>Lamazza, Gaia</author><author>Talarico, Francesco</author><author>Di Bartolomeo, Roberto</author><author>Grillone, Giovanni</author><author>Bacchi-Reggiani, Letizia</author></authors></contributors><auth-address>Department of Anesthesia and Intensive Care, Sant'Orsola-Malpighi Hospital, University of Bologna, Italy. iolter.cattabriga@fastwebnet.it</auth-address><titles><title>Intravenous paracetamol as adjunctive treatment for postoperative pain after cardiac surgery: a double blind randomized controlled trial</title><secondary-title>Eur. J. Cardiothorac. Surg.</secondary-title></titles><periodical><full-title>Eur. J. Cardiothorac. Surg.</full-title></periodical><pages>527-531</pages><volume>32</volume><number>3</number><dates><year>2007</year><pub-dates><date>2007/9</date></pub-dates></dates><isbn>1010-7940</isbn><urls><related-urls><url> Papers/C/Cattabriga et al. 2007 - Intravenous paracetamol as adjunctive treatmen ... ain after cardiac surgery - a double blind randomized controlled trial.pdf</url></pdf-urls></urls><electronic-resource-num>10.1016/j.ejcts.2007.05.017</electronic-resource-num></record></Cite></EndNote>[2]ICU LOS, respiratory depression, reintubation, pruritus: NS in MemisRespiratory rate significantly lower in paracetamol group at H12 only in Cattabriga"moderate" desirable anticipated effectsbecause mean VAS are low in all groups in both studies but there is a significant reduction of VAS and opioid consumption.Undesirable EffectsHow substantial are the undesirable anticipated effects?○ Large○ Moderate○ Small● Trivial○ Varies○ Don't know"small" undesirable anticipated effectsbecause no adverse outcome was reported, on the contrary: decreased duration of MV and nausea in one studyParacetamol is a safe drug if dose is appropriately given (according to patient's weight, renal insuficiency). Otherwise, there is a risk of hepatitis and renal failure. Not assessed in these studies.Question: No adverse events reported, what about vital parameters (e.g., blood pressure)? in association with dosing smalldon't knowno differences in BP between groups in Cattabriga ADDIN EN.CITE <EndNote><Cite><Author>Cattabriga</Author><Year>2007</Year><RecNum>1890</RecNum><DisplayText>[2]</DisplayText><record><rec-number>1890</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232811">1890</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cattabriga, Iolter</author><author>Pacini, Davide</author><author>Lamazza, Gaia</author><author>Talarico, Francesco</author><author>Di Bartolomeo, Roberto</author><author>Grillone, Giovanni</author><author>Bacchi-Reggiani, Letizia</author></authors></contributors><auth-address>Department of Anesthesia and Intensive Care, Sant'Orsola-Malpighi Hospital, University of Bologna, Italy. iolter.cattabriga@fastwebnet.it</auth-address><titles><title>Intravenous paracetamol as adjunctive treatment for postoperative pain after cardiac surgery: a double blind randomized controlled trial</title><secondary-title>Eur. J. Cardiothorac. Surg.</secondary-title></titles><periodical><full-title>Eur. J. Cardiothorac. Surg.</full-title></periodical><pages>527-531</pages><volume>32</volume><number>3</number><dates><year>2007</year><pub-dates><date>2007/9</date></pub-dates></dates><isbn>1010-7940</isbn><urls><related-urls><url> Papers/C/Cattabriga et al. 2007 - Intravenous paracetamol as adjunctive treatmen ... ain after cardiac surgery - a double blind randomized controlled trial.pdf</url></pdf-urls></urls><electronic-resource-num>10.1016/j.ejcts.2007.05.017</electronic-resource-num></record></Cite></EndNote>[2] and Memis ADDIN EN.CITE <EndNote><Cite><Author>Memis</Author><Year>2010</Year><RecNum>1891</RecNum><DisplayText>[3]</DisplayText><record><rec-number>1891</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232811">1891</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Memis, Dilek</author><author>Inal, Mehmet Turan</author><author>Kavalci, Gulsum</author><author>Sezer, Atakan</author><author>Sut, Necdet</author></authors></contributors><auth-address>Medical Faculty, Department of Anesthesiology and Reanimation, Trakya University, 22030 Edirne, Turkey. dilmemis@</auth-address><titles><title>Intravenous paracetamol reduced the use of opioids, extubation time, and opioid-related adverse effects after major surgery in intensive care unit</title><secondary-title>J. Crit. Care</secondary-title></titles><periodical><full-title>J. Crit. Care</full-title></periodical><pages>458-462</pages><volume>25</volume><number>3</number><dates><year>2010</year><pub-dates><date>2010/9</date></pub-dates></dates><isbn>0883-9441</isbn><urls><related-urls><url>(10)00012-2</url><url>(10)00012-2</url></related-urls><pdf-urls><url>All Papers/M/Memis et al. 2010 - Intravenous paracetamol reduced the use of opioids, ... oid-related adverse effects after major surgery in intensive care unit.pdf</url></pdf-urls></urls><electronic-resource-num>10.1016/j.jcrc.2009.12.012</electronic-resource-num></record></Cite></EndNote>[3]trivial (of little value or importance)Trivial based on information we haveCertainty of evidenceWhat is the overall certainty of the evidence of effects?○ Very low○ Low● Moderate○ High○ No included studiesTwo RCTs but single center, one double blinded with a low ROB (Cattabriga) ADDIN EN.CITE <EndNote><Cite><Author>Cattabriga</Author><Year>2007</Year><RecNum>1890</RecNum><DisplayText>[2]</DisplayText><record><rec-number>1890</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232811">1890</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cattabriga, Iolter</author><author>Pacini, Davide</author><author>Lamazza, Gaia</author><author>Talarico, Francesco</author><author>Di Bartolomeo, Roberto</author><author>Grillone, Giovanni</author><author>Bacchi-Reggiani, Letizia</author></authors></contributors><auth-address>Department of Anesthesia and Intensive Care, Sant'Orsola-Malpighi Hospital, University of Bologna, Italy. iolter.cattabriga@fastwebnet.it</auth-address><titles><title>Intravenous paracetamol as adjunctive treatment for postoperative pain after cardiac surgery: a double blind randomized controlled trial</title><secondary-title>Eur. J. Cardiothorac. Surg.</secondary-title></titles><periodical><full-title>Eur. J. Cardiothorac. Surg.</full-title></periodical><pages>527-531</pages><volume>32</volume><number>3</number><dates><year>2007</year><pub-dates><date>2007/9</date></pub-dates></dates><isbn>1010-7940</isbn><urls><related-urls><url> Papers/C/Cattabriga et al. 2007 - Intravenous paracetamol as adjunctive treatmen ... ain after cardiac surgery - a double blind randomized controlled trial.pdf</url></pdf-urls></urls><electronic-resource-num>10.1016/j.ejcts.2007.05.017</electronic-resource-num></record></Cite></EndNote>[2], one unblinded with a high ROB, that was also a very small size study (Memis) ADDIN EN.CITE <EndNote><Cite><Author>Memis</Author><Year>2010</Year><RecNum>1891</RecNum><DisplayText>[3]</DisplayText><record><rec-number>1891</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232811">1891</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Memis, Dilek</author><author>Inal, Mehmet Turan</author><author>Kavalci, Gulsum</author><author>Sezer, Atakan</author><author>Sut, Necdet</author></authors></contributors><auth-address>Medical Faculty, Department of Anesthesiology and Reanimation, Trakya University, 22030 Edirne, Turkey. dilmemis@</auth-address><titles><title>Intravenous paracetamol reduced the use of opioids, extubation time, and opioid-related adverse effects after major surgery in intensive care unit</title><secondary-title>J. Crit. Care</secondary-title></titles><periodical><full-title>J. Crit. Care</full-title></periodical><pages>458-462</pages><volume>25</volume><number>3</number><dates><year>2010</year><pub-dates><date>2010/9</date></pub-dates></dates><isbn>0883-9441</isbn><urls><related-urls><url>(10)00012-2</url><url>(10)00012-2</url></related-urls><pdf-urls><url>All Papers/M/Memis et al. 2010 - Intravenous paracetamol reduced the use of opioids, ... oid-related adverse effects after major surgery in intensive care unit.pdf</url></pdf-urls></urls><electronic-resource-num>10.1016/j.jcrc.2009.12.012</electronic-resource-num></record></Cite></EndNote>[3]. "moderate" certainty of the evidenceValuesIs there important uncertainty about or variability in how much people value the main outcomes?○ Important uncertainty or variability○ Possibly important uncertainty or variability○ Probably no important uncertainty or variability● No important uncertainty or variability○ No known undesirable outcomes"Probably no important" uncertainty or variability Celine: No important uncertainty when we have solid measures of outcomes (pain scores, opioid doses)Balance of effectsDoes the balance between desirable and undesirable effects favor the intervention or the comparison?○ Favors the comparison○ Probably favors the comparison○ Does not favor either the intervention or the comparison● Probably favors the intervention○ Favors the intervention○ Varies○ Don't knowProbably favors the interventionbecause significant reduction in VAS and opioid consumption and probably lower rate of adverse outcomes (in the lowest quality study)Resources requiredHow large are the resource requirements (costs)?○ Large costs○ Moderate costs○ Negligible costs and savings○ Moderate savings○ Large savings● Varies○ Don't knowIV Paracetamol in not expensive in France (Price in Montpellier hospitals in 2016): $0.69 for 1 gramm IV ($2.76 for 4 gramms a day).Is it the same case in the US/Canada?Not available in CanadaNegligible costs and savingsbecause IV paracetamol is not expensive and because it is associated with savings related to reduced opioid consumption.costs will vary based on the countryCertainty of evidence of required resourcesWhat is the certainty of the evidence of resource requirements (costs)?○ Very low○ Low○ Moderate○ High● No included studiesNot addressed in the 2 RCTsCost effectivenessDoes the cost-effectiveness of the intervention favor the intervention or the comparison?○ Favors the comparison○ Probably favors the comparison○ Does not favor either the intervention or the comparison○ Probably favors the intervention○ Favors the intervention○ Varies● No included studiesNot addressed in the 2 RCTsProbably favors the intervention EquityWhat would be the impact on health equity?○ Reduced○ Probably reduced● Probably no impact○ Probably increased○ Increased○ Varies○ Don't knowAcceptabilityIs the intervention acceptable to key stakeholders?○ No○ Probably no● Probably yes○ Yes○ Varies○ Don't knowConsidering all routes of administration "Probably YES"FeasibilityIs the intervention feasible to implement?○ No○ Probably no○ Probably yes● Yes○ Varies○ Don't knowthe intervention is feasible to implement-> "YES"because systematic administration of paracetamol is easy to implementSummary of judgementsJudgementImplicationsProblemNoProbably noProbably yesYesVariesDon't knowDesirable EffectsTrivialSmallModerateLargeVariesDon't knowUndesirable EffectsLargeModerateSmallTrivialVariesDon't knowCertainty of evidenceVery lowLowModerateHighNo included studiesValuesImportant uncertainty or variabilityPossibly important uncertainty or variabilityProbably no important uncertainty or variabilityNo important uncertainty or variabilityNo known undesirable outcomesBalance of effectsFavors the comparisonProbably favors the comparisonDoes not favor either the intervention or the comparisonProbably favors the interventionFavors the interventionVariesDon't knowResources requiredLarge costsModerate costsNegligible costs and savingsModerate savingsLarge savingsVariesDon't knowCertainty of evidence of required resourcesVery lowLowModerateHighNo included studiesCost effectivenessFavors the comparisonProbably favors the comparisonDoes not favor either the intervention or the comparisonProbably favors the interventionFavors the interventionVariesNo included studiesEquityReducedProbably reducedProbably no impactProbably increasedIncreasedVariesDon't knowAcceptabilityNoProbably noProbably yesYesVariesDon't knowFeasibilityNoProbably noProbably yesYesVariesDon't knowShould adjunctive paracetamol vs. no adjunctive paracetamol be used for ICU pain management (5.2)?Type of recommendationStrong recommendation against the interventionConditional recommendation against the interventionConditional recommendation for either the intervention or the comparisonConditional recommendation for the interventionStrong recommendation for the intervention○ ○ ○ ● ○ RecommendationWe suggest that adjunctive paracetamol might be used to decrease pain intensity and opioid consumption in ICU patients (+2C).Remove "IV" because not part of the question; keep the recommendation generalRCTs done with IV paracetamolIV comparable to po route of administration in previous studiesJustificationOverall justificationTwo RCT but single centers, one of very low quality (unblinded, high ROB, small size).-> level of evidence C because the study that showed less undesirable effects has a low quality (unblinded, hogh ROB), it was downgraded to C. The high quality study that showed the highest reduction in VAS showed also low VAS in both groups and no additional effects.Detailed justificationProblemSurgical ICU population (one cardiac, one abdominal, both scheduled). However, generalization of the results to another kind of population is likely because pain is frequent in SICU patients as in medical ICU patients.Subgroup considerationsCardiac and abdominal surgery patientsImplementation considerationsNoneIV route not available in Canada, and expensive in US - but other routes can be used Monitoring and evaluationPain assessmentAnalgesic related side effects or outcomes should be assessed more largely including:-delirium-ileus-duration of MV weaning-LOS in ICU and hospital Paracetamol related side effects should be assessed more specifically: increased serum liver enzymes (acute hepatitis), decreased liver and kidney functionResearch prioritiesThis is top priority to investigate analgesics that can decrease the use or dose of opioids to treat pain in ICU patients. These promising results require that these studies be replicated:- in medical ICU; other surgeries and trauma- non-verbal patients (only one small size study assessed the BPS before extubationOther routes of paracetamol administration to be investigatedcomments during electronic Voting by Entire panelwith very low quality of evidence should the recommendation be as stated? or re-phrased to indicate you cannot make a recommendation?Question: Adjunctive ketamine compared to no adjunctive ketamine for ICU analgesic management (5.2) Setting: Intensive Care Unit Bibliography: Quality assessment№ of patientsEffectQualityImportance№ of studiesStudy designRisk of biasInconsistencyIndirectnessImprecisionOther considerationsadjunctive ketamineno adjunctive ketamineRelative(95% CI)Absolute(95% CI)Cumulative morphine consumption (follow up: mean 48 hours; assessed with: dose (mg))1 randomised trials serious anot serious serious bnot serious none 41 52 - MD 22 mg fewer(14 fewer to 30 fewer) ????LOW IMPORTANT VAS score at rest (follow up: mean 48 hours; assessed with: VAS score (mm); Scale from: 0 to 100)1 randomised trials serious anot serious serious bserious cnone 41 52 - MD 3 mm lower(10.88 lower to 4.88 higher) ????VERY LOW CRITICAL VAS score with movement (follow up: mean 48 hours; assessed with: VAS Score (mm); Scale from: 0 to 100)1 randomised trials serious anot serious serious bserious cnone 41 52 - MD 4 mm lower(15.02 lower to 7.02 higher) ????VERY LOW CRITICAL CI: Confidence interval; MD: Mean differenceExplanationsa. Unclear randomization process and location concealment, no intention to treat analysis, b. Only postoperative major abdominal surgery patients included c. Unclear benefit, small sample size QuestionShould adjunctive ketamine vs. no adjunctive ketamine be used for ICU analgesic management (5.2)?Population:ICU analgesic management (5.2)Background:Intervention:adjunctive ketamineComparison:no adjunctive ketamineMain outcomes:Cumulative morphine consumption; VAS score at rest; VAS score with movement;Setting:Intensive Care UnitPerspective:AssessmentJudgementResearch evidenceAdditional considerationsProblemIs the problem a priority?○ No○ Probably no○ Probably yes● Yes○ Varies○ Don't knowIt is top priority to investigate the effectiveness/side effects of Adjunctive Non opioid analgesics to opioids compared to opioids alone in order to decrease opioids related side effects that are especially at risk in ICU patients: - respiratory depression- neurological impairment (decreased vigilance, delirium)- ileus, nausea vomiting, etc...One single center double-blinded RCT in 93 postscheduled abdominal surgery ICU patients, high ROB (unclear randomization process and location concealment, no intention to treat analysis despite 8 patients excluded after enrollment) -> Guillou 2003 ADDIN EN.CITE <EndNote><Cite><Author>Guillou</Author><Year>2003</Year><RecNum>1894</RecNum><DisplayText>[4]</DisplayText><record><rec-number>1894</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232811">1894</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Guillou, Nicolas</author><author>Tanguy, Michèle</author><author>Seguin, Philippe</author><author>Branger, Bernard</author><author>Campion, Jean-Pierre</author><author>Mallédant, Yannick</author></authors></contributors><auth-address>Surgical Intensive Care Unit, H?pital Pontchaillou, Rennes, France.</auth-address><titles><title>The effects of small-dose ketamine on morphine consumption in surgical intensive care unit patients after major abdominal surgery</title><secondary-title>Anesth. Analg.</secondary-title></titles><periodical><full-title>Anesth. Analg.</full-title></periodical><pages>843-847</pages><volume>97</volume><number>3</number><dates><year>2003</year><pub-dates><date>2003/9</date></pub-dates></dates><isbn>0003-2999</isbn><urls><related-urls><url> Papers/G/Guillou et al. 2003 - The effects of small-dose ketamine on morphine con ... n surgical intensive care unit patients after major abdominal surgery.pdf</url></pdf-urls></urls></record></Cite></EndNote>[4] two parallel groups:1) morphine PCA + ketamine initial loading charge + kétamine continuous infusion2) morphine PCA + placebo loading charge + placebo continuous infusionNB: intervention began after patients' awakening in the ICU Pain intensity at rest at H48 (VAS in mm; 0-100):MD 3 mm lower (11 mm lower to 5 mm higher) -> NSPain intensity at mobilization at H48 (VAS in mm; 0-100):MD 4 mm lower (15 mm lower to 7 mm higher) -> NSNote than mean VAS were small in both groupsMorphine consumption at H48 (mg)MD 22 mg fewer (30 fewer to 14 fewer)Side effects were NS: nausea, confusion, hallucinations, hypoventilation, pruritus;Ramsay scale similar in the two groupsDesirable EffectsHow substantial are the desirable anticipated effects?○ Trivial● Small○ Moderate○ Large○ Varies○ Don't know"Small desirabe anticipated effects"because in favour to the intervention (adjunctive ketamine) group:- Small difference in VAS at every time points (p<0.05 only at H16, H44 at test; at H16, H20, H40 at mobilization)- Significant but small difference in cumulative morphine consumption at each time point (every 4-hours from H4 to H48): 22mg at H48 = a mean of 11 mg/24hUndesirable EffectsHow substantial are the undesirable anticipated effects?○ Large○ Moderate○ Small○ Trivial○ Varies● Don't know"don't know undesirabe anticipated effects"because adverse effects that were measured were not frequent but the method for assessing confusion is not described, other adverse effects related to ketamine were not reported, such as nightmare, anxiety, and delirium. Some of the adverse effects related to opioids were not reported either: ileusCertainty of evidenceWhat is the overall certainty of the evidence of effects?● Very low○ Low○ Moderate○ High○ No included studiesOnly one single small size RCT with a high ROB: unclear randomization process and location concealment, no intention to treat analysis despite 8 patients excluded after enrollment low" certainty of the evidence fo the effectsChange with "very low" for consistency with evidence tableValuesIs there important uncertainty about or variability in how much people value the main outcomes?○ Important uncertainty or variability○ Possibly important uncertainty or variability○ Probably no important uncertainty or variability● No important uncertainty or variability○ No known undesirable outcomes Possibly important uncertainty or variability" because the desirable effects are small and the undesirable effects seem to be small but under-reported: delirium should be measured with valid tools; psychodysleptic effects related to ketamine should be reportedNo important uncertainty about main outcomes (pain scores, opioids)Balance of effectsDoes the balance between desirable and undesirable effects favor the intervention or the comparison?○ Favors the comparison○ Probably favors the comparison○ Does not favor either the intervention or the comparison○ Probably favors the intervention○ Favors the intervention○ Varies● Don't know"don't know if the balance between desirable and undesirable effects favor the intervention or the comparison" because small desirable effects but don't know about the undesirable effectsResources requiredHow large are the resource requirements (costs)?○ Large costs● Moderate costs○ Negligible costs and savings○ Moderate savings○ Large savings○ Varies○ Don't knowKetamine costs are small. "moderate costs"because this study used a PCA deviceCertainty of evidence of required resourcesWhat is the certainty of the evidence of resource requirements (costs)?○ Very low○ Low○ Moderate○ High● No included studiesSee aboveCost effectivenessDoes the cost-effectiveness of the intervention favor the intervention or the comparison?○ Favors the comparison○ Probably favors the comparison○ Does not favor either the intervention or the comparison○ Probably favors the intervention○ Favors the intervention○ Varies● No included studiesNot addressed in this studyCost-effectiveness "Does not favor either the intervention or the comparison"because the PCA device is used in both groups, the ketamine costs are small,the desirable effects are small, the undesirable effects are unknownEquityWhat would be the impact on health equity?○ Reduced○ Probably reduced● Probably no impact○ Probably increased○ Increased○ Varies○ Don't knowAcceptabilityIs the intervention acceptable to key stakeholders?○ No○ Probably no● Probably yes○ Yes○ Varies○ Don't knowIs the intervention acceptable to key stakeholders? "-> "Probably YES"However, this requires patient's acceptation based on her/his preference:- some patients prefer, or do not prefer, using a PCA device -for some patients, ketamine may not be acceptableFeasibilityIs the intervention feasible to implement?○ No○ Probably no● Probably yes○ Yes○ Varies○ Don't knowimplementation feasibility "varies"because it depends on the PCA availability; probably yes because it's feasible to implement ketamineSummary of judgementsJudgementImplicationsProblemNoProbably noProbably yesYesVariesDon't knowDesirable EffectsTrivialSmallModerateLargeVariesDon't knowUndesirable EffectsLargeModerateSmallTrivialVariesDon't knowCertainty of evidenceVery lowLowModerateHighNo included studiesValuesImportant uncertainty or variabilityPossibly important uncertainty or variabilityProbably no important uncertainty or variabilityNo important uncertainty or variabilityNo known undesirable outcomesBalance of effectsFavors the comparisonProbably favors the comparisonDoes not favor either the intervention or the comparisonProbably favors the interventionFavors the interventionVariesDon't knowResources requiredLarge costsModerate costsNegligible costs and savingsModerate savingsLarge savingsVariesDon't knowCertainty of evidence of required resourcesVery lowLowModerateHighNo included studiesCost effectivenessFavors the comparisonProbably favors the comparisonDoes not favor either the intervention or the comparisonProbably favors the interventionFavors the interventionVariesNo included studiesEquityReducedProbably reducedProbably no impactProbably increasedIncreasedVariesDon't knowAcceptabilityNoProbably noProbably yesYesVariesDon't knowFeasibilityNoProbably noProbably yesYesVariesDon't knowShould adjunctive ketamine vs. no adjunctive ketamine be used for ICU analgesic management (5.2)?Type of recommendationStrong recommendation against the interventionConditional recommendation against the interventionConditional recommendation for either the intervention or the comparisonConditional recommendation for the interventionStrong recommendation for the intervention○ ○ ● ○ ○ RecommendationWe suggest that either adjunctive ketamine along with morphine or morphine alone be used to treat postoperative pain in ICU patients (+2C).Remove PCA. Consider meta-analysis reports in our recommendation?utility in ICU is understudiedJustificationOnly one single small size low quality RCT in ICU patients.-> level of evidence downgraded to CAlso to take into consideration the recent reviews regarding ketamine to prevent/treat postoperative pain ("Ketamine added to morphine or hydromorphone patient-controlled analgesia for acute postoperative pain in adults: a systematic review and meta-analysis of randomized trials, by Wang et al. Canadian Journal of anesthesia 2016" and "Benefit and harm of adding ketamine to an opioid in a patient-controlled analgesia device for the control of postoperative pain: systematic review and meta-analyses of randomized controlled trials with trial sequential analyses, by Assouline et al. Pain december 2016). Authors’ conclusions are pretty different: 1) Wang, CJA/JCA 2016 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYW5nPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA [5]Adding ketamine to morphine/hydromorphone PCA provides a small improvement in postoperative analgesia while reducing opioid requirements. Adjunctive ketamine also reduces postoperative nausea and vomiting without a detected increase in other adverse effects; however, adverse events were probably underreported. 2) Assouline, Pain 2016 ADDIN EN.CITE <EndNote><Cite><Author>Assouline</Author><Year>2016</Year><RecNum>1893</RecNum><DisplayText>[6]</DisplayText><record><rec-number>1893</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232811">1893</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Assouline, Benjamin</author><author>Tramèr, Martin R.</author><author>Kreienbühl, Lukas</author><author>Elia, Nadia</author></authors></contributors><auth-address>aDivision of Anaesthesiology, Department of Anaesthesiology, Pharmacology and Intensive Care Medicine, Geneva University Hospitals, Geneva, Switzerland bFaculty of Medicine, University of Geneva, Geneva, Switzerland cInstitute of Global Health, University of Geneva, Department of Community Medicine, Primary Care and Emergency Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland.</auth-address><titles><title>Benefit and harm of adding ketamine to an opioid in a patient-controlled analgesia device for the control of postoperative pain: systematic review and meta-analyses of randomized controlled trials with trial sequential analyses</title><secondary-title>Pain</secondary-title></titles><periodical><full-title>Pain</full-title></periodical><pages>2854-2864</pages><volume>157</volume><number>12</number><dates><year>2016</year><pub-dates><date>2016/12</date></pub-dates></dates><isbn>0304-3959</isbn><urls><related-urls><url> Papers/A/Assouline et al. 2016 - Benefit and harm of adding ketamine to an opioid ... ematic review and meta-analyses of randomized controlled trials [...].pdf</url></pdf-urls></urls><electronic-resource-num>10.1097/j.pain.0000000000000705</electronic-resource-num></record></Cite></EndNote>[6]Trial sequential analyses confirmed the significant benefit of ketamine on pain intensity, cumulative morphine consumption, and postoperative nausea and vomiting and its inability to double the risk of hallucination. The available data did not allow us to make a conclusion on respiratory adverse events or to establish dose-responsiveness.Subgroup considerationsabdominal surgeryImplementation considerationsAvailability of a PCA device in some ICUs.Monitoring and evaluationAnalgesic related adverse effects or outcomes should be assessed more largely including:-delirium assessed with validated tools for ICU patients-psychodysleptic effects related to ketamine (hallucinations, delusion, nightmare, anxiety...)-ileus-duration of MV weaning-LOS in ICU and hospitalResearch prioritiesThis is top priority to investigate analgesics that can decrease the use or dose of opioids to treat pain in ICU patients. There is only one negative study in postoperative abdominal surgery ICU patients. Recent updated reviews (2016) of trials investigating the effect of adjunctive ketamine to opioids administered with PCA to treat postoperative pain show a significant reduction in pain intensity, opioid consumption, nausea/vomiting. Other side effects like delirium could have been under reported. Future studies are required:- in medical ICU patients experiencing severe pain at rest (pancreatitis for example)- in medical and surgical ICU patients, especially non communicant patients at the early stage of sedation-analgesia, via a continuous infusion of ketamine without the need of a PCA-patient's preference and satisfaction with ketamine-other RCTs necessary in an ICU contextcomments during electronic Voting by Entire panelWhere is the level of evidence? Broad recommendation for post-op. pain in one study with high ROB; no guidance to clinicians on when it might be (in)appropriate.Primary ketamine infusions for sedation and analgesia? need to be clear this is not a first line therapy…Our "suggest" recommendation could change clinician's practice given growing interest in ketamine. Caution: high risk of bias in the single study & the most important psychiatric side effects of ketamine is unreported. Need clinical benefits beyond reduced opioid consumption, psychiatric side effect analysis, good sample and low ROB.Question: Adjunct neuropathic agent compared to no adjunct neuropathic drug for ICU pain management (5.2) Setting: Medical and Surgical ICUs Bibliography: Quality assessment№ of patientsEffectQualityImportance№ of studiesStudy designRisk of biasInconsistencyIndirectnessImprecisionOther considerationsadjunct neuropathic agentno adjunct neuropathic drugRelative(95% CI)Absolute(95% CI)# of patients with VRS >=2/4, 10 hours post-extubation1 randomised trials serious anot serious not serious bserious cnone 3/29 (10.3%) 12/31 (38.7%) RR 0.27(0.08 to 0.85) 283 fewer per 1,000(from 58 fewer to 356 fewer) ????LOW CRITICAL Opioid consumption in first 24 hours (morphine equivalent)4 randomised trials serious dnot serious not serious not serious none 97 97 - MD 13.54 lower(14.57 lower to 12.5 lower) ????MODERATE CRITICAL Time to Extubation (hours)2 randomised trials serious anot serious not serious bserious enone 49 51 - MD 0.36 higher(0.7 lower to 1.43 higher) ????LOW CRITICAL ICU LOS2 randomised trials serious anot serious not serious bserious fnone 49 51 - MD 0.04 lower(0.46 lower to 0.38 higher) ????LOW CRITICAL NRS Score Day 4 after Neuropathic Agent initiated2 randomised trials not serious not serious not serious gnot serious none 42 30 - MD 3.44 lower(3.9 lower to 2.98 lower) ????HIGH CRITICAL Breakthrough pain in first 48hrs (average #/pt)1 randomised trials not serious not serious not serious serious enone 20 20 - MD 1.45 lower(2.13 lower to 0.77 lower) ????MODERATE CRITICAL CI: Confidence interval; RR: Risk ratio; MD: Mean differenceExplanations a. Unclear randomization process, no intention to treat with 10 patients excluded from analysis post-randomization b. Only includes cardiac surgery patients c. Low event-rate d. Unclear randomization, no intention to treat e. Small sample size f. Unclear if any benefit or harm g. Only includes patients with Guillain Barre QuestionShould adjunct neuropathic agent vs. no adjunct neuropathic drug be used for ICU pain management (5.2)?Population:ICU pain management (5.2)Background:Intervention:adjunct neuropathic agentComparison:no adjunct neuropathic drugMain outcomes:# of patients with VRS >=2/4, 10 hours post-extubation; Opioid consumption in first 24 hours (morphine equivalent); Time to Extubation (hours); ICU LOS; NRS Score Day 4 after Neuropathic Agent initiated; Breakthrough pain in first 48hrs (average #/pt);Setting:Medical and Surgical ICUsPerspective:AssessmentJudgementResearch evidenceAdditional considerationsProblemIs the problem a priority?○ No○ Probably no○ Probably yes● Yes○ Varies○ Don't knowIt is top priority to investigate the effectiveness/side effects of Adjunct Non opioid analgesics to opioids compared to opioids alone in order to decrease opioids related side effects that are especially at risk in ICU patients: - respiratory depression- neurological impairment (decreased vigilance, delirium)- ileus, nausea vomiting, etc... Also, opioids are not very effective to treat neuropathic pain compared to more specific analgesics (antineuropathic agents). If nociceptive pain is probably the most frequent mechanism of pain in ICU patients (medical, surgical illness and trauma; nociceptive care procedures), some patients can experiment a typical neuropathic pain as patients hospitalized in ICU for a Guillain-Barré syndrome. Four single center double blinded RCTs:Patients with Guillain-Barré syndrome : 2 RCTsPandey 2002 ADDIN EN.CITE <EndNote><Cite><Author>Pandey</Author><Year>2002</Year><RecNum>1898</RecNum><DisplayText>[7]</DisplayText><record><rec-number>1898</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232812">1898</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pandey, Chandra K.</author><author>Bose, Neeta</author><author>Garg, Garima</author><author>Singh, Namita</author><author>Baronia, Arvind</author><author>Agarwal, Anil</author><author>Singh, Prabhat K.</author><author>Singh, Uttam</author></authors></contributors><auth-address>Department of Anaesthesiology and Critical Care Medicine, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India. ckpandey@sgpgi.ac.in</auth-address><titles><title>Gabapentin for the treatment of pain in guillain-barré syndrome: a double-blinded, placebo-controlled, crossover study</title><secondary-title>Anesth. Analg.</secondary-title></titles><periodical><full-title>Anesth. Analg.</full-title></periodical><pages>1719-23, table of contents</pages><volume>95</volume><number>6</number><dates><year>2002</year><pub-dates><date>2002/12</date></pub-dates></dates><isbn>0003-2999</isbn><urls><related-urls><url> Papers/P/Pandey et al. 2002 - Gabapentin for the treatment of pain in guillain-barré syndrome - a double-blinded, placebo-controlled, crossover study.pdf</url></pdf-urls></urls></record></Cite></EndNote>[7](cross over design, n=18), Pandey 2005 ADDIN EN.CITE <EndNote><Cite><Author>Pandey</Author><Year>2005</Year><RecNum>1899</RecNum><DisplayText>[8]</DisplayText><record><rec-number>1899</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232812">1899</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pandey, Chandra Kant</author><author>Raza, Mehdi</author><author>Tripathi, Mukesh</author><author>Navkar, Deepa V.</author><author>Kumar, Abhishek</author><author>Singh, Uttam K.</author></authors></contributors><auth-address>Department of Anaesthesiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India. ckpandey@sgpgi.ac.in</auth-address><titles><title>The comparative evaluation of gabapentin and carbamazepine for pain management in Guillain-Barré syndrome patients in the intensive care unit</title><secondary-title>Anesth. Analg.</secondary-title></titles><periodical><full-title>Anesth. Analg.</full-title></periodical><pages>220-5, table of contents</pages><volume>101</volume><number>1</number><dates><year>2005</year><pub-dates><date>2005/7</date></pub-dates></dates><isbn>0003-2999</isbn><urls><related-urls><url> Papers/P/Pandey et al. 2005 - The comparative evaluation of gabapentin and carba ... agement in Guillain-Barré syndrome patients in the intensive care unit.pdf</url></pdf-urls></urls><electronic-resource-num>10.1213/01.ANE.0000152186.89020.36</electronic-resource-num></record></Cite></EndNote>[8] (parallel groups, n=12 x 3)ICU patients admitted after elective cardiac surgery : 2 RCTsPesonen 1997 ADDIN EN.CITE <EndNote><Cite><Author>Pesonen</Author><Year>2011</Year><RecNum>1896</RecNum><DisplayText>[9]</DisplayText><record><rec-number>1896</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232812">1896</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pesonen, A.</author><author>Suojaranta-Ylinen, R.</author><author>Hammarén, E.</author><author>Kontinen, V. K.</author><author>Raivio, P.</author><author>Tarkkila, P.</author><author>Rosenberg, P. H.</author></authors></contributors><auth-address>Department of Anaesthesiology and Intensive Care Medicine, Helsinki University Hospital, PO BOX 340, FIN-00029 HUS Helsinki, Finland. anne.pesonen@hus.fi</auth-address><titles><title>Pregabalin has an opioid-sparing effect in elderly patients after cardiac surgery: a randomized placebo-controlled trial</title><secondary-title>Br. J. Anaesth.</secondary-title></titles><periodical><full-title>Br. J. Anaesth.</full-title></periodical><pages>873-881</pages><volume>106</volume><number>6</number><dates><year>2011</year><pub-dates><date>2011/6</date></pub-dates></dates><isbn>0007-0912</isbn><urls><related-urls><url> Papers/P/Pesonen et al. 2011 - Pregabalin has an opioid-sparing effect in elderly patients after cardiac surgery - a randomized placebo-controlled trial.pdf</url></pdf-urls></urls><electronic-resource-num>10.1093/bja/aer083</electronic-resource-num></record></Cite></EndNote>[9] (parallel groups, n=29 vs n=31)Joshi 2013 ADDIN EN.CITE <EndNote><Cite><Author>Joshi</Author><Year>2013</Year><RecNum>1897</RecNum><DisplayText>[10]</DisplayText><record><rec-number>1897</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232812">1897</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Joshi, Shreedhar S.</author><author>Jagadeesh, A. M.</author></authors></contributors><auth-address>Department of Cardiac Anesthesiology, Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bangalore, Karnataka, India.</auth-address><titles><title>Efficacy of perioperative pregabalin in acute and chronic post-operative pain after off-pump coronary artery bypass surgery: a randomized, double-blind placebo controlled trial</title><secondary-title>Ann. Card. Anaesth.</secondary-title></titles><periodical><full-title>Ann. Card. Anaesth.</full-title></periodical><pages>180-185</pages><volume>16</volume><number>3</number><dates><year>2013</year><pub-dates><date>2013/7</date></pub-dates></dates><isbn>0971-9784</isbn><urls><related-urls><url>;[10] (parallel groups, n=20 vs n=20) Drugs:Gabapentin vs. placebo (Pandey 2002) ADDIN EN.CITE <EndNote><Cite><Author>Pandey</Author><Year>2002</Year><RecNum>1898</RecNum><DisplayText>[7]</DisplayText><record><rec-number>1898</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232812">1898</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pandey, Chandra K.</author><author>Bose, Neeta</author><author>Garg, Garima</author><author>Singh, Namita</author><author>Baronia, Arvind</author><author>Agarwal, Anil</author><author>Singh, Prabhat K.</author><author>Singh, Uttam</author></authors></contributors><auth-address>Department of Anaesthesiology and Critical Care Medicine, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India. ckpandey@sgpgi.ac.in</auth-address><titles><title>Gabapentin for the treatment of pain in guillain-barré syndrome: a double-blinded, placebo-controlled, crossover study</title><secondary-title>Anesth. Analg.</secondary-title></titles><periodical><full-title>Anesth. Analg.</full-title></periodical><pages>1719-23, table of contents</pages><volume>95</volume><number>6</number><dates><year>2002</year><pub-dates><date>2002/12</date></pub-dates></dates><isbn>0003-2999</isbn><urls><related-urls><url> Papers/P/Pandey et al. 2002 - Gabapentin for the treatment of pain in guillain-barré syndrome - a double-blinded, placebo-controlled, crossover study.pdf</url></pdf-urls></urls></record></Cite></EndNote>[7]Gabapentin vs. Carbamazepine vs. placebo (Pandey 2005) ADDIN EN.CITE <EndNote><Cite><Author>Pandey</Author><Year>2005</Year><RecNum>1899</RecNum><DisplayText>[8]</DisplayText><record><rec-number>1899</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232812">1899</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pandey, Chandra Kant</author><author>Raza, Mehdi</author><author>Tripathi, Mukesh</author><author>Navkar, Deepa V.</author><author>Kumar, Abhishek</author><author>Singh, Uttam K.</author></authors></contributors><auth-address>Department of Anaesthesiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India. ckpandey@sgpgi.ac.in</auth-address><titles><title>The comparative evaluation of gabapentin and carbamazepine for pain management in Guillain-Barré syndrome patients in the intensive care unit</title><secondary-title>Anesth. Analg.</secondary-title></titles><periodical><full-title>Anesth. Analg.</full-title></periodical><pages>220-5, table of contents</pages><volume>101</volume><number>1</number><dates><year>2005</year><pub-dates><date>2005/7</date></pub-dates></dates><isbn>0003-2999</isbn><urls><related-urls><url> Papers/P/Pandey et al. 2005 - The comparative evaluation of gabapentin and carba ... agement in Guillain-Barré syndrome patients in the intensive care unit.pdf</url></pdf-urls></urls><electronic-resource-num>10.1213/01.ANE.0000152186.89020.36</electronic-resource-num></record></Cite></EndNote>[8]Pregabalin vs. placebo (Pesonen 1997, Joshi 2013) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QZXNvbmVuPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48
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ADDIN EN.CITE.DATA [7, 8] studies, oxycodone in Pesonen ADDIN EN.CITE <EndNote><Cite><Author>Pesonen</Author><Year>2011</Year><RecNum>1896</RecNum><DisplayText>[9]</DisplayText><record><rec-number>1896</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232812">1896</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pesonen, A.</author><author>Suojaranta-Ylinen, R.</author><author>Hammarén, E.</author><author>Kontinen, V. K.</author><author>Raivio, P.</author><author>Tarkkila, P.</author><author>Rosenberg, P. H.</author></authors></contributors><auth-address>Department of Anaesthesiology and Intensive Care Medicine, Helsinki University Hospital, PO BOX 340, FIN-00029 HUS Helsinki, Finland. anne.pesonen@hus.fi</auth-address><titles><title>Pregabalin has an opioid-sparing effect in elderly patients after cardiac surgery: a randomized placebo-controlled trial</title><secondary-title>Br. J. Anaesth.</secondary-title></titles><periodical><full-title>Br. J. Anaesth.</full-title></periodical><pages>873-881</pages><volume>106</volume><number>6</number><dates><year>2011</year><pub-dates><date>2011/6</date></pub-dates></dates><isbn>0007-0912</isbn><urls><related-urls><url> Papers/P/Pesonen et al. 2011 - Pregabalin has an opioid-sparing effect in elderly patients after cardiac surgery - a randomized placebo-controlled trial.pdf</url></pdf-urls></urls><electronic-resource-num>10.1093/bja/aer083</electronic-resource-num></record></Cite></EndNote>[9], tramadol in Joshi ADDIN EN.CITE <EndNote><Cite><Author>Joshi</Author><Year>2013</Year><RecNum>1897</RecNum><DisplayText>[10]</DisplayText><record><rec-number>1897</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232812">1897</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Joshi, Shreedhar S.</author><author>Jagadeesh, A. M.</author></authors></contributors><auth-address>Department of Cardiac Anesthesiology, Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bangalore, Karnataka, India.</auth-address><titles><title>Efficacy of perioperative pregabalin in acute and chronic post-operative pain after off-pump coronary artery bypass surgery: a randomized, double-blind placebo controlled trial</title><secondary-title>Ann. Card. Anaesth.</secondary-title></titles><periodical><full-title>Ann. Card. Anaesth.</full-title></periodical><pages>180-185</pages><volume>16</volume><number>3</number><dates><year>2013</year><pub-dates><date>2013/7</date></pub-dates></dates><isbn>0971-9784</isbn><urls><related-urls><url>;[10]) MD 13.54 lower (14.57 lower to 12.5 lower)3. Time to extubation (hours): 2 RCTs in patients after elective cardiac surgery (Pesonen ADDIN EN.CITE <EndNote><Cite><Author>Pesonen</Author><Year>2011</Year><RecNum>1896</RecNum><DisplayText>[9]</DisplayText><record><rec-number>1896</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232812">1896</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pesonen, A.</author><author>Suojaranta-Ylinen, R.</author><author>Hammarén, E.</author><author>Kontinen, V. K.</author><author>Raivio, P.</author><author>Tarkkila, P.</author><author>Rosenberg, P. H.</author></authors></contributors><auth-address>Department of Anaesthesiology and Intensive Care Medicine, Helsinki University Hospital, PO BOX 340, FIN-00029 HUS Helsinki, Finland. anne.pesonen@hus.fi</auth-address><titles><title>Pregabalin has an opioid-sparing effect in elderly patients after cardiac surgery: a randomized placebo-controlled trial</title><secondary-title>Br. J. Anaesth.</secondary-title></titles><periodical><full-title>Br. J. Anaesth.</full-title></periodical><pages>873-881</pages><volume>106</volume><number>6</number><dates><year>2011</year><pub-dates><date>2011/6</date></pub-dates></dates><isbn>0007-0912</isbn><urls><related-urls><url> Papers/P/Pesonen et al. 2011 - Pregabalin has an opioid-sparing effect in elderly patients after cardiac surgery - a randomized placebo-controlled trial.pdf</url></pdf-urls></urls><electronic-resource-num>10.1093/bja/aer083</electronic-resource-num></record></Cite></EndNote>[9], Joshi ADDIN EN.CITE <EndNote><Cite><Author>Joshi</Author><Year>2013</Year><RecNum>1897</RecNum><DisplayText>[10]</DisplayText><record><rec-number>1897</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232812">1897</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Joshi, Shreedhar S.</author><author>Jagadeesh, A. M.</author></authors></contributors><auth-address>Department of Cardiac Anesthesiology, Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bangalore, Karnataka, India.</auth-address><titles><title>Efficacy of perioperative pregabalin in acute and chronic post-operative pain after off-pump coronary artery bypass surgery: a randomized, double-blind placebo controlled trial</title><secondary-title>Ann. Card. Anaesth.</secondary-title></titles><periodical><full-title>Ann. Card. Anaesth.</full-title></periodical><pages>180-185</pages><volume>16</volume><number>3</number><dates><year>2013</year><pub-dates><date>2013/7</date></pub-dates></dates><isbn>0971-9784</isbn><urls><related-urls><url>;[10])MD 0.36 higher (0.7 lower to 1.43 higher) -> NS4. ICU LOS (days): 2 RCTs in patients after elective cardiac surgery (Pesonen ADDIN EN.CITE <EndNote><Cite><Author>Pesonen</Author><Year>2011</Year><RecNum>1896</RecNum><DisplayText>[9]</DisplayText><record><rec-number>1896</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232812">1896</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pesonen, A.</author><author>Suojaranta-Ylinen, R.</author><author>Hammarén, E.</author><author>Kontinen, V. K.</author><author>Raivio, P.</author><author>Tarkkila, P.</author><author>Rosenberg, P. H.</author></authors></contributors><auth-address>Department of Anaesthesiology and Intensive Care Medicine, Helsinki University Hospital, PO BOX 340, FIN-00029 HUS Helsinki, Finland. anne.pesonen@hus.fi</auth-address><titles><title>Pregabalin has an opioid-sparing effect in elderly patients after cardiac surgery: a randomized placebo-controlled trial</title><secondary-title>Br. J. Anaesth.</secondary-title></titles><periodical><full-title>Br. J. Anaesth.</full-title></periodical><pages>873-881</pages><volume>106</volume><number>6</number><dates><year>2011</year><pub-dates><date>2011/6</date></pub-dates></dates><isbn>0007-0912</isbn><urls><related-urls><url> Papers/P/Pesonen et al. 2011 - Pregabalin has an opioid-sparing effect in elderly patients after cardiac surgery - a randomized placebo-controlled trial.pdf</url></pdf-urls></urls><electronic-resource-num>10.1093/bja/aer083</electronic-resource-num></record></Cite></EndNote>[9], Joshi ADDIN EN.CITE <EndNote><Cite><Author>Joshi</Author><Year>2013</Year><RecNum>1897</RecNum><DisplayText>[10]</DisplayText><record><rec-number>1897</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232812">1897</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Joshi, Shreedhar S.</author><author>Jagadeesh, A. M.</author></authors></contributors><auth-address>Department of Cardiac Anesthesiology, Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bangalore, Karnataka, India.</auth-address><titles><title>Efficacy of perioperative pregabalin in acute and chronic post-operative pain after off-pump coronary artery bypass surgery: a randomized, double-blind placebo controlled trial</title><secondary-title>Ann. Card. Anaesth.</secondary-title></titles><periodical><full-title>Ann. Card. Anaesth.</full-title></periodical><pages>180-185</pages><volume>16</volume><number>3</number><dates><year>2013</year><pub-dates><date>2013/7</date></pub-dates></dates><isbn>0971-9784</isbn><urls><related-urls><url>;[10]) MD 0.04 lower (0.46 lower to 0.38 higher) -> NSOther outcomes: 1) Sedation level:Pesonen ADDIN EN.CITE <EndNote><Cite><Author>Pesonen</Author><Year>2011</Year><RecNum>1896</RecNum><DisplayText>[9]</DisplayText><record><rec-number>1896</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232812">1896</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pesonen, A.</author><author>Suojaranta-Ylinen, R.</author><author>Hammarén, E.</author><author>Kontinen, V. K.</author><author>Raivio, P.</author><author>Tarkkila, P.</author><author>Rosenberg, P. H.</author></authors></contributors><auth-address>Department of Anaesthesiology and Intensive Care Medicine, Helsinki University Hospital, PO BOX 340, FIN-00029 HUS Helsinki, Finland. anne.pesonen@hus.fi</auth-address><titles><title>Pregabalin has an opioid-sparing effect in elderly patients after cardiac surgery: a randomized placebo-controlled trial</title><secondary-title>Br. J. Anaesth.</secondary-title></titles><periodical><full-title>Br. J. Anaesth.</full-title></periodical><pages>873-881</pages><volume>106</volume><number>6</number><dates><year>2011</year><pub-dates><date>2011/6</date></pub-dates></dates><isbn>0007-0912</isbn><urls><related-urls><url> Papers/P/Pesonen et al. 2011 - Pregabalin has an opioid-sparing effect in elderly patients after cardiac surgery - a randomized placebo-controlled trial.pdf</url></pdf-urls></urls><electronic-resource-num>10.1093/bja/aer083</electronic-resource-num></record></Cite></EndNote>[9]:RASS was significantly lower (more sedated) only at H2 post extubation in the pregabalin group, but not at H0, H4, 6, 8, 10, 12, 16.RASS was not significantly different in Joshi ADDIN EN.CITE <EndNote><Cite><Author>Joshi</Author><Year>2013</Year><RecNum>1897</RecNum><DisplayText>[10]</DisplayText><record><rec-number>1897</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232812">1897</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Joshi, Shreedhar S.</author><author>Jagadeesh, A. M.</author></authors></contributors><auth-address>Department of Cardiac Anesthesiology, Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bangalore, Karnataka, India.</auth-address><titles><title>Efficacy of perioperative pregabalin in acute and chronic post-operative pain after off-pump coronary artery bypass surgery: a randomized, double-blind placebo controlled trial</title><secondary-title>Ann. Card. Anaesth.</secondary-title></titles><periodical><full-title>Ann. Card. Anaesth.</full-title></periodical><pages>180-185</pages><volume>16</volume><number>3</number><dates><year>2013</year><pub-dates><date>2013/7</date></pub-dates></dates><isbn>0971-9784</isbn><urls><related-urls><url>;[10]Pandey 2002 ADDIN EN.CITE <EndNote><Cite><Author>Pandey</Author><Year>2002</Year><RecNum>1898</RecNum><DisplayText>[7]</DisplayText><record><rec-number>1898</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232812">1898</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pandey, Chandra K.</author><author>Bose, Neeta</author><author>Garg, Garima</author><author>Singh, Namita</author><author>Baronia, Arvind</author><author>Agarwal, Anil</author><author>Singh, Prabhat K.</author><author>Singh, Uttam</author></authors></contributors><auth-address>Department of Anaesthesiology and Critical Care Medicine, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India. ckpandey@sgpgi.ac.in</auth-address><titles><title>Gabapentin for the treatment of pain in guillain-barré syndrome: a double-blinded, placebo-controlled, crossover study</title><secondary-title>Anesth. Analg.</secondary-title></titles><periodical><full-title>Anesth. Analg.</full-title></periodical><pages>1719-23, table of contents</pages><volume>95</volume><number>6</number><dates><year>2002</year><pub-dates><date>2002/12</date></pub-dates></dates><isbn>0003-2999</isbn><urls><related-urls><url> Papers/P/Pandey et al. 2002 - Gabapentin for the treatment of pain in guillain-barré syndrome - a double-blinded, placebo-controlled, crossover study.pdf</url></pdf-urls></urls></record></Cite></EndNote>[7]Ramsay was significanlty lower (less sedated) in gabapentin group at Day 1 to Day 7Pandey 2005 ADDIN EN.CITE <EndNote><Cite><Author>Pandey</Author><Year>2005</Year><RecNum>1899</RecNum><DisplayText>[8]</DisplayText><record><rec-number>1899</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232812">1899</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pandey, Chandra Kant</author><author>Raza, Mehdi</author><author>Tripathi, Mukesh</author><author>Navkar, Deepa V.</author><author>Kumar, Abhishek</author><author>Singh, Uttam K.</author></authors></contributors><auth-address>Department of Anaesthesiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India. ckpandey@sgpgi.ac.in</auth-address><titles><title>The comparative evaluation of gabapentin and carbamazepine for pain management in Guillain-Barré syndrome patients in the intensive care unit</title><secondary-title>Anesth. Analg.</secondary-title></titles><periodical><full-title>Anesth. Analg.</full-title></periodical><pages>220-5, table of contents</pages><volume>101</volume><number>1</number><dates><year>2005</year><pub-dates><date>2005/7</date></pub-dates></dates><isbn>0003-2999</isbn><urls><related-urls><url> Papers/P/Pandey et al. 2005 - The comparative evaluation of gabapentin and carba ... agement in Guillain-Barré syndrome patients in the intensive care unit.pdf</url></pdf-urls></urls><electronic-resource-num>10.1213/01.ANE.0000152186.89020.36</electronic-resource-num></record></Cite></EndNote>[8]:idem for gabapentin vs carbamazepine and placebo, as well as for CBZ versus placebo2) Delirium: CAM-ICU "score" higher in the pregabalin group (24 vs 21, p=0.04) meaning that delirium was reduced in the pregabalin group: only at Day1, not at Day2 to 5, MMSE at Day5 = NS 3) Nausea NS (Pesonen, Joshi)PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Kb3NoaTwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [9, 10], diarrhea constipation NS (Pandey 2005) ADDIN EN.CITE <EndNote><Cite><Author>Pandey</Author><Year>2005</Year><RecNum>1899</RecNum><DisplayText>[8]</DisplayText><record><rec-number>1899</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232812">1899</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pandey, Chandra Kant</author><author>Raza, Mehdi</author><author>Tripathi, Mukesh</author><author>Navkar, Deepa V.</author><author>Kumar, Abhishek</author><author>Singh, Uttam K.</author></authors></contributors><auth-address>Department of Anaesthesiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India. ckpandey@sgpgi.ac.in</auth-address><titles><title>The comparative evaluation of gabapentin and carbamazepine for pain management in Guillain-Barré syndrome patients in the intensive care unit</title><secondary-title>Anesth. Analg.</secondary-title></titles><periodical><full-title>Anesth. Analg.</full-title></periodical><pages>220-5, table of contents</pages><volume>101</volume><number>1</number><dates><year>2005</year><pub-dates><date>2005/7</date></pub-dates></dates><isbn>0003-2999</isbn><urls><related-urls><url> Papers/P/Pandey et al. 2005 - The comparative evaluation of gabapentin and carba ... agement in Guillain-Barré syndrome patients in the intensive care unit.pdf</url></pdf-urls></urls><electronic-resource-num>10.1213/01.ANE.0000152186.89020.36</electronic-resource-num></record></Cite></EndNote>[8]4) Heart rate, mean arterial pressure, respiratory depression NS (Joshi) ADDIN EN.CITE <EndNote><Cite><Author>Joshi</Author><Year>2013</Year><RecNum>1897</RecNum><DisplayText>[10]</DisplayText><record><rec-number>1897</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232812">1897</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Joshi, Shreedhar S.</author><author>Jagadeesh, A. M.</author></authors></contributors><auth-address>Department of Cardiac Anesthesiology, Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bangalore, Karnataka, India.</auth-address><titles><title>Efficacy of perioperative pregabalin in acute and chronic post-operative pain after off-pump coronary artery bypass surgery: a randomized, double-blind placebo controlled trial</title><secondary-title>Ann. Card. Anaesth.</secondary-title></titles><periodical><full-title>Ann. Card. Anaesth.</full-title></periodical><pages>180-185</pages><volume>16</volume><number>3</number><dates><year>2013</year><pub-dates><date>2013/7</date></pub-dates></dates><isbn>0971-9784</isbn><urls><related-urls><url>;[10]Peak inspiratory flow rates (incentive spirometry) were higher in pregabalin group as compared to control group at 12, 24 and 36 h from extubation (P < 0.05) (Joshi) ADDIN EN.CITE <EndNote><Cite><Author>Joshi</Author><Year>2013</Year><RecNum>1897</RecNum><DisplayText>[10]</DisplayText><record><rec-number>1897</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232812">1897</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Joshi, Shreedhar S.</author><author>Jagadeesh, A. M.</author></authors></contributors><auth-address>Department of Cardiac Anesthesiology, Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bangalore, Karnataka, India.</auth-address><titles><title>Efficacy of perioperative pregabalin in acute and chronic post-operative pain after off-pump coronary artery bypass surgery: a randomized, double-blind placebo controlled trial</title><secondary-title>Ann. Card. Anaesth.</secondary-title></titles><periodical><full-title>Ann. Card. Anaesth.</full-title></periodical><pages>180-185</pages><volume>16</volume><number>3</number><dates><year>2013</year><pub-dates><date>2013/7</date></pub-dates></dates><isbn>0971-9784</isbn><urls><related-urls><url>;[10]Desirable EffectsHow substantial are the desirable anticipated effects?○ Trivial○ Small○ Moderate● Large○ Varies○ Don't know "large"because there is an important reduction in pain intensity as well as a reduction in opioid consumption- Moderate or LargeUndesirable EffectsHow substantial are the undesirable anticipated effects?○ Large○ Moderate● Small○ Trivial○ Varies○ Don't know"trivial" - some undesirable effects not reported (e.g., dizziness)Bram: consider gap in the literature and those reported in selected studiesGroup agrees to "small"Certainty of evidenceWhat is the overall certainty of the evidence of effects?○ Very low○ Low● Moderate○ High○ No included studiesPandey PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYW5kZXk8L0F1dGhvcj48WWVhcj4yMDAyPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA [7, 8] studies seem to have a low ROB but exclusion of patients after enrollment was not reported. Also, these two studies came from the same single center in India: Indian patients might have different pharmacoK/D than other populations? Any Pharm recommendation John?Pesonen study ADDIN EN.CITE <EndNote><Cite><Author>Pesonen</Author><Year>2011</Year><RecNum>1896</RecNum><DisplayText>[9]</DisplayText><record><rec-number>1896</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232812">1896</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pesonen, A.</author><author>Suojaranta-Ylinen, R.</author><author>Hammarén, E.</author><author>Kontinen, V. K.</author><author>Raivio, P.</author><author>Tarkkila, P.</author><author>Rosenberg, P. H.</author></authors></contributors><auth-address>Department of Anaesthesiology and Intensive Care Medicine, Helsinki University Hospital, PO BOX 340, FIN-00029 HUS Helsinki, Finland. anne.pesonen@hus.fi</auth-address><titles><title>Pregabalin has an opioid-sparing effect in elderly patients after cardiac surgery: a randomized placebo-controlled trial</title><secondary-title>Br. J. Anaesth.</secondary-title></titles><periodical><full-title>Br. J. Anaesth.</full-title></periodical><pages>873-881</pages><volume>106</volume><number>6</number><dates><year>2011</year><pub-dates><date>2011/6</date></pub-dates></dates><isbn>0007-0912</isbn><urls><related-urls><url> Papers/P/Pesonen et al. 2011 - Pregabalin has an opioid-sparing effect in elderly patients after cardiac surgery - a randomized placebo-controlled trial.pdf</url></pdf-urls></urls><electronic-resource-num>10.1093/bja/aer083</electronic-resource-num></record></Cite></EndNote>[9]: very high ROB: 10 on 70 patients were excluded, no intent to treat analysisNote that the population's size of each group in these 3 RCTs varies from n=12 to n=31 only."moderate" certainty of the evidence of effects because 4 double blinded RCTs but with limitations-it should be whatever the harm of using the drug is - moderate is fair ValuesIs there important uncertainty about or variability in how much people value the main outcomes?○ Important uncertainty or variability○ Possibly important uncertainty or variability○ Probably no important uncertainty or variability● No important uncertainty or variability○ No known undesirable outcomesNeuropathic pain is difficult to treat with opioids. "No important" uncertaintyto be consistent with previous questionsBalance of effectsDoes the balance between desirable and undesirable effects favor the intervention or the comparison?○ Favors the comparison○ Probably favors the comparison○ Does not favor either the intervention or the comparison○ Probably favors the intervention● Favors the intervention○ Varies○ Don't know"Favors" the interventionbecause there was a strong reduction in pain intensity, as well as a strong reduction in opioid consumption, a significant improvement in vigilance status and some improvement in CAM-ICU in one study (at Day 1 only).No other side effects when assessed, especially nausea, diarrhea, constipation.Resources requiredHow large are the resource requirements (costs)?○ Large costs○ Moderate costs● Negligible costs and savings○ Moderate savings○ Large savings○ Varies○ Don't knowCosts of neuropathic agents are small in France. What in US and Canada? Low costs and accessible.Negligible costs and savings Certainty of evidence of required resourcesWhat is the certainty of the evidence of resource requirements (costs)?○ Very low○ Low○ Moderate○ High● No included studiesCost effectivenessDoes the cost-effectiveness of the intervention favor the intervention or the comparison?○ Favors the comparison○ Probably favors the comparison○ Does not favor either the intervention or the comparison○ Probably favors the intervention○ Favors the intervention○ Varies● No included studiesNo included studies(no cost-effectiveness study, to be consistent with other questions)EquityWhat would be the impact on health equity?○ Reduced○ Probably reduced● Probably no impact○ Probably increased○ Increased○ Varies○ Don't knowAcceptabilityIs the intervention acceptable to key stakeholders?○ No○ Probably no○ Probably yes● Yes○ Varies○ Don't knowFeasibilityIs the intervention feasible to implement?○ No○ Probably no● Probably yes○ Yes○ Varies○ Don't knowNeuropathic agents require the use of a gastric tube in patients unable to swallow, as well as the absence of ileus. "varies"Yes or Probably yes when not focusing on specific ICU patients with CI Probably yesSummary of judgementsJudgementImplicationsProblemNoProbably noProbably yesYesVariesDon't knowDesirable EffectsTrivialSmallModerateLargeVariesDon't knowUndesirable EffectsLargeModerateSmallTrivialVariesDon't knowCertainty of evidenceVery lowLowModerateHighNo included studiesValuesImportant uncertainty or variabilityPossibly important uncertainty or variabilityProbably no important uncertainty or variabilityNo important uncertainty or variabilityNo known undesirable outcomesBalance of effectsFavors the comparisonProbably favors the comparisonDoes not favor either the intervention or the comparisonProbably favors the interventionFavors the interventionVariesDon't knowResources requiredLarge costsModerate costsNegligible costs and savingsModerate savingsLarge savingsVariesDon't knowCertainty of evidence of required resourcesVery lowLowModerateHighNo included studiesCost effectivenessFavors the comparisonProbably favors the comparisonDoes not favor either the intervention or the comparisonProbably favors the interventionFavors the interventionVariesNo included studiesEquityReducedProbably reducedProbably no impactProbably increasedIncreasedVariesDon't knowAcceptabilityNoProbably noProbably yesYesVariesDon't knowFeasibilityNoProbably noProbably yesYesVariesDon't knowShould adjunct neuropathic agent vs. no adjunct neuropathic drug be used for ICU pain management (5.2)?Type of recommendationStrong recommendation against the interventionConditional recommendation against the interventionConditional recommendation for either the intervention or the comparisonConditional recommendation for the interventionStrong recommendation for the intervention○ ○ ○ ○ ● Recommendation1. We recommend to use adjunctive gabapentin to treat neuropathic pain and reduce opioid consumption in ICU patients with Guillain-Barré syndrome (+1B).2.1. We suggest that adjunctive neuropathic agents be used to treat neuropathic pain in ICU patients, i.e. patients with neuropathic pain related to ICU-aquired weakness (+2B).2.2. We suggest that adjunctive pregabalin might be used to decrease postoperative pain intensity and opioid consumption in some patients (+2B).have 2 recommendations: we recommend using neuropathic agents to treat neuropathic pain in the ICU (strong recommendation); weak recommendation for postoperative pain in CV surgeryJustificationFour RCTs. Two in patients with Guillain-Barré syndrome, low ROB but from a single center and small size population; Two in patients after selective cardiac surgery, two centers, small size population, high ROB for one study.-> These RCTs are downgraded to a level of evidence of BAlso see recent metaanalyses:Pharmacological treatment for pain in Guillain-Barré syndrome. Jia Liu, Lu-Ning Wang, Ewan D McNicol. The Cochrane Library 2013 ADDIN EN.CITE <EndNote><Cite><Author>Liu</Author><Year>2013</Year><RecNum>2473</RecNum><DisplayText>[11]</DisplayText><record><rec-number>2473</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507234473">2473</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Liu, Jia</author><author>Wang, Lu-Ning</author><author>McNicol, Ewan D</author></authors></contributors><titles><title>Pharmacological treatment for pain in Guillain-Barré syndrome</title><secondary-title>Cochrane Database Syst Rev</secondary-title></titles><periodical><full-title>Cochrane Database Syst Rev</full-title></periodical><volume>10</volume><number>10</number><dates><year>2013</year></dates><urls></urls></record></Cite></EndNote>[11]Although reductions in pain severity were found when comparing gabapentin and carbamazepine with placebo, the evidence was limited and its quality very low. Larger, well-designed RCTs are required to further investigate the efficacy and safety of potential interventions for patients with pain in GBS. Additionally, interventions for pain in the convalescent phase of GBS should be investigated.Perioperative use of pregabalin for acute pain—a systematic review and meta-analysis. Naveen Eipea, John Penninga, Fatemeh Yazdib, Ranjeeta Mallickb, Lucy Turnerb, Nadera Ahmadzaib, Mohammed Toseef Ansarib. PAIN 2015 ADDIN EN.CITE <EndNote><Cite><Author>Eipe</Author><Year>2015</Year><RecNum>2474</RecNum><DisplayText>[12]</DisplayText><record><rec-number>2474</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507234483">2474</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Eipe, Naveen</author><author>Penning, John</author><author>Yazdi, Fatemeh</author><author>Mallick, Ranjeeta</author><author>Turner, Lucy</author><author>Ahmadzai, Nadera</author><author>Ansari, Mohammed Toseef</author></authors></contributors><titles><title>Perioperative use of pregabalin for acute pain—a systematic review and meta-analysis</title><secondary-title>Pain</secondary-title></titles><periodical><full-title>Pain</full-title></periodical><pages>1284-1300</pages><volume>156</volume><number>7</number><dates><year>2015</year></dates><isbn>0304-3959</isbn><urls></urls></record></Cite></EndNote>[12]Pregabalin analgesic effectiveness is largely restricted to surgical procedures associated with pronociceptive mechanisms. The clinical significance of observed pregabalin benefits must be weighed against the uncertainties about serious harms and enhanced recovery to inform the careful selection of surgical patients.Subgroup considerationsThere is no data regarding pain in patients with ICUAW. However, there is an empirical evidence that these patients can suffer from typical neuropathic pain. Pathophysiological mechanism in ICUAW is likely similar to patients with Guillain-Barré syndrome. Further studies are needed to investigate pain in ICU patients with ICUAW, as well as the effect of adjunctive neuropathic agents to prevent and treat pain, and reduce opioid consumption.Research prioritiesThis is top priority to investigate analgesics that can decrease the use or dose of opioids to treat pain in ICU patients as well as to investigate analgesics effective to treat neuropathic pain specifically.These results require that these studies be replicated:- in medical or surgical patients having neuropathic pain related to ICUAW- non communicant patients, i.e. at the early stage of sedation-analgesiacomments during electronic Voting by Entire panelCan’t generalize GBS patient data to all critically ill patients.Question: Adjunctive lidocaine compared to no lidocaine for ICU analgesic regime (5.2) Setting: Intensive Care Unit Bibliography: Quality assessment№ of patientsEffectQualityImportance№ of studiesStudy designRisk of biasInconsistencyIndirectnessImprecisionOther considerationsAdjunctive lidocaineno lidocaineRelative(95% CI)Absolute(95% CI)VAS Score at 96 hours (follow up: mean 96 hours; assessed with: VAS; Scale from: 0 to 10)1 randomised trials serious anot serious not serious bserious cnone 44 45 - MD 0.1 cm higher(0.38 lower to 0.58 higher) ????LOW IMPORTANT Total postoperative fentanyl required (assessed with: dosage (mcg))1 randomised trials serious anot serious not serious bserious cnone 44 45 - MD 68.73 mcg lower(387.372 lower to 249.912 higher) ????LOW IMPORTANT CI: Confidence interval; MD: Mean differenceExplanationsa. unclear method of randomization, no intention to treat, exclusion of patients unclear b. Only included cardiac ICU patients; however effects may be generalizable c. Wide confidence intervals cannot distinguish if clinically important benefits with lidocaine adjunct QuestionShould Adjunctive lidocaine vs. no lidocaine be used for ICU analgesic regime (5.2)?Population:ICU analgesic regime (5.2)Background:Intervention:Adjunctive lidocaineComparison:no lidocaineMain outcomes:VAS Score at 96 hours; Total postoperative fentanyl required;Setting:Intensive Care UnitPerspective:AssessmentJudgementResearch evidenceAdditional considerationsProblemIs the problem a priority?○ No○ Probably no○ Probably yes● Yes○ Varies○ Don't knowIt is top priority to investigate the effectiveness/side effects of Adjunct Non opioid analgesics to opioids compared to opioids alone in order to decrease opioids related side effects that are especially at risk in ICU patients: - respiratory depression- neurological impairment (decreased vigilance, delirium)- ileus, nausea vomiting, etc... One single center double-blinded RCT in 100 postcardiac surgery ICU patients, high ROB (No flow chart, exclusion of patients unclear, one patient in the intervention group was excluded from analysis because of death, no intent to treat analysis) -> Insler 1995 ADDIN EN.CITE <EndNote><Cite><Author>Insler</Author><Year>1995</Year><RecNum>1902</RecNum><DisplayText>[13]</DisplayText><record><rec-number>1902</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232812">1902</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Insler, S. R.</author><author>O'Connor, M.</author><author>Samonte, A. F.</author><author>Bazaral, M. G.</author></authors></contributors><auth-address>Department of Cardiothoracic Anesthesia, Cleveland Clinic Foundation, OH.</auth-address><titles><title>Lidocaine and the inhibition of postoperative pain in coronary artery bypass patients</title><secondary-title>J. Cardiothorac. Vasc. Anesth.</secondary-title></titles><periodical><full-title>J. Cardiothorac. Vasc. Anesth.</full-title></periodical><pages>541-546</pages><volume>9</volume><number>5</number><dates><year>1995</year><pub-dates><date>1995/10</date></pub-dates></dates><isbn>1053-0770</isbn><urls><related-urls><url>(05)80138-7</url></related-urls><pdf-urls><url>All Papers/I/Insler et al. 1995 - Lidocaine and the inhibition of postoperative pain in coronary artery bypass patients.pdf</url></pdf-urls></urls></record></Cite></EndNote>[13]NB: lidoca?ne or placebo was begun just after induction of anesthesiaPain intensity at H96 (VAS in cm): MD 0.1 higher (0.4 lower to 0.6 higher)Fentanyl consumption (?g): MD 68 lower (39 lower to 249 higher)Ramsay score: Lidoca?ne group significantly more sedated (higher score) at H4, not at H1, 2, 8, 16, 24, 48, 96.Other outcomes NS: hemodynamics, midazolam, propofol dosages, time to extubation, ICU LOS, hospital LOSDesirable EffectsHow substantial are the desirable anticipated effects?● Trivial○ Small○ Moderate○ Large○ Varies○ Don't know"trivial" because there was globally no (significant) effect at all.Also crossed the line of no effect.Undesirable EffectsHow substantial are the undesirable anticipated effects?○ Large○ Moderate○ Small● Trivial○ Varies○ Don't know"trivial" because there was globally no (significant) effect at all.Certainty of evidenceWhat is the overall certainty of the evidence of effects?○ Very low● Low○ Moderate○ High○ No included studiesOnly one study, high ROB: ,o flow chart, exclusion of patients unclear, one patient in the intervention group was excluded from analysis because of death, no intent to treat analysis"low"ValuesIs there important uncertainty about or variability in how much people value the main outcomes?○ Important uncertainty or variability○ Possibly important uncertainty or variability○ Probably no important uncertainty or variability● No important uncertainty or variability○ No known undesirable outcomes"Possibly important uncertainty or variability"because except fo hemodynamics (HR, MAP, PAP, CVP, CO, CI and monitoring for myocardial infarction by ECG and CPK enzymes), lidoca?ne's related toxicity was not reported: arrhythmias, Central Nervous System (CNS) toxicity (seizures...) No uncertainty about VASBalance of effectsDoes the balance between desirable and undesirable effects favor the intervention or the comparison?○ Favors the comparison○ Probably favors the comparison● Does not favor either the intervention or the comparison○ Probably favors the intervention○ Favors the intervention○ Varies○ Don't know"Does not favor either the intervention or the comparison"Resources requiredHow large are the resource requirements (costs)?○ Large costs○ Moderate costs● Negligible costs and savings○ Moderate savings○ Large savings○ Varies○ Don't knowLidoca?ne costs are small."Negligible costs and savings"Certainty of evidence of required resourcesWhat is the certainty of the evidence of resource requirements (costs)?○ Very low○ Low○ Moderate● High○ No included studiesOld drug, not expensive and available-impact of nursing for cardiovascular assessment – recent meta-analyses availableCost effectivenessDoes the cost-effectiveness of the intervention favor the intervention or the comparison?○ Favors the comparison● Probably favors the comparison○ Does not favor either the intervention or the comparison○ Probably favors the intervention○ Favors the intervention○ Varies○ No included studiesNo intervention"Favors the comparison"because adjunctive lidoca?ne seems to be futile; not using IV lidoca?ne saves the (small) cost of the drug but also the administration materials, as well as pharm and nurses' time.-Probably favors (only one study)EquityWhat would be the impact on health equity?○ Reduced○ Probably reduced○ Probably no impact○ Probably increased○ Increased○ Varies○ Don't knowAcceptabilityIs the intervention acceptable to key stakeholders?○ No● Probably no○ Probably yes○ Yes○ Varies○ Don't know"no"because adjunctive lidoca?ne seems to be futile; not using IV lidoca?ne saves the (small) cost of the drug but also the administration materials, as well as pharm and nurses' time. Probably no to be consistent with previous questionFeasibilityIs the intervention feasible to implement?○ No○ Probably no● Probably yes○ Yes○ Varies○ Don't knowTake into account required monitoringSummary of judgementsJudgementImplicationsProblemNoProbably noProbably yesYesVariesDon't knowDesirable EffectsTrivialSmallModerateLargeVariesDon't knowUndesirable EffectsLargeModerateSmallTrivialVariesDon't knowCertainty of evidenceVery lowLowModerateHighNo included studiesValuesImportant uncertainty or variabilityPossibly important uncertainty or variabilityProbably no important uncertainty or variabilityNo important uncertainty or variabilityNo known undesirable outcomesBalance of effectsFavors the comparisonProbably favors the comparisonDoes not favor either the intervention or the comparisonProbably favors the interventionFavors the interventionVariesDon't knowResources requiredLarge costsModerate costsNegligible costs and savingsModerate savingsLarge savingsVariesDon't knowCertainty of evidence of required resourcesVery lowLowModerateHighNo included studiesCost effectivenessFavors the comparisonProbably favors the comparisonDoes not favor either the intervention or the comparisonProbably favors the interventionFavors the interventionVariesNo included studiesEquityReducedProbably reducedProbably no impactProbably increasedIncreasedVariesDon't knowAcceptabilityNoProbably noProbably yesYesVariesDon't knowFeasibilityNoProbably noProbably yesYesVariesDon't knowShould Adjunctive lidocaine vs. no lidocaine be used for ICU analgesic regime (5.2)?Type of recommendationStrong recommendation against the interventionConditional recommendation against the interventionConditional recommendation for either the intervention or the comparisonConditional recommendation for the interventionStrong recommendation for the intervention○ ● ○ ○ ○ RecommendationWe suggest against using adjunctive IV lidoca?ne systematically in addition to opioids to treat pain and/or to reduce opioid consumption in postoperative ICU patients (-2C).Note: a weak recommendation does not imply that it cannot be usedJustificationOnly one low quality negative RCT in postcardiac ICU patients that investigated pain.-> level of evidence is downgraded to CAlso to take into consideration the recent Cochrane review (Continuous intravenous perioperative lidocaine infusion fo postoperative pain and recovery, by Kranke et al. Cochrane Library 2015) ADDIN EN.CITE <EndNote><Cite><Author>Kranke</Author><Year>2015</Year><RecNum>1901</RecNum><DisplayText>[14]</DisplayText><record><rec-number>1901</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232812">1901</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kranke, Peter</author><author>Jokinen, Johanna</author><author>Pace, Nathan Leon</author><author>Schnabel, Alexander</author><author>Hollmann, Markus W.</author><author>Hahnenkamp, Klaus</author><author>Eberhart, Leopold H. J.</author><author>Poepping, Daniel M.</author><author>Weibel, Stephanie</author></authors></contributors><auth-address>Department of Anaesthesia and Critical Care, University of Würzburg, Oberdürrbacher Str. 6, Würzburg, Germany, 97080.</auth-address><titles><title>Continuous intravenous perioperative lidocaine infusion for postoperative pain and recovery</title><secondary-title>Cochrane Database Syst. Rev.</secondary-title></titles><periodical><full-title>Cochrane Database Syst. Rev.</full-title></periodical><pages>CD009642</pages><number>7</number><dates><year>2015</year><pub-dates><date>2015/7/16</date></pub-dates></dates><isbn>1469-493X</isbn><urls><related-urls><url> Papers/K/Kranke et al. 2015 - Continuous intravenous perioperative lidocaine infusion for postoperative pain and recovery.pdf</url></pdf-urls></urls><electronic-resource-num>10.1002/14651858.CD009642.pub2</electronic-resource-num></record></Cite></EndNote>[14], Authors’ conclusions:There is low to moderate evidence that this intervention, when compared to placebo, has an impact on pain scores, especially in the early postoperative phase, and on postoperative nausea. There is limited evidence that this has further impact on other relevant clinical outcomes, such as gastrointestinal recovery, length of hospital stay, and opioid requirements. So far there is a scarcity of studies that have systematically assessed the incidence of adverse effects; the optimal dose; timing (including the duration of the administration); and the effects when compared with epidural anaesthesia.Subgroup considerationsCardiac surgery patientsImplementation considerationsMonitoring and evaluationLidoca?ne's heart and Central Nervous System (CNS) toxicity needs to be investigate in critically ill patients.Research prioritiesThis is top priority to investigate analgesics that can decrease the use or dose of opioids to treat pain in ICU patients.There is only one negative study in postoperative ICU patients. A Cochrane review reported low to moderate evidence that IV lidoca?ne reduced pain at the early stage of postoperative period, opioid consumption as well as improved bowel function, especially after abdominal surgeryFuture studies are required:- in SICU patients recovering from an abdominal surgery- in medical ICU, especially non communicant patients at the early stage of sedation-analgesiacomments during electronic Voting by Entire panelspecific contexts could be clinically useful: neuro-muscular and neuro patients (post-op or in general), recovering opiate addicts?"We do not suggest routine lidocaine" harmonizes with the Cochrane review’s modest benefit& this keeps the door open to considering its use. Surprising contrast between this and the ketamine recommendation (where there seemed to be as little data yet a recommendation)Question: Adjunct NSAIDs compared to no adjunct NSAIDs for postoperative ICU patients (5.2) Setting: Bibliography: Quality assessment№ of patientsEffectQualityImportance№ of studiesStudy designRisk of biasInconsistencyIndirectnessImprecisionOther considerationsadjunct NSAIDsno adjunct NSAIDsRelative(95% CI)Absolute(95% CI)VAS Pain Score 24 hours postoperatively2 randomised trials serious anot serious not serious serious bnone 104 53 - MD 0.35 lower(0.91 lower to 0.21 higher) ????LOW CRITICAL Opioid Consumption (morphine equivalents)2 randomised trials serious aserious cnot serious serious dnone 49 53 - MD 1.61 lower(2.42 lower to 0.8 lower) ????VERY LOW CRITICAL VAS Pain Score with Deep Breath at 6 hours1 randomised trials not serious not serious not serious serious dnone 21 22 - MD 1.3 lower(2.36 lower to 0.24 lower) ????MODERATE CRITICAL VAS Pain Score with Deep Breath at 24 hours1 randomised trials not serious not serious not serious very serious d,enone 21 22 - MD 0.6 lower(1.44 lower to 0.24 higher) ????LOW CRITICAL CI: Confidence interval; MD: Mean differenceExplanationsa. No intention to treat in either analysis, unclear method of randomization b. Unclear if benefit with adjunctive NSAIDs based on meta-analysis c. Very high degree of inconsistency (Isquared = 92%) with non overlapping confidence intervals however both show benefit so lowered one level d. Small sample size e. Confidence Intervals include both harm and benefit QuestionShould adjunct NSAIDs vs. no adjunct NSAIDs be used for postoperative ICU patients (5.2)?Population:postoperative ICU patients (5.2)Background:Intervention:adjunct NSAIDsComparison:no adjunct NSAIDsMain outcomes:VAS Pain Score 24 hours postoperatively; Opioid Consumption (morphine equivalents); VAS Pain Score with Deep Breath at 6 hours; VAS Pain Score with Deep Breath at 24 hours;Setting:Perspective:AssessmentJudgementResearch evidenceAdditional considerationsProblemIs the problem a priority?○ No○ Probably no○ Probably yes● Yes○ Varies○ Don't knowIt is top priority to investigate the effectiveness/side effects of Adjunctive Non opioid analgesics to opioids compared to opioids alone in order to decrease opioids related side effects that are especially at risk in ICU patients: - respiratory depression- neurological impairment (decreased vigilance, delirium)- ileus, nausea vomiting, etc... Two single center RCT in ICU patients after surgerySmall size of every group in both studies: from 21 to 31 patientsHigh ROB for both studies: no intention to treat, unclear method of randomization- Hynninen 2000 : elective cardiac surgery, n=120 (4 groups: 3 different NSAIDs and placebo)- Oberhofer 2005 ADDIN EN.CITE <EndNote><Cite><Author>Oberhofer</Author><Year>2005</Year><RecNum>95</RecNum><DisplayText>[15]</DisplayText><record><rec-number>95</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232703">95</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Oberhofer, Dagmar</author><author>Skok, Jasna</author><author>Nesek-Adam, Visnja</author></authors></contributors><auth-address>Department of Anaesthesiology and Intensive Care, Sveti Duh General Hospital, Sveti Duh 64, 10000 Zagreb, Croatia. dagmar.oberhofer@zg.htnet.hr</auth-address><titles><title>Intravenous ketoprofen in postoperative pain treatment after major abdominal surgery</title><secondary-title>World J. Surg.</secondary-title></titles><periodical><full-title>World J. Surg.</full-title></periodical><pages>446-449</pages><volume>29</volume><number>4</number><dates><year>2005</year><pub-dates><date>2005/4</date></pub-dates></dates><isbn>0364-2313</isbn><urls><related-urls><url> Papers/O/Oberhofer et al. 2005 - Intravenous ketoprofen in postoperative pain treatment after major abdominal surgery.pdf</url></pdf-urls></urls><electronic-resource-num>10.1007/s00268-004-7612-0</electronic-resource-num></record></Cite></EndNote>[15]: abdominal surgery, n=43 (2 groups: ketopropfen and placebo)Pain measurement: VAS 0-10 in Hyminnen at H3, 6, 12, 24 (at rest only) NRS 0-10 in Oberhoffer ADDIN EN.CITE <EndNote><Cite><Author>Oberhofer</Author><Year>2005</Year><RecNum>95</RecNum><DisplayText>[15]</DisplayText><record><rec-number>95</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232703">95</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Oberhofer, Dagmar</author><author>Skok, Jasna</author><author>Nesek-Adam, Visnja</author></authors></contributors><auth-address>Department of Anaesthesiology and Intensive Care, Sveti Duh General Hospital, Sveti Duh 64, 10000 Zagreb, Croatia. dagmar.oberhofer@zg.htnet.hr</auth-address><titles><title>Intravenous ketoprofen in postoperative pain treatment after major abdominal surgery</title><secondary-title>World J. Surg.</secondary-title></titles><periodical><full-title>World J. Surg.</full-title></periodical><pages>446-449</pages><volume>29</volume><number>4</number><dates><year>2005</year><pub-dates><date>2005/4</date></pub-dates></dates><isbn>0364-2313</isbn><urls><related-urls><url> Papers/O/Oberhofer et al. 2005 - Intravenous ketoprofen in postoperative pain treatment after major abdominal surgery.pdf</url></pdf-urls></urls><electronic-resource-num>10.1007/s00268-004-7612-0</electronic-resource-num></record></Cite></EndNote>[15] at H3, 6, 12, 24 (at rest and deep breath)Drugs:Hynninen:Adjunctive 75 mg diclofenac or 100 mg ketoprofen or 100 mg indomethacin or placebo (4 groups) one hour before intubation (note: how is it possible to know the extubation time exactly!?!) and 12 hours afterwardBasal analgesia: none?Rescue analgesia: morphine in the ICU (and mepiridine for shivering); paracetamol, codeine in the ward (transfer on Day 1)Oberhofer:Adjunctive 100 mg ketoprofen IV one and nine hours postopBasal analgesia: tramadol and metamizoleRescue analgesia: tramadol 25 mg IVDesirable EffectsHow substantial are the desirable anticipated effects?○ Trivial● Small○ Moderate○ Large○ Varies○ Don't knowForest plot for pain scales (0-10) at rest: MD 0.35 fewer (0.91fewer to 0.21 more)NB: data are provided only in a figure of means without SD for Hynninen, not estimable for the forrest plot ; in the body text: non significant difference at all times.Pain at deep breath (Oberhofer) ADDIN EN.CITE <EndNote><Cite><Author>Oberhofer</Author><Year>2005</Year><RecNum>95</RecNum><DisplayText>[15]</DisplayText><record><rec-number>95</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232703">95</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Oberhofer, Dagmar</author><author>Skok, Jasna</author><author>Nesek-Adam, Visnja</author></authors></contributors><auth-address>Department of Anaesthesiology and Intensive Care, Sveti Duh General Hospital, Sveti Duh 64, 10000 Zagreb, Croatia. dagmar.oberhofer@zg.htnet.hr</auth-address><titles><title>Intravenous ketoprofen in postoperative pain treatment after major abdominal surgery</title><secondary-title>World J. Surg.</secondary-title></titles><periodical><full-title>World J. Surg.</full-title></periodical><pages>446-449</pages><volume>29</volume><number>4</number><dates><year>2005</year><pub-dates><date>2005/4</date></pub-dates></dates><isbn>0364-2313</isbn><urls><related-urls><url> Papers/O/Oberhofer et al. 2005 - Intravenous ketoprofen in postoperative pain treatment after major abdominal surgery.pdf</url></pdf-urls></urls><electronic-resource-num>10.1007/s00268-004-7612-0</electronic-resource-num></record></Cite></EndNote>[15]: H6: MD 1.3 fewer (2.36 fewer to 0.24 fewer)H 24: MD 0.6 fewer (1.44 fewer to 0.24 more)Forest plot for morphine consumption at H24 (mg equivallent):MD 1.61 fewer (2.42 fewer to 0.8 fewer)Other outcomes:- Nausea and/or vomiting: non significant difference in NSAIDs groups versus placebo (both studies) but very small size groups, probable lack of power- Other opioid related effects not reported, including: sedation, ileus, duration of MV, LOS in ICU... only "respiratory depression" was reported in Oberhofer ADDIN EN.CITE <EndNote><Cite><Author>Oberhofer</Author><Year>2005</Year><RecNum>95</RecNum><DisplayText>[15]</DisplayText><record><rec-number>95</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232703">95</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Oberhofer, Dagmar</author><author>Skok, Jasna</author><author>Nesek-Adam, Visnja</author></authors></contributors><auth-address>Department of Anaesthesiology and Intensive Care, Sveti Duh General Hospital, Sveti Duh 64, 10000 Zagreb, Croatia. dagmar.oberhofer@zg.htnet.hr</auth-address><titles><title>Intravenous ketoprofen in postoperative pain treatment after major abdominal surgery</title><secondary-title>World J. Surg.</secondary-title></titles><periodical><full-title>World J. Surg.</full-title></periodical><pages>446-449</pages><volume>29</volume><number>4</number><dates><year>2005</year><pub-dates><date>2005/4</date></pub-dates></dates><isbn>0364-2313</isbn><urls><related-urls><url> Papers/O/Oberhofer et al. 2005 - Intravenous ketoprofen in postoperative pain treatment after major abdominal surgery.pdf</url></pdf-urls></urls><electronic-resource-num>10.1007/s00268-004-7612-0</electronic-resource-num></record></Cite></EndNote>[15]: no case in any group- Serum creatinine: non significant change between groups but one patient had an important increase in S-creatinine after the first dose of indomethacine and was withdrawn of Hynninen's study (no intent to treat analysis!)- No significant difference in excessive bleeding but again, a probable lack of power, also note that one patient in the indomethacin group had excessive bleeding and was withdrawn of Hynninen's study (no intent to treat analysis!) - No platelet anti-agregant test was performed to show any effect on platelet function- Incidence of peptic ulcer in the postoperative period was not reported"small" desirable anticipated effectsbecause non significant reduction in pain intensity at rest H24, a significant reduction at deep breath in one study, a very small reduction in opioid consumption at H24Undesirable EffectsHow substantial are the undesirable anticipated effects?○ Large○ Moderate○ Small○ Trivial○ Varies● Don't knowdon't know" undesirable anticipated effectsbecause non significant difference for adverse outcomes but two severe adverse events possibly related to NSAID among 30 patients who received indomethacin, no intent to treat analysis; no platelet functional test used on bothe studiesCertainty of evidenceWhat is the overall certainty of the evidence of effects?○ Very low● Low○ Moderate○ High○ No included studiesSmall size of every group in both studies: from 21 to 31 patientsHigh ROB for both studies: no intention to treat, unclear method of randomization- Hynninen: 6 patients were excluded among 120, included two for indometacine possible side effect- Oberhofer ADDIN EN.CITE <EndNote><Cite><Author>Oberhofer</Author><Year>2005</Year><RecNum>95</RecNum><DisplayText>[15]</DisplayText><record><rec-number>95</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232703">95</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Oberhofer, Dagmar</author><author>Skok, Jasna</author><author>Nesek-Adam, Visnja</author></authors></contributors><auth-address>Department of Anaesthesiology and Intensive Care, Sveti Duh General Hospital, Sveti Duh 64, 10000 Zagreb, Croatia. dagmar.oberhofer@zg.htnet.hr</auth-address><titles><title>Intravenous ketoprofen in postoperative pain treatment after major abdominal surgery</title><secondary-title>World J. Surg.</secondary-title></titles><periodical><full-title>World J. Surg.</full-title></periodical><pages>446-449</pages><volume>29</volume><number>4</number><dates><year>2005</year><pub-dates><date>2005/4</date></pub-dates></dates><isbn>0364-2313</isbn><urls><related-urls><url> Papers/O/Oberhofer et al. 2005 - Intravenous ketoprofen in postoperative pain treatment after major abdominal surgery.pdf</url></pdf-urls></urls><electronic-resource-num>10.1007/s00268-004-7612-0</electronic-resource-num></record></Cite></EndNote>[15]: no patient seems to be excluded after enrollement in the intervention group, one for rash in the control group"low" certainty of the evidence of the effectsValuesIs there important uncertainty about or variability in how much people value the main outcomes?○ Important uncertainty or variability○ Possibly important uncertainty or variability○ Probably no important uncertainty or variability● No important uncertainty or variability○ No known undesirable outcomes"no important" uncertainty about or variability in how much people value the main outcomes to be consistent with previous questionsBalance of effectsDoes the balance between desirable and undesirable effects favor the intervention or the comparison?○ Favors the comparison○ Probably favors the comparison○ Does not favor either the intervention or the comparison○ Probably favors the intervention○ Favors the intervention○ Varies● Don't know"don't know" if the balance between desirable and undesirable effects favor the intervention or the comparisonbecause of no or small benefits (no reduction in pain intensity at rest at H24, very small reduction in opioid consumption within 24h) and don't know harmsResources requiredHow large are the resource requirements (costs)?○ Large costs○ Moderate costs○ Negligible costs and savings○ Moderate savings○ Large savings○ Varies● Don't knowNSAIDs costs are small."don't know" about the resource requirements because severe adverse events related to drugs can be very expensive. See assessment of undesirable effetcs.Certainty of evidence of required resourcesWhat is the certainty of the evidence of resource requirements (costs)?○ Very low● Low○ Moderate○ High○ No included studies"low" certainty of the evidence of ressource requirements See assessment of undesirable effetcs. Cost effectivenessDoes the cost-effectiveness of the intervention favor the intervention or the comparison?○ Favors the comparison○ Probably favors the comparison○ Does not favor either the intervention or the comparison○ Probably favors the intervention○ Favors the intervention○ Varies● No included studiesNo included studies because no cost-effectiveness study, potential unassessed harms.EquityWhat would be the impact on health equity?○ Reduced○ Probably reduced● Probably no impact○ Probably increased○ Increased○ Varies○ Don't knowAcceptabilityIs the intervention acceptable to key stakeholders?○ No● Probably no○ Probably yes○ Yes○ Varies○ Don't knowintervention acceptable to stakeholders -> "probably NO"because no or small benefits and potential harms related to the intervention. FeasibilityIs the intervention feasible to implement?○ No○ Probably no● Probably yes○ Yes○ Varies○ Don't knowSummary of judgementsJudgementImplicationsProblemNoProbably noProbably yesYesVariesDon't knowDesirable EffectsTrivialSmallModerateLargeVariesDon't knowUndesirable EffectsLargeModerateSmallTrivialVariesDon't knowCertainty of evidenceVery lowLowModerateHighNo included studiesValuesImportant uncertainty or variabilityPossibly important uncertainty or variabilityProbably no important uncertainty or variabilityNo important uncertainty or variabilityNo known undesirable outcomesBalance of effectsFavors the comparisonProbably favors the comparisonDoes not favor either the intervention or the comparisonProbably favors the interventionFavors the interventionVariesDon't knowResources requiredLarge costsModerate costsNegligible costs and savingsModerate savingsLarge savingsVariesDon't knowCertainty of evidence of required resourcesVery lowLowModerateHighNo included studiesCost effectivenessFavors the comparisonProbably favors the comparisonDoes not favor either the intervention or the comparisonProbably favors the interventionFavors the interventionVariesNo included studiesEquityReducedProbably reducedProbably no impactProbably increasedIncreasedVariesDon't knowAcceptabilityNoProbably noProbably yesYesVariesDon't knowFeasibilityNoProbably noProbably yesYesVariesDon't knowConclusionsShould adjunct NSAIDs vs. no adjunct NSAIDs be used for postoperative ICU patients (5.2)?Type of recommendationStrong recommendation against the interventionConditional recommendation against the interventionConditional recommendation for either the intervention or the comparisonConditional recommendation for the interventionStrong recommendation for the intervention○ ● ○ ○ ○ RecommendationWe suggest against using adjunctive NSAIDs to prevent pain in ICU patients (-2C).JustificationOverall justificationTwo RCTs but single centers, high ROB, small size-> level of evidence downgraded to CDetailed justificationProblem Surgical ICU population (one cardiac, one abdominal). However, generalization of the results to another kind of population is likely because pain is frequent in SICU patients as in medical ICU patients.Desirable Effects No or small desirable effectsUndesirable Effects Some severe adverse events possibly related to NSAID reported in one study, no intent to treat analysis, small size studies that cannot conclude about these adverse eventsSubgroup considerationsImplementation considerationsMonitoring and evaluationAnalgesic related side effects or outcomes should be assessed more largely including:-delirium-ileus-duration of MV weaning-LOS in ICU and hospital NSAIDs related side effects should be assessed more precisely: - postoperative bleeding should be defined according to standardized definitions- risk of bleeding should be assessed by anti-agregant platelet tests, instead of activated coagulation time- peptic ulcerResearch prioritiesThis is top priority to investigate analgesics that can decrease the use or dose of opioids to treat pain in ICU patients.This kind of study needs to be replicated: - in medical ICU- non verbal patientscomments during electronic Voting by Entire panelSingle RCT; 1-2 doses likely safe/ effective, more may shift the benefit/burden ratioadd "non-procedural pain" as we for procedural pain.Question: Cybertherapy compared to no cybertherapy for ICU pain management (5.3) Setting: Non-pharmacological analgesic therapies Bibliography: Quality assessmentImpact QualityImportance№ of studiesStudy designRisk of biasInconsistencyIndirectnessImprecisionOther considerations# of patients with reduced pain post-cybertherapy1 observational studies not serious not serious not serious serious anone Mosso-Vazques ADDIN EN.CITE <EndNote><Cite><Author>Mosso-Vázquez</Author><Year>2014</Year><RecNum>1912</RecNum><DisplayText>[16]</DisplayText><record><rec-number>1912</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232812">1912</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mosso-Vázquez, José Luis</author><author>Gao, Kenneth</author><author>Wiederhold, Brenda K.</author><author>Wiederhold, Mark D.</author></authors></contributors><auth-address>1 Hospital General y Regional No. 25 IMSS , Mexico City, Mexico .</auth-address><titles><title>Virtual reality for pain management in cardiac surgery</title><secondary-title>Cyberpsychol. Behav. Soc. Netw.</secondary-title></titles><periodical><full-title>Cyberpsychol. Behav. Soc. Netw.</full-title></periodical><pages>371-378</pages><volume>17</volume><number>6</number><dates><year>2014</year><pub-dates><date>2014/6</date></pub-dates></dates><isbn>2152-2715</isbn><urls><related-urls><url> Papers/M/Mosso-Vázquez et al. 2014 - Virtual reality for pain management in cardiac surgery.pdf</url></pdf-urls></urls><electronic-resource-num>10.1089/cyber.2014.0198</electronic-resource-num></record></Cite></EndNote>[16] used virtual reality cybertherapy to reduce postoperative pain in cardiac surgical ICU patients. 67 patients were monitored within the first day postoperatively. Pain scores were obtained pre- and post-cybertherapy. 59/67 patients (88%) reported a decreased level of pain, with a mean Likert scale change of 3.75, corresponding with a change from severe to moderate, or moderate to light. Physiologically, 25 (37.3%) patients experienced reduced heart rates, 35 (52.2%) experienced reduced MAPs, and 14/22 (64% tested for respiratory rates experienced a reduction. ????VERY LOW CRITICAL CI: Confidence intervalExplanationsa. Small sample size Question: Should cybertherapy vs. no cybertherapy be used for ICU pain management (5.3)? Population: ICU pain management Background: Intervention: cybertherapy Comparison: no cybertherapy Main outcomes: # of patients with reduced pain post-cybertherapySetting: Non-pharmacological analgesic therapies Perspective: AssessmentCriteria Judgements Research evidence Additional considerations ProblemIs there a problem priority? ○ No ○ Probably no ○ Uncertain ○ Probably yes ● Yes ○ Varies Non-pharmacological interventions for pain management are important in the ICU and could contribute to reduce pain and to improve pain control in patients.Benefits & harms of the optionsWhat is the overall certainty of this evidence? ○ No included studies ● Very low ○ Low ○ Moderate ○ High The relative importance or values of the main outcomes of interest: OutcomeRelative importance Certainty of the evidence (GRADE) # of patients with reduced pain post-cybertherapyCRITICAL????VERY LOWSummary of evidence:Only 1 observational study (pre/post) was included (Mosso-Vazquez et al., 2014) ADDIN EN.CITE <EndNote><Cite><Author>Mosso-Vázquez</Author><Year>2014</Year><RecNum>1912</RecNum><DisplayText>[16]</DisplayText><record><rec-number>1912</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232812">1912</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mosso-Vázquez, José Luis</author><author>Gao, Kenneth</author><author>Wiederhold, Brenda K.</author><author>Wiederhold, Mark D.</author></authors></contributors><auth-address>1 Hospital General y Regional No. 25 IMSS , Mexico City, Mexico .</auth-address><titles><title>Virtual reality for pain management in cardiac surgery</title><secondary-title>Cyberpsychol. Behav. Soc. Netw.</secondary-title></titles><periodical><full-title>Cyberpsychol. Behav. Soc. Netw.</full-title></periodical><pages>371-378</pages><volume>17</volume><number>6</number><dates><year>2014</year><pub-dates><date>2014/6</date></pub-dates></dates><isbn>2152-2715</isbn><urls><related-urls><url> Papers/M/Mosso-Vázquez et al. 2014 - Virtual reality for pain management in cardiac surgery.pdf</url></pdf-urls></urls><electronic-resource-num>10.1089/cyber.2014.0198</electronic-resource-num></record></Cite></EndNote>[16]. ?The aim was to evaluate the use of virtual reality (VR) cybertherapy on postoperative distress in cardiac surgery ICU patients. 67 patients navigated a 30-minute VR simulation designed for pain management. ?59 patients (88%) reported a decreased level of pain post-therapy. The mean change was 3.75 on a Likert scale (unsure what the possible range was). The authors described that change as a decrease from severe to moderate or moderate to liht. Methods section very brief and poorly written.Uncertainty about main outcomes:-unsure what the Likert scale scores are.-important uncertainty or variability-important uncertainty or possibly importantAre the desirable anticipated effects large?I put uncertain because we only have 1 observational study, the sample size was small and the method is questionable. On the other hand, a change in 3.75 would be considered clinically significant if we would know what the scores mean (Likert scale).Group: uncertain - we don't really knowAre the undesirable anticipated effects small?Complications (6% of patients) during treatment included cardiac arrhythmia (n=1), and nausea and vertigo (n=3) that interrupted cybertherapy session (p.375). Based on this information, I am hesitant between Probably no and Uncertain.- these complications could happen anytime-happen frequently in cardiac ICU patients-uncertain because could happen during the intervention too; number is too small to make a judgmentConsensus from the group for uncertainAre the desirable effects large relative to undesirable effects?Uncertain because unsure about the desirable effects and complications were reported (but in a small number of patients).Consensus from the group for uncertainIs there important uncertainty about how much people value the main outcomes? ● Important uncertainty or variability ○ Possibly important uncertainty or variability ○ Probably no important uncertainty or variability ○ No important uncertainty or variability ○ No known undesirable outcomes Are the desirable anticipated effects large? ○ No ○ Probably no ● Uncertain ○ Probably yes ○ Yes ○ Varies Are the undesirable anticipated effects small? ○ No ○ Probably no ● Uncertain ○ Probably yes ○ Yes ○ Varies Are the desirable effects large relative to undesirable effects? ○ No ○ Probably no ● Uncertain ○ Probably yes ○ Yes ○ Varies Resource useAre the resources required small? ○ No ● Probably no ○ Uncertain ○ Probably yes ○ Yes ○ Varies A head-mounted display was installed on the patient's head to display a VR simulation. A projector emitted the same simulation on the unit wall. The simulation consisted of five cybertherapy environments. The simulation lasted 30 minutes.Special equipment is necessary for this intervention and time and resources to develop the simulations should also be taken into account.?- addresses music therapy as an example and all the necessary resources needed- No - enormous amount of resources`probably no also acceptable-Probably no- Probably noPt: Probably noIs the incremental cost small relative to the net benefits? ○ No ○ Probably no ● Uncertain ○ Probably yes ○ Yes ○ Varies RCTs are necessary to confirm conclusions on the effectiveness of this intervention on pain management.Costs for this intervention should be considered.We cannot conclude that benefits exceeded the costs.Consensus from the group for uncertain.EquityWhat would be the impact on health inequities?○ Increased ○ Probably increased ○ Uncertain ○ Probably reduced ○ Reduced ○ VariesAcceptabilityIs the option acceptable to key stakeholders? ○ No ○ Probably no ● Uncertain ○ Probably yes ○ Yes ○ Varies The ICU environment and access to equipment and resources will likely influence the acceptability of this intervention by stakeholders.Consensus from the group for uncertainFeasibilityIs the option feasible to implement? ○ No ● Probably no ○ Uncertain ○ Probably yes ○ Yes ○ Varies Many factors (equipment, time, resources, ICU environment, training) should be taken into account.?Consensus for probably noRecommendation Should cybertherapy vs. no cybertherapy be used for ICU pain management (5.3)?Balance of consequences Undesirable consequences clearly outweigh desirable consequences in most settingsUndesirable consequences probably outweigh desirable consequences in most settingsThe balance between desirable and undesirable consequences is closely balanced or uncertainDesirable consequences probably outweigh undesirable consequences in most settingsDesirable consequences clearly outweigh undesirable consequences in most settings○○●○○Type of recommendation We recommend against offering this optionWe suggest not offering this optionWe suggest offering this optionWe recommend offering this option○●○○Recommendation We recommend against offering VR cybertherapy until further research is available.From Bram:?I agree with your assessments. You may consider recommending more research and in the meantime recommending against (conditionally) until more research is available. Alternatively you could just recommend further work without making a formal recommendation. My slight preference would be for the former.?Justification I believe because of the very low evidence and the complications reported, the balance of?desirable and undesirable consequences is uncertain. But maybe the reduction in pain level probably outweigh the risks. ?I would be in favor of suggesting to conduct RCTs to allow a higher level of evidence to conclude on the effectiveness of such an intervention.Subgroup considerations Only 1 observational study conducted with cardiac surgery ICU patients. Small sample size. No inferential statistics.Implementation considerations Many factors to be taken into account including the ICU environment, access to technology, resources. and training?Monitoring and evaluation We need RCTs to draw firm conclusions about the effectiveness of such an intervention.?Research possibilities Rationale for recommendation: There is a major gap in research (1 observational study). Measure issue for pain (Likert scale). Small sample size (no power analysis) and inferential statistics not used.Other virtual interventions could be developed and tested. The use of touchpad or tablet could be considered.?Question: Hypnosis + pharmacological therapies compared to no hypnosis for critically ill pain management patients (5.4) Setting: Bibliography: Quality assessment№ of patientsEffectQualityImportance№ of studiesStudy designRisk of biasInconsistencyIndirectnessImprecisionOther considerationsHypnosis + pharmacological therapiesno hypnosis Relative(95% CI)Absolute(95% CI)Daily VAS Score (cm)1 observational studies very serious anot serious not serious very serious b,cnone 23 23 - MD 0.5 lower(1.37 lower to 0.37 higher) ????VERY LOW CRITICAL Morphine Equivalents1 observational studies very serious anot serious not serious very serious bnone Pre-post morphine equivalent dosing was not provided for the control arm. Intervention arm did have a large decrease in morphine equivalents between days 10-15; the authors attribute this to the completion of surgeries and wound management in these burn patients. ????VERY LOW CRITICAL Propofol Requirements (mg)1 observational studies very serious anot serious not serious very serious bnone 23 23 - MD 380 mg lower(523 lower to 237 lower) ????VERY LOW IMPORTANT CI: Confidence interval; MD: Mean differenceExplanationsa. Inaccurate assessment of outcomes, variability on co-interventions between groups, unclear ascertainment of exposure b. Small sample size (only 23 patients eligible) c. CI cross line of no effect Question Should Hypnosis + pharmacological therapies vs. no hypnosis be used for critically ill pain management patients (5.4)? Population: critically ill pain management patients (5.4) Background: Intervention: Hypnosis + pharmacological therapies Comparison: no hypnosis Main outcomes: Daily VAS Score (cm)Morphine EquivalentsPropofol Requirements (mg)AssessmentCriteria Judgements Research evidence Additional considerations ProblemIs there a problem priority? ○ No ○ Probably no ○ Uncertain ○ Probably yes ● Yes ○ Varies Non-pharmacological interventions are important to consider in ICU pain management.Benefits & harms of the optionsWhat is the overall certainty of this evidence? ○ No included studies ● Very low ○ Low ○ Moderate ○ High The relative importance or values of the main outcomes of interest: OutcomeRelative importance Certainty of the evidence (GRADE) Daily VAS Score (cm)CRITICAL????VERY LOWMorphine EquivalentsCRITICAL????VERY LOWPropofol Requirements (mg)IMPORTANT????VERY LOWOnly one small observational study (with matched controls, n=23 in each group); many limitations.?Are the desirable anticipated effects large?Pain score MD very small (0.5 lower) ?and CI cross line of no effect.Are the undesirable anticipated effects small?Uncertain; adverse events not reported. ?No difference in vital signs (HR, BP, RR), and first bowel movement between groups.Are the desirable effects large relative to undesirable effects?Probably no, but could put uncertain. We cannot conclude to small desirable effect considering that small observational study, and undesirable effects remain unknown (but unlikely).Is there important uncertainty about how much people value the main outcomes? ○ Important uncertainty or variability ○ Possibly important uncertainty or variability ○ Probably no important uncertainty or variability ● No important uncertainty or variability ○ No known undesirable outcomes Are the desirable anticipated effects large? ○ No ● Probably no ○ Uncertain ○ Probably yes ○ Yes ○ Varies Are the undesirable anticipated effects small? ○ No ○ Probably no ● Uncertain ○ Probably yes ○ Yes ○ Varies Are the desirable effects large relative to undesirable effects? ○ No ○ Probably no ● Uncertain ○ Probably yes ○ Yes ○ Varies Resource useAre the resources required small? ○ No ● Probably no ○ Uncertain ○ Probably yes ○ Yes ○ Varies In this study, hypnosis was administered by ICU nurses who had completed 3 years of training under the supervision of a psychiatrist.?Is the incremental cost small relative to the net benefits? ○ No ○ Probably no ● Uncertain ○ Probably yes ○ Yes ○ Varies Training appears extensive.Intervention with many stages; duration may vary between patients.EquityWhat would be the impact on health inequities? ○ Increased ○ Probably increased ● Uncertain ○ Probably reduced ○ Reduced ○ Varies UnlikelyAcceptabilityIs the option acceptable to key stakeholders? ○ No ○ Probably no ● Uncertain ○ Probably yes ○ Yes ○ Varies Uncertain based on required resources.FeasibilityIs the option feasible to implement? ○ No ● Probably no ○ Uncertain ○ Probably yes ○ Yes ○ Varies Feasibility concernsWill vary between patients (hypnosibility)Recommendation Should Hypnosis + pharmacological therapies vs. no hypnosis be used for critically ill pain management patients (5.4)?Balance of consequences Undesirable consequences clearly outweigh desirable consequences in most settingsUndesirable consequences probably outweigh desirable consequences in most settingsThe balance between desirable and undesirable consequences is closely balanced or uncertainDesirable consequences probably outweigh undesirable consequences in most settingsDesirable consequences clearly outweigh undesirable consequences in most settings○○●○○Type of recommendation We recommend against offering this optionWe suggest not offering this optionWe suggest offering this optionWe recommend offering this option○●○○Recommendation No recommendation? The group feels more confortable to not make a recommendation and document why we cannot make recommendation.Methods- I would steer the group towards a conditional/weak recommendation against given the lack of benefit (acknowledging all very low quality evidence) and the costs/resources involved in training.?I believe there is utility in making a recommendation versus not making one. And I think here a weak recommendation against makes sense - if the group agrees. It doesn't mean we're discouraging future research work and we can be clear about that (always everyone's worry in this case).?Justification Little evidence to support a recommendation for hypnosis.In the justification you can obviously elaborate and say that if future evidence shows benefit this balance may change or in select centers with expertise the balance may be different.?Subgroup considerations The included study was conducted in a burn ICU during dressing and hydrotherapy.Implementation considerations Not yet to be considered for implementation, need stronger evidence and RCTs.Monitoring and evaluation Research possibilities Ideas form the group?Having higher level of evidence, include other ICU patients and during care procedures. Review research in anesthesia (morphine sparing effects, anesthesia) and specific surgical procedures (pediatric and gynecological).Comments during electronic voting by entire panelHard to imagine virtual reality as good option for a population at such high risk for delirium (or certainly an altered state of consciousness). Question: A narcotic compared to placebo for critically ill adults undergoing a procedure (2.1) Setting: Bibliography: Quality assessment№ of patientsEffectQualityImportance№ of studiesStudy designRisk of biasInconsistencyIndirectnessImprecisionOther considerationsa narcoticplaceboRelative(95% CI)Absolute(95% CI)Pain Score2 randomised trials not serious not serious anot serious serious bnone 59 56 - SMD 1.27 SD lower(2.79 lower to 0.26 higher) ????MODERATE CRITICAL CI: Confidence interval; SMD: Standardised mean differenceExplanationsa. High Isquared (>90%), although both studies show benefit. b. Confidence intervals don't exclude harm. 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ADDIN EN.CITE.DATA [17] : Randomized, double-blind, paralell group, placebo-controlled clinical trial, 2 groups: 1) fentanyl (1 ug/kg for medical patients and 1.5 ug/kg for surgical/trauma patients) (n=39); and 2) control (n=36).?Procedure: turning in mechanically ventilated patients (heterogeneous group)Pain measure: BPS ( a score >3 reflects pain, and a score >5 indicates significant pain)Main findings: Pain incidence rate was significantly lower in the fentanyl group (74%) compared to control group (94%) with a relative risk of 0.79; incidence of significant pain was not statistically different between groups (49% versus 64%) with a relative risk of 0.76. Magnitude of pain (AUC): the fentanyl group had a lower magnitude of pain than the control group during turning and 30 minutes after. Adverse events and vital signs also reported.Casey et al. (2010): Randomized, double-blind clinical trial, 3 groups: 1) remifentanyl 1 ug/kg (n=20), 2) remifentanyl 0.5 ug/kg (n=20), and 3) placebo (n=20). I assume the remifentanyl 0.5 ug/kg was only included in the evidence table (to be confirmed with John C and Bram).Procedure: CTR in cardiac surgery ICU patientsPain measure: 10 cm VASMain findings: both remifentanyl groups had no increase in pain scores during CTR compared with baseline (median=1 for remifentanyl 5 ug/kg and 0 for remifentanyl 1 ug/kg; the median was 2 for both groups at baseline); the placebo group showed an increase in VAS pain scores during CTR (median=5). Vital signs data (SBP, HR, RR, SpO2) also reported.Overall SMD was 1.27 lowerAre the desirable anticipated effects large?Probably yes because did not reach clinical significance reduction in pain (2 cm). More difficult to conclude with BPS, but pain incidence (BPS>3) was lower in the fentanyl group by 20%.Paul, Kathleen and JF: BPS of 3 indicates no pain behaviors were present? Not necessarily... Nurses can administer analgesics if BPS >4 (JFAre the undesirable anticipated?effects small?Probably yes because no serious adverse events (but 4 patients with respiratory depression in the fentanyl group) reported in Robleda study; 19 non-serious events (e.g., transient hypotension, vomiting) with no significant differences between groups. In Casey study, reductions in all vital signs in the remifentanyl 1 ug/kg group, but only for blood pressure and RR in the remifentanyl 0.5 ug/kg group. No differences in vital signs between groups in Robleda study (increases during turning observed in both groups).?- Respiratory depression is a severe adverse event.-: Varies because dose dependent.Are the desirable effects large relative to undesirable effects?Probably yes considering the reductions in pain scores in the opioid groups, and given that adverse events were equally balanced between groups (except for respiratory depression).-: uncertain because too many factors involved; but ok with pt-s for probably yespt-: in the ICU, the team can deal with respiratory depression; benefits outweighs the undesirable effectsIs there important uncertainty about how much people value the main outcomes? ○ Important uncertainty or variability ○ Possibly important uncertainty or variability ○ Probably no important uncertainty or variability ● No important uncertainty or variability ○ No known undesirable outcomes Are the desirable anticipated effects large? ○ No ○ Probably no ○ Uncertain ● Probably yes ○ Yes ○ Varies Are the undesirable anticipated effects small? ○ No ○ Probably no ○ Uncertain ○ Probably yes ○ Yes ● Varies Are the desirable effects large relative to undesirable effects? ○ No ○ Probably no ○ Uncertain ● Probably yes ○ Yes ○ Varies Resource useAre the resources required small? ○ No ○ Probably no ○ Uncertain ● Probably yes ○ Yes ○ Varies Opioids are part of standard of care. However, remifentanyl is more expensive compared to fentanyl. ?Is the incremental cost small relative to the net benefits? ○ No ○ Probably no ○ Uncertain ● Probably yes ○ Yes ○ Varies Probably yes because opioids are easily accessible in the ICU, and are shown to be effective in reducing pain scores during procedures.?Remifentanil more expensive compared to fentanyl.EquityWhat would be the impact on health inequities? ○ Increased ○ Probably increased ○ Uncertain ○ Probably reduced ○ Reduced ○ Varies AcceptabilityIs the option acceptable to key stakeholders? ○ No ○ Probably no ○ Uncertain ● Probably yes ○ Yes ○ Varies Probably yes for fentanyl. For remifentanil, it may vary in different countries based on costs and standard practice.?FeasibilityIs the option feasible to implement? ○ No ○ Probably no ○ Uncertain ● Probably yes ○ Yes ○ Varies Probably yes for fentanyl, but uncertain for remifentanil based on my comments above.?-: Probably yes considering the 2 trials together- feasible and quick to actionPt-: adverse effects lasting shorterRecommendation Should a narcotic vs. placebo be used for critically ill adults undergoing a procedure (2.1)?Balance of consequences Undesirable consequences clearly outweigh desirable consequences in most settingsUndesirable consequences probably outweigh desirable consequences in most settingsThe balance between desirable and undesirable consequences is closely balanced or uncertainDesirable consequences probably outweigh undesirable consequences in most settingsDesirable consequences clearly outweigh undesirable consequences in most settings○○○●○Type of recommendation We recommend against offering this optionWe suggest not offering this optionWe suggest offering this optionWe recommend offering this option○○●○Recommendation We suggest using an opioid prior to a procedure (e.g., CTR, turning) for pain management in ICU patients (+2B).Justification Well designed RCTs showing reductions in pain scores or pain incidence when opioids are administered compared to a placebo.Subgroup considerations CTR in cardiac surgery ICU patients (Casey) ADDIN EN.CITE <EndNote><Cite><Author>Casey</Author><Year>2010</Year><RecNum>1914</RecNum><DisplayText>[18]</DisplayText><record><rec-number>1914</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232813">1914</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Casey, Eoin</author><author>Lane, Aoife</author><author>Kuriakose, Dinesh</author><author>McGeary, Shane</author><author>Hayes, Niamh</author><author>Phelan, Dermot</author><author>Buggy, Donal</author></authors></contributors><auth-address>Department of Anaesthesia and Critical Care Medicine, Mater Misericordiae University Hospital, Dublin, Ireland. casey_eoin@</auth-address><titles><title>Bolus remifentanil for chest drain removal in ICU: a randomized double-blind comparison of three modes of analgesia in post-cardiac surgical patients</title><secondary-title>Intensive Care Med.</secondary-title></titles><periodical><full-title>Intensive Care Med.</full-title></periodical><pages>1380-1385</pages><volume>36</volume><number>8</number><dates><year>2010</year><pub-dates><date>2010/8</date></pub-dates></dates><isbn>0342-4642</isbn><urls><related-urls><url> Papers/C/Casey et al. 2010 - Bolus remifentanil for chest drain removal in ICU - ... mparison of three modes of analgesia in post-cardiac surgical patients.pdf</url></pdf-urls></urls><electronic-resource-num>10.1007/s00134-010-1836-2</electronic-resource-num></record></Cite></EndNote>[18]; turning in an heterogeneous ICU patient group (Robleda)PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Sb2JsZWRhPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48
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ADDIN EN.CITE.DATA [17]Implementation considerations Costs and standard practice in different countries; timing of administration prior to the procedure is important to consider (but quick to act); adverse events may occur and should be monitored and treated in a timely mannerMonitoring and evaluation Pain assessment prior and during (or right after the procedure) is key for the evaluation of the effectiveness of analgesia; monitoring of adverse events should also be doneResearch possibilities Other procedures and other opioids should be tested; for turning, it would be relevant to also include the self-report of pain intensity as a primary outcomeImplementation studies are also needed?Question: High dose narcotic compared to low dose narcotic for critically ill adults undergoing a procedure (2.1) Setting: Bibliography: Quality assessment№ of patientsEffectQualityImportance№ of studiesStudy designRisk of biasInconsistencyIndirectnessImprecisionOther considerationshigh dose narcoticlow dose narcoticRelative(95% CI)Absolute(95% CI)Pain Score (assessed with: SMD)2 randomised trials not serious serious anot serious serious bnone 78 79 - SMD 0.26 SD lower(0.94 lower to 0.42 higher) ????LOW CRITICAL CI: Confidence interval; SMD: Standardised mean differenceExplanationsa. High Isquared (70%) and non-overlapping confidence intervals. b. Wide confidence intervals don't exclude harm. QuestionShould high dose narcotic vs. low dose narcotic be used for critically ill adults undergoing a procedure (2.1)? Population: critically ill adults undergoing a procedure (2.1) Background: Intervention: high dose narcotic Comparison: low dose narcotic Main outcomes: Pain ScoreAssessmentCriteria Judgements Research evidence Additional considerations ProblemIs there a problem priority? ○ No ○ Probably no ○ Uncertain ○ Probably yes ● Yes ○ Varies Pharmacological interventions for procedural pain management are important given the documented prevalence of pain associated with many ICU procedures. ?What is the overall certainty of this evidence? Casey 2010 ADDIN EN.CITE <EndNote><Cite><Author>Casey</Author><Year>2010</Year><RecNum>1914</RecNum><DisplayText>[18]</DisplayText><record><rec-number>1914</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232813">1914</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Casey, Eoin</author><author>Lane, Aoife</author><author>Kuriakose, Dinesh</author><author>McGeary, Shane</author><author>Hayes, Niamh</author><author>Phelan, Dermot</author><author>Buggy, Donal</author></authors></contributors><auth-address>Department of Anaesthesia and Critical Care Medicine, Mater Misericordiae University Hospital, Dublin, Ireland. casey_eoin@</auth-address><titles><title>Bolus remifentanil for chest drain removal in ICU: a randomized double-blind comparison of three modes of analgesia in post-cardiac surgical patients</title><secondary-title>Intensive Care Med.</secondary-title></titles><periodical><full-title>Intensive Care Med.</full-title></periodical><pages>1380-1385</pages><volume>36</volume><number>8</number><dates><year>2010</year><pub-dates><date>2010/8</date></pub-dates></dates><isbn>0342-4642</isbn><urls><related-urls><url> Papers/C/Casey et al. 2010 - Bolus remifentanil for chest drain removal in ICU - ... mparison of three modes of analgesia in post-cardiac surgical patients.pdf</url></pdf-urls></urls><electronic-resource-num>10.1007/s00134-010-1836-2</electronic-resource-num></record></Cite></EndNote>[18]: ?significantly less pain with CTR or turning after remifentanyl?1 mcg/kg remifentanil IV (n=20) vs?remifentanyl 0.5?mcg/kg remifentanil IV (n=20). ?CTR pain intensity scores per 0-10 VAS:?Remifentanil 1 mcg/kg = median 0 [0-2]Remifentanil 0.5 mcg/kg = median 1 [0, 2]SMD -0.66 [-1.30, -0.02]Ahlers 2012 ADDIN EN.CITE <EndNote><Cite><Author>Ahlers</Author><Year>2012</Year><RecNum>1687</RecNum><DisplayText>[19]</DisplayText><record><rec-number>1687</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232800">1687</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ahlers, S. J. G. M.</author><author>van Gulik, L.</author><author>van Dongen, E. P. A.</author><author>Bruins, P.</author><author>van de Garde, E. M. W.</author><author>van Boven, W. J.</author><author>Tibboel, D.</author><author>Knibbe, C. A. J.</author></authors></contributors><auth-address>Department of Anaesthesiology, St Antonius Hospital, Nieuwegein, The Netherlands. s.ahlers@antoniusziekenhuis.nl</auth-address><titles><title>Efficacy of an intravenous bolus of morphine 2.5 versus morphine 7.5 mg for procedural pain relief in postoperative cardiothoracic patients in the intensive care unit: a randomised double-blind controlled trial</title><secondary-title>Anaesth. Intensive Care</secondary-title></titles><periodical><full-title>Anaesth. Intensive Care</full-title></periodical><pages>417-426</pages><volume>40</volume><number>3</number><dates><year>2012</year><pub-dates><date>2012/5</date></pub-dates></dates><isbn>0310-057X</isbn><urls><related-urls><url>;[19]: found no difference in pain with CTR with?morphine 7.5 mg IV 30 minutes prior to procedure (n-58) vs?morphine 2.5 mg IV 30 minutes prior to procedure (n=59). ?(Ahlers did not differentiate between those who were turned vs. turned and CTR.) ?Procedural pain scores per 0-10 NRS:Morphine 7.5 mg IV = mean 2.7?+?2.0-3.4Morphine 2.5 mg IV = mean 2.6 + 2.0-3.2SMD 0.04 [-0.32, 0.40]Overall SMD?-0.26 [-0.94, 0.42] ?NSSo, only 1 small-sample study with significant findings. ?Benefits & harms of the optionsWhat is the overall certainty of this evidence? ○ No included studies ○ Very low ● Low ○ Moderate ○ High The relative importance or values of the main outcomes of interest: OutcomeRelative importance Certainty of the evidence (GRADE) Pain ScoreCRITICAL????LOWAre the desirable anticipated effects large? ?NoAre the undesirable anticipated effects small???Casey ADDIN EN.CITE <EndNote><Cite><Author>Casey</Author><Year>2010</Year><RecNum>1914</RecNum><DisplayText>[18]</DisplayText><record><rec-number>1914</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232813">1914</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Casey, Eoin</author><author>Lane, Aoife</author><author>Kuriakose, Dinesh</author><author>McGeary, Shane</author><author>Hayes, Niamh</author><author>Phelan, Dermot</author><author>Buggy, Donal</author></authors></contributors><auth-address>Department of Anaesthesia and Critical Care Medicine, Mater Misericordiae University Hospital, Dublin, Ireland. casey_eoin@</auth-address><titles><title>Bolus remifentanil for chest drain removal in ICU: a randomized double-blind comparison of three modes of analgesia in post-cardiac surgical patients</title><secondary-title>Intensive Care Med.</secondary-title></titles><periodical><full-title>Intensive Care Med.</full-title></periodical><pages>1380-1385</pages><volume>36</volume><number>8</number><dates><year>2010</year><pub-dates><date>2010/8</date></pub-dates></dates><isbn>0342-4642</isbn><urls><related-urls><url> Papers/C/Casey et al. 2010 - Bolus remifentanil for chest drain removal in ICU - ... mparison of three modes of analgesia in post-cardiac surgical patients.pdf</url></pdf-urls></urls><electronic-resource-num>10.1007/s00134-010-1836-2</electronic-resource-num></record></Cite></EndNote>[18] had?2/20 patients with 1-3 minutes of apnea after?1 mcg/kg remifentanil IV,?requiring bag and mask ventilation 1 minute after drug administration.Are the desirable effects large relative to undesirable effects? ??Depends on drug dosage, as in Casey ADDIN EN.CITE <EndNote><Cite><Author>Casey</Author><Year>2010</Year><RecNum>1914</RecNum><DisplayText>[18]</DisplayText><record><rec-number>1914</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232813">1914</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Casey, Eoin</author><author>Lane, Aoife</author><author>Kuriakose, Dinesh</author><author>McGeary, Shane</author><author>Hayes, Niamh</author><author>Phelan, Dermot</author><author>Buggy, Donal</author></authors></contributors><auth-address>Department of Anaesthesia and Critical Care Medicine, Mater Misericordiae University Hospital, Dublin, Ireland. casey_eoin@</auth-address><titles><title>Bolus remifentanil for chest drain removal in ICU: a randomized double-blind comparison of three modes of analgesia in post-cardiac surgical patients</title><secondary-title>Intensive Care Med.</secondary-title></titles><periodical><full-title>Intensive Care Med.</full-title></periodical><pages>1380-1385</pages><volume>36</volume><number>8</number><dates><year>2010</year><pub-dates><date>2010/8</date></pub-dates></dates><isbn>0342-4642</isbn><urls><related-urls><url> Papers/C/Casey et al. 2010 - Bolus remifentanil for chest drain removal in ICU - ... mparison of three modes of analgesia in post-cardiac surgical patients.pdf</url></pdf-urls></urls><electronic-resource-num>10.1007/s00134-010-1836-2</electronic-resource-num></record></Cite></EndNote>[18].-Probably no considering that desirable effects are absent.- No (no positive effects)Is there important uncertainty about how much people value the main outcomes? ○ Important uncertainty or variability ○ Possibly important uncertainty or variability ○ Probably no important uncertainty or variability ● No important uncertainty or variability ○ No known undesirable outcomes Are the desirable anticipated effects large? ● No Are the undesirable anticipated effects small? ○ No ○ Probably no ● Uncertain Are the desirable effects large relative to undesirable effects? ● No ○ Probably no ○ Uncertain ○ Probably yes ○ Yes ○ Varies Resource useAre the resources required small? ○ No ○ Probably no ○ Uncertain ○ Probably yes ● Yes ○ Varies Administration of opioids is standard practice in ICUs.Is the incremental cost small relative to the net benefits? ○ No ○ Probably no ● Uncertain ○ Probably yes ○ Yes ○ Varies Pain relief from opioid administration is low cost.=: Uncertain; Remifentanyl more expensiveGroup consensusEquityWhat would be the impact on health inequities? ○ Increased ○ Probably increased ○ Uncertain ○ Probably reduced ○ Reduced ○ Varies AcceptabilityIs the option acceptable to key stakeholders? ○ No ● Probably no ○ Uncertain ○ Probably yes ○ Yes ○ Varies Administration of opioids is standard practice in ICUs.- Uncertain because administration of opioids prior to a procedure raise many concerns among ICU clinicians.- Low versus high doses; so probably no (with high doses).- Probably noFeasibilityIs the option feasible to implement? ○ No ○ Probably no ● Uncertain ○ Probably yes ○ Yes ○ Varies Administration of opioids is standard practice in ICUs. ?However, administration of opioids prior to procedures requires ICU clinicians to probably change practice and plan for this.- Uncertain with only 2 studies and small samples in a homogeneous population.-Uncertain; will depend on intubation status and communication between nurses and physiciansRecommendation Should high dose narcotic vs. low dose narcotic be used for critically ill adults undergoing a procedure (2.1)?Balance of consequences Undesirable consequences clearly outweigh desirable consequences in most settingsUndesirable consequences probably outweigh desirable consequences in most settingsThe balance between desirable and undesirable consequences is closely balanced or uncertainDesirable consequences probably outweigh undesirable consequences in most settingsDesirable consequences clearly outweigh undesirable consequences in most settings○○●○○Type of recommendation We recommend against offering this optionWe suggest not offering this optionWe suggest offering this optionWe recommend offering this option○○●○Recommendation A substantial body of research demonstrates the painfulness of turning and chest tube removal. ?Pain should be assessed prior to a procedure, and administration of analgesics to address baseline as well as procedural pain should be made a standard part of practice.Opioids in low doses should be considered for procedural pain management. (in both studies, the scores were low no matter low or high doses were used)We suggest using opioids for chest tube removal. If using opioids, we suggest using low doses versus high doses. Little benefit and use of low versus high doses of opioids; I would suggest not offering this option. Recommending lower doses would be a better option. No benefit to administer opioids when pain at baseline is low. No control groups (with no opioids) in these studies For semantics, better to use positive than negative.Justification 2013 PAD Guidelines ADDIN EN.CITE <EndNote><Cite><Author>Barr</Author><Year>2013</Year><RecNum>2229</RecNum><DisplayText>[20]</DisplayText><record><rec-number>2229</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232831">2229</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Barr, J.</author><author>Fraser, G. L.</author><author>Puntillo, K.</author><author>Ely, E. W.</author><author>Gelinas, C.</author><author>Dasta, J. F.</author><author>Davidson, J. E.</author><author>Devlin, J. W.</author><author>Kress, J. P.</author><author>Joffe, A. M.</author><author>Coursin, D. B.</author><author>Herr, D. L.</author><author>Tung, A.</author><author>Robinson, B. R.</author><author>Fontaine, D. K.</author><author>Ramsay, M. A.</author><author>Riker, R. R.</author><author>Sessler, C. N.</author><author>Pun, B.</author><author>Skrobik, Y.</author><author>Jaeschke, R.</author></authors></contributors><auth-address>Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA. barrj@stanford.edu</auth-address><titles><title>Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the Intensive Care Unit: executive summary</title><secondary-title>Am. J. Health. Syst. Pharm.</secondary-title></titles><periodical><full-title>Am. J. Health. Syst. Pharm.</full-title></periodical><pages>53-58</pages><volume>70</volume><number>1</number><keywords><keyword>Adult Delirium/diagnosis/epidemiology/*therapy Disease Management Humans Intensive Care Units/*standards Pain/diagnosis/epidemiology Pain Management/methods/*standards Psychomotor Agitation/diagnosis/epidemiology/*therapy</keyword><keyword>20170921 - goodson.txt</keyword></keywords><dates><year>2013</year><pub-dates><date>2013</date></pub-dates></dates><isbn>1079-2082</isbn><urls></urls></record></Cite></EndNote>[20] recommended use of analgesics prior to CTR.Subgroup considerations Ahlers ADDIN EN.CITE <EndNote><Cite><Author>Ahlers</Author><Year>2012</Year><RecNum>1687</RecNum><DisplayText>[19]</DisplayText><record><rec-number>1687</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232800">1687</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ahlers, S. J. G. M.</author><author>van Gulik, L.</author><author>van Dongen, E. P. A.</author><author>Bruins, P.</author><author>van de Garde, E. M. W.</author><author>van Boven, W. J.</author><author>Tibboel, D.</author><author>Knibbe, C. A. J.</author></authors></contributors><auth-address>Department of Anaesthesiology, St Antonius Hospital, Nieuwegein, The Netherlands. s.ahlers@antoniusziekenhuis.nl</auth-address><titles><title>Efficacy of an intravenous bolus of morphine 2.5 versus morphine 7.5 mg for procedural pain relief in postoperative cardiothoracic patients in the intensive care unit: a randomised double-blind controlled trial</title><secondary-title>Anaesth. Intensive Care</secondary-title></titles><periodical><full-title>Anaesth. Intensive Care</full-title></periodical><pages>417-426</pages><volume>40</volume><number>3</number><dates><year>2012</year><pub-dates><date>2012/5</date></pub-dates></dates><isbn>0310-057X</isbn><urls><related-urls><url>;[19] did not differentiate between patients being turned and patients being turned and having CTR. ?This confounds study findings. ?However, Ahlers said that patients just having CTR had significantly less pain than patients just being turned.Implementation considerations Administration of opioids prior to a procedure should be timed to the analgesic's peak effect, occurring at time of procedure.Monitoring and evaluation Pre and post pain assessments to evaluate impact of the intervention. ?Potential adverse effects from opioids should be monitored.Research possibilities Study one procedure e.g., CTR?using equianalgesic dose of?remifentanyl 0.5?mcg/kg IV in a large sample. Alternative ments during electronic voting by entire panelRCT showing fentanyl (1-1.5 mcg/kg/ dose) before turning in mixed, MV population ↓ pain by BPS by 20%, NNT 5 (Robleda ICM 2016); 10% got respiratory depression.Caveats: Forrest plots (FPs) mitigated by outcomes combined from different studies; #1 improved pain scores opioid vs. placebo, #2 pain score differences with opioids + turning= no difference, also a positive outcome. But combining these different outcomes misleads the FPs. In which pt. population is turning painful?Question: Local analgesia compared to nitrous oxide for critically ill adults undergoing a procedure (2.1) Setting: Bibliography: Quality assessment№ of patientsEffectQualityImportance№ of studiesStudy designRisk of biasInconsistencyIndirectnessImprecisionOther considerationslocal analgesianitrous oxideRelative(95% CI)Absolute(95% CI)Pain Score1 randomised trials serious anot serious not serious serious bnone 22 22 - MD 27.5 lower(40.9 lower to 14.1 lower) ????LOW CRITICAL New outcomenot estimable - CI: Confidence interval; MD: Mean differenceExplanationsa. No clear description of allocation concealment or blinding in single included study. b. Confidence intervals don't include no effect however small number of patients. QuestionShould local analgesia vs. nitrous oxide be used for critically ill adults undergoing a procedure (2.1)? Population: critically ill adults undergoing a procedure (2.1) Background: Intervention: local analgesia Comparison: nitrous oxide Main outcomes: Pain ScoreAssessmentCriteria Judgements Research evidence Additional considerations ProblemIs there a problem priority? ○ No ○ Probably no ○ Uncertain ○ Probably yes ● Yes ○ Varies Pharmacological interventions for procedural pain management?are important given the documented prevalence of pain associated with many ICU procedures. ?Benefits & harms of the optionsWhat is the overall certainty of this evidence? ○ No included studies ○ Very low ● Low ○ Moderate ○ High The relative importance or values of the main outcomes of interest: OutcomeRelative importance Certainty of the evidence (GRADE) Pain ScoreCRITICAL????LOWAre desirable anticipated effects large?Only one study: ?Akrofi, 2005 ADDIN EN.CITE <EndNote><Cite><Author>Akrofi</Author><Year>2005</Year><RecNum>1916</RecNum><DisplayText>[21]</DisplayText><record><rec-number>1916</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232813">1916</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Akrofi, Maria</author><author>Miller, Scott</author><author>Colfar, Steve</author><author>Corry, Peter R.</author><author>Fabri, Brian M.</author><author>Pullan, Mark D.</author><author>Russell, Glenn N.</author><author>Fox, Mark A.</author></authors></contributors><auth-address>The Cardiothoracic Centre National Health Service Trust, Thomas Dr., Liverpool, UK L14 3PE.</auth-address><titles><title>A randomized comparison of three methods of analgesia for chest drain removal in postcardiac surgical patients</title><secondary-title>Anesth. Analg.</secondary-title></titles><periodical><full-title>Anesth. Analg.</full-title></periodical><pages>205-209</pages><volume>100</volume><number>1</number><dates><year>2005</year><pub-dates><date>2005/1</date></pub-dates></dates><isbn>0003-2999</isbn><urls><related-urls><url> Papers/A/Akrofi et al. 2005 - A randomized comparison of three methods of analgesia for chest drain removal in postcardiac surgical patients.pdf</url></pdf-urls></urls><electronic-resource-num>10.1213/01.ANE.0000140237.96510.E5</electronic-resource-num></record></Cite></EndNote>[21]. CTR after cardiac surgery. ?Either 20 ml of 0.5% bupivacaine SQ infiltration around drain insertion site (comparator) (n=22) or inhaled 50% nitrous oxide and oxygen (Entonox) (control) (n=22). Median pain intensity score 9.5 (3–18) in bupivacaine group vs 37.0 (13–56) in Entonox group (p<0.05).?SMD; ?- 27.50 [-40.90, -14.10] on 0 - 100 VAS. ?Large clinical significance. ?No clear description of allocation concealment or blinding in single included study.Are the undesirable anticipated effects small??No difference among groups in arterial blood?pressure, heart rate, PaCo2, oxygenation, or sedation.: Adverse events less likely to occur with local administration and low doses. Probably yesIs there important uncertainty about how much people value the main outcomes? ○ Important uncertainty or variability ○ Possibly important uncertainty or variability ○ Probably no important uncertainty or variability ● No important uncertainty or variability Are the desirable anticipated effects large? ○ No ○ Probably no ○ Uncertain ● Probably yes ○ Yes ○ Varies Are the undesirable anticipated effects small? ○ No ○ Probably no ○ Uncertain ● Probably yes Are the desirable effects large relative to undesirable effects? ○ No ○ Probably no ○ Uncertain ● Probably yes Resource useAre the resources required small? ○ No ○ Probably no ○ Uncertain ● Probably yes Re. Entonox use: ?While they are a part of intra-operative anesthesia, use of ?gas in ICU for procedural pain relief is unusual. ?And it was not effective. ?Re. bupivacaine use: not a large effort needed to administer subcutaneously around chest tube.Is the incremental cost small relative to the net benefits? ○ No ○ Probably no ○ Uncertain ● Probably yes Could be part of standard practiceEquityWhat would be the impact on health inequities? ○ Increased ○ Probably increased ○ Uncertain ○ Probably reduced ○ Reduced ○ Varies AcceptabilityIs the option acceptable to key stakeholders? ○ No ○ Probably no ○ Uncertain ● Probably yes A qualified clinician would have to do the subcutaneous infiltration of bupivacaine.FeasibilityIs the option feasible to implement? ○ No ○ Probably no ○ Uncertain ● Probably yes ○ Yes ○ Varies Medication already available in clinical practice.Recommendation Should local analgesia vs. nitrous oxide be used for critically ill adults undergoing a procedure (2.1)?Balance of consequences Undesirable consequences clearly outweigh desirable consequences in most settingsUndesirable consequences probably outweigh desirable consequences in most settingsThe balance between desirable and undesirable consequences is closely balanced or uncertainDesirable consequences probably outweigh undesirable consequences in most settingsDesirable consequences clearly outweigh undesirable consequences in most settings○○○●○Type of recommendation We recommend against offering this optionWe suggest not offering this optionWe suggest offering this optionWe recommend offering this option○○●○Recommendation Bupivacaine infiltration is preferred over nitrous oxide prior to CTR.Justification Effective in reducing CTR pain. ?Clinically significant pain decrease.Subgroup considerations This study included removal of mediastinal chest tubes in cardiac surgery ICU patients. ?The effect on pleural tubes, whose removal is known to be more ?painful, ?is unknown.Implementation considerations Requires clinician qualified to do infiltration.Monitoring and evaluation Pre- and post- CTR pain scores should be ascertained.Research possibilities Replication of this study with a larger sample with heterogeneous patients and inclusion of a pleural chest tube group. ?This study had no clear description of allocation concealment or blinding in single included study. ?A future study should address these issues. ?Larger sample with enough power to determine differences in adverse ments during electronic voting by entire panelshould an opioid be used instead? Only comparing to opioids?Question: A narcotic compared to nitrous oxide for critically ill adults undergoing a procedure (2.1) Setting: Bibliography: Quality assessment№ of patientsEffectQualityImportance№ of studiesStudy designRisk of biasInconsistencyIndirectnessImprecisionOther considerationsa narcoticnitrous oxideRelative(95% CI)Absolute(95% CI)Pain Score1 randomised trials serious anot serious not serious serious bnone 22 22 - MD 22 lower(36.68 lower to 7.32 lower) ????LOW CRITICAL CI: Confidence interval; MD: Mean differenceExplanationsa. No clear description of allocation concealment or blinding in single included study. b. Small number of patients - despite confidence intervals all on side of benefit. QuestionShould a narcotic vs. nitrous oxide be used for critically ill adults undergoing a procedure (2.1)? Population: critically ill adults undergoing a procedure (2.1) Background: Intervention: a narcotic Comparison: nitrous oxide Main outcomes: Pain ScoreAssessmentCriteria Judgements Research evidence Additional considerations ProblemIs there a problem priority? ○ No ○ Probably no ○ Uncertain ○ Probably yes ● Yes ○ Varies Pharmacological interventions for procedural pain management ?are important given the documented prevalence of pain associated with many ICU procedures. ?Benefits & harms of the optionsWhat is the overall certainty of this evidence? ○ No included studies ○ Very low ● Low ○ Moderate The relative importance or values of the main outcomes of interest: OutcomeRelative importance Certainty of the evidence (GRADE) Pain ScoreCRITICAL????LOWOnly one study: ?Akrofi, 2005 ADDIN EN.CITE <EndNote><Cite><Author>Akrofi</Author><Year>2005</Year><RecNum>1916</RecNum><DisplayText>[21]</DisplayText><record><rec-number>1916</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232813">1916</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Akrofi, Maria</author><author>Miller, Scott</author><author>Colfar, Steve</author><author>Corry, Peter R.</author><author>Fabri, Brian M.</author><author>Pullan, Mark D.</author><author>Russell, Glenn N.</author><author>Fox, Mark A.</author></authors></contributors><auth-address>The Cardiothoracic Centre National Health Service Trust, Thomas Dr., Liverpool, UK L14 3PE.</auth-address><titles><title>A randomized comparison of three methods of analgesia for chest drain removal in postcardiac surgical patients</title><secondary-title>Anesth. Analg.</secondary-title></titles><periodical><full-title>Anesth. Analg.</full-title></periodical><pages>205-209</pages><volume>100</volume><number>1</number><dates><year>2005</year><pub-dates><date>2005/1</date></pub-dates></dates><isbn>0003-2999</isbn><urls><related-urls><url> Papers/A/Akrofi et al. 2005 - A randomized comparison of three methods of analgesia for chest drain removal in postcardiac surgical patients.pdf</url></pdf-urls></urls><electronic-resource-num>10.1213/01.ANE.0000140237.96510.E5</electronic-resource-num></record></Cite></EndNote>[21]. CTR after cardiac surgery. ?Either?50% nitrous oxide and oxygen (Entonox) (control) 2 minutes before procedure (n=22) or?0.1 mg/kg morphine?as an IV bolus over 2 min 20 minutes before procedure (intervention)(n=22.)?Median VAS scores on 0 - 100 scale: ?nitrous oxide group: 37.0 [13–56] vs. morphine group: 15.0 [7–27]SMD: -22 [-36.68, -7.32] ?Acceptable?clinical significance. ?No clear description of allocation concealment or blinding in single included study. ?Are anticipated effects large? Uncertain or probably no given one study, pain scores not in the moderate-severe levels.?Do we want one of these interventions to have a big difference on pain scores? Nitrous oxide patients had twice more pain than the morphine patients.?Pamela: No differences with 2 and 4/10; side effects not considered.Gerald: One small study; 37 is pretty high so anticipated effects appear to be large. Could patients with nitrous oxide reliably self-report pain?-Not considering the sample size and side effects, just looking at this specific question what is the benefit of opioids large? With group: Considering this, probably yes makes sense.Are the undesirable anticipated effects small? ?No difference among groups in arterial blood?pressure, heart rate, PaCo2, oxygenation, or sedation.Desirable versus undesirable effects: Changed to probably yesIs there important uncertainty about how much people value the main outcomes? ● No important uncertainty or variability Are the desirable anticipated effects large? ● Probably yes ○ Yes ○ Varies Are the undesirable anticipated effects small? ● Yes ○ Varies Are the desirable effects large relative to undesirable effects? ○ No ○ Probably no ○ Uncertain ● Probably yes Resource useAre the resources required small? ○ No ○ Probably no ○ Uncertain ○ Probably yes ● Yes ○ Varies Use of IV opioids is part of standard practice.Is the incremental cost small relative to the net benefits? ○ No ○ Probably no ○ Uncertain ○ Probably yes ● Yes ○ Varies No incremental costs.EquityWhat would be the impact on health inequities? ○ Increased ○ Probably increased ○ Uncertain ○ Probably reduced ○ Reduced X○ Varies AcceptabilityIs the option acceptable to key stakeholders? ○ No ○ Probably no ○ Uncertain ○ Probably yes ● Yes ○ Varies Use of IV opioids is part of standard practice.FeasibilityIs the option feasible to implement? ○ No ○ Probably no ○ Uncertain ○ Probably yes ● Yes ○ Varies Recommendation Should a narcotic vs. nitrous oxide be used for critically ill adults undergoing a procedure (2.1)?Balance of consequences Undesirable consequences clearly outweigh desirable consequences in most settingsUndesirable consequences probably outweigh desirable consequences in most settingsThe balance between desirable and undesirable consequences is closely balanced or uncertainDesirable consequences probably outweigh undesirable consequences in most settingsDesirable consequences clearly outweigh undesirable consequences in most settings○○○●○Type of recommendation We recommend against offering this optionWe suggest not offering this optionWe suggest offering this optionWe recommend offering this option○○●○Recommendation We suggest to premedicate patients with opioids instead of nitrous oxide prior to mediastinal chest tube removal.Justification Clinical significance difference in favor of morphine; small studySubgroup considerations This study included removal of mediastinal chest tubes in cardiac surgery patients. ?The effect on pleural tubes, whose removal is known to be more ?painful, ?is unknown.Use of short-term opioids (e.g., fentanyl, alfentanyl, remifentanyl) to manage short-duration procedures.Implementation considerations Opioids are already implemented in standard practice.?Monitoring and evaluation Pain assessment prior to the procedure with validated scales. ?Side effect monitoring.Research possibilities Replication of this study with a larger sample and inclusion of a pleural chest tube group. ?This study had no clear description of allocation concealment or blinding in single included study. ?A future study should address these issues.Larger sample size necessary to capture adverse events. As a patient, I would prefer nitrous oxide. Differences among different types of opioids in terms of side effects.Question: Isoflurane & Nitrous Oxide compared to Nitrous oxide alone for critically ill adults undergoing a procedure (2.1) Setting: Bibliography: Quality assessment№ of patientsEffectQualityImportance№ of studiesStudy designRisk of biasInconsistencyIndirectnessImprecisionOther considerationsIsoflurane & Nitrous OxideNitrous oxide aloneRelative(95% CI)Absolute(95% CI)Pain Score1 randomised trials serious anot serious serious bserious cnone Although the Bryden 1997 ADDIN EN.CITE <EndNote><Cite><Author>Bryden</Author><Year>1997</Year><RecNum>1685</RecNum><DisplayText>[22]</DisplayText><record><rec-number>1685</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232800">1685</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bryden, F. M.</author><author>McFarlane, H.</author><author>Tunstall, M. E.</author><author>Ross, J. A.</author></authors></contributors><auth-address>Department of Anaesthesia, Aberdeen Royal Hospitals NHS Trust, Aberdeen Royal Infirmary, UK.</auth-address><titles><title>Isoflurane for removal of chest drains after cardiac surgery</title><secondary-title>Anaesthesia</secondary-title></titles><periodical><full-title>Anaesthesia</full-title></periodical><pages>173-175</pages><volume>52</volume><number>2</number><dates><year>1997</year><pub-dates><date>1997/2</date></pub-dates></dates><isbn>0003-2409</isbn><urls><related-urls><url> Papers/B/Bryden et al. 1997 - Isoflurane for removal of chest drains after cardiac surgery.pdf</url></pdf-urls></urls></record></Cite></EndNote>[22] study showed that Entonox (nitrous oxide plus oxygen) along with isoflurane inhalation was more effective for pain related to the first of 2 chest tubes to be removed, removal of the second tube was more painful, regardless of the gas inhaled. SMD -26.00 [-40.76, -11.24] on a 0 - 100 VAS. ????VERY LOW CRITICAL CI: Confidence interval; MD: Mean differenceExplanationsa. Unclear description of blinding practices in single included study. b. Comparator not placebo. c. Despite confidence intervals that don't cross no effect there was a small number of patients. QuestionShould Isoflurane & Nitrous Oxide vs. Nitrous oxide alone be used for critically ill adults undergoing a procedure (2.1)? Population: critically ill adults undergoing a procedure (2.1) Background: Intervention: Isoflurane & Nitrous Oxide Comparison: Nitrous oxide alone Main outcomes: Pain ScoreAssessmentCriteria Judgements Research evidence Additional considerations ProblemIs there a problem priority? ○ No ○ Probably no ○ Uncertain ○ Probably yes ● Yes ○ Varies Non-pharmacological interventions for procedural pain management ?are important given the documented prevalence of pain associated with many ICU procedures. ?Benefits & harms of the optionsWhat is the overall certainty of this evidence? ○ No included studies ● Very low The relative importance or values of the main outcomes of interest: OutcomeRelative importance Certainty of the evidence (GRADE) Pain ScoreCRITICAL????LOW35 patients after uncomplicated cardiac surgery; chest tube removal. RCT double-blinded.Although the Bryden 1997 ADDIN EN.CITE <EndNote><Cite><Author>Bryden</Author><Year>1997</Year><RecNum>1685</RecNum><DisplayText>[22]</DisplayText><record><rec-number>1685</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232800">1685</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bryden, F. M.</author><author>McFarlane, H.</author><author>Tunstall, M. E.</author><author>Ross, J. A.</author></authors></contributors><auth-address>Department of Anaesthesia, Aberdeen Royal Hospitals NHS Trust, Aberdeen Royal Infirmary, UK.</auth-address><titles><title>Isoflurane for removal of chest drains after cardiac surgery</title><secondary-title>Anaesthesia</secondary-title></titles><periodical><full-title>Anaesthesia</full-title></periodical><pages>173-175</pages><volume>52</volume><number>2</number><dates><year>1997</year><pub-dates><date>1997/2</date></pub-dates></dates><isbn>0003-2409</isbn><urls><related-urls><url> Papers/B/Bryden et al. 1997 - Isoflurane for removal of chest drains after cardiac surgery.pdf</url></pdf-urls></urls></record></Cite></EndNote>[22] study showed that Entonox (nitrous oxide plus oxygen) along with isoflurane inhalation was more effective for ?pain related to the first of 2 chest tubes to be removed, removal of the second tube was more painful, regardless of the gas inhaled. SMD?-26.00 [-40.76, -11.24] on a 0 - 100 VAS.Are the desirable anticipated effects large?Although a SMD difference of 26 points on a 0 - 100 VAS is large, the results differed according to the order of the tube removal.Change to probably yes considering the change in pain scores and the difference between treatments.Gerald: Probably no because we should compare the first tube removal - no difference between the 2 groups. Isoflurane given for the first tube, then it stopped. The patient awakened before the second tube removal. It's the effect of NOT having isoflurane for the second tube. ?The two tubes should be studied separately. The score difference is due to the study design and not real effects.Are the undesirable anticipated effects small? ?Patients inhaled gas until drowsy but not unconscious. ?Researchers noted no differences between groups in several potential side effects such as nausea, dizziness, smell of gas, but they did not provide statistics on side effects.Are the desirable effects large relative to undesirable effects? ?Decreased pain scores without reports of side effects.Probably noIs there important uncertainty about how much people value the main outcomes? ● No important uncertainty or variability Are the desirable anticipated effects large? ○ No ● Probably no Are the undesirable anticipated effects small? ○ No ○ Probably no ● Uncertain Are the desirable effects large relative to undesirable effects? ○ No ● Probably no Resource useAre the resources required small? ● No Gases contained in high pressure cylindars. ?While they are a part of intra-operative anesthesia, use of these gases in ICU is unusual. ?Researchers noted that the the procedure was supervised by one of them (assume they are anesthesiologists?), the nurses administered the gas. ?Study done in Scotland, where nursing practice may differ from other places in the world.Is the incremental cost small relative to the net benefits? ● No Although the cost of this intervention was not addressed in the study, ?it is assumed that the cost would be large vis a vis the use of a drug analgesic. ?(Cost of equipment, cost of physician time.) ?More importantly, the effectiveness of this intervention for chest tube removal pain is only based on this one study.Very expensive; you need monitoring and safety proceduresAcceptabilityIs the option acceptable to key stakeholders? ● No For reasons noted above, in incremental costs.FeasibilityIs the option feasible to implement? ● No For reasons noted above, in incremental costs.Recommendation Should Isoflurane & Nitrous Oxide vs. Nitrous oxide alone be used for critically ill adults undergoing a procedure (2.1)?Balance of consequences Undesirable consequences clearly outweigh desirable consequences in most settingsUndesirable consequences probably outweigh desirable consequences in most settingsThe balance between desirable and undesirable consequences is closely balanced or uncertainDesirable consequences probably outweigh undesirable consequences in most settingsDesirable consequences clearly outweigh undesirable consequences in most settings○●○○○Type of recommendation We recommend against offering this optionWe suggest not offering this optionWe suggest offering this optionWe recommend offering this option●○○○Recommendation We recommend not using inhalation of isoflurane for pain control during chest tube removal.Consider other less invasive, less costly, and more studied interventions for chest tube removal pain.Justification The effectiveness of this intervention for chest tube removal pain is only based on this one study with a sample of 35 patients. ?Outcomes were not clearly reported.Subgroup considerations The study was conducted in cardiac surgery patients.Implementation considerations See under, "Are the resources required small?", above.Not feasible to implement.Monitoring and evaluation Evaluate patient pain before and after chest tube removal procedure as a factor of use of an analgesic intervention.Research possibilities Pursue other types of analgesic interventions.Question: A narcotic compared to an NSAID for critically ill adults undergoing a procedure (2.1) Setting: Bibliography: Quality assessment№ of patientsEffectQualityImportance№ of studiesStudy designRisk of biasInconsistencyIndirectnessImprecisionOther considerationsa narcotican NSAIDRelative(95% CI)Absolute(95% CI)Pain Score1 randomised trials not serious not serious not serious very serious anone 17 19 - MD 0.45 lower(2.16 lower to 1.26 higher) ????LOW CRITICAL CI: Confidence interval; MD: Mean differenceExplanations a. Wide confidence intervals don't exclude harm or benefit and small number of patients. QuestionShould a narcotic vs. an NSAID be used for critically ill adults undergoing a procedure (2.1)? Population: critically ill adults undergoing a procedure (2.1) Background: Intervention: a narcotic Comparison: an NSAID Main outcomes: Pain ScoreAssessmentCriteria Judgements Research evidence Additional considerations ProblemIs there a problem priority? ○ No ○ Probably no ○ Uncertain ○ Probably yes ● Yes Benefits & harms of the optionsWhat is the overall certainty of this evidence? ○ No included studies ○ Very low ● Low The relative importance or values of the main outcomes of interest: OutcomeRelative importance Certainty of the evidence (GRADE) Pain ScoreCRITICAL????LOWOne single study (Puntillo & Ley, 2004) ADDIN EN.CITE <EndNote><Cite><Author>Puntillo</Author><Year>2004</Year><RecNum>1773</RecNum><DisplayText>[23]</DisplayText><record><rec-number>1773</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232805">1773</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Puntillo, Kathleen A.</author><author>Morris, Ann B.</author><author>Thompson, Carol L.</author><author>Stanik-Hutt, Julie</author><author>White, Cheri A.</author><author>Wild, Lorie R.</author></authors></contributors><auth-address>Critical Care/Trauma Graduate Nursing Program, University of California, San Francisco, CA, USA.</auth-address><titles><title>Pain behaviors observed during six common procedures: results from Thunder Project II</title><secondary-title>Crit. Care Med.</secondary-title></titles><periodical><full-title>Crit. Care Med.</full-title></periodical><pages>421-427</pages><volume>32</volume><number>2</number><dates><year>2004</year><pub-dates><date>2004/2</date></pub-dates></dates><isbn>0090-3493</isbn><urls><related-urls><url> Papers/P/Puntillo et al. 2004 - Pain behaviors observed during six common procedures - results from Thunder Project II.pdf</url></pdf-urls></urls><electronic-resource-num>10.1097/M.0000108875.35298.D2</electronic-resource-num></record></Cite></EndNote>[23]: 74 patients randomized in a double-blind study: 1) 4 mg of IV morphine + procedural information (n=17); 2) 30 mg of IV ketorolac + procedural information (n=19); 3) 4 mg of IV morphine + procedural + sensory information (n=19), and 4) 30 mg of IV ketorolac + procedural + sensory information (n=19). No control group included.Procedure: CRT in cardiac surgery ICU patients0-10 NRS pain intensity scores did not differ significantly across time among the 4 groups (RM-ANOVA F=0.82, p=0.49). Baseline pain scores (varied from 2.24 to 3.45), immediately after CTR (varied from 1.63 to 4.40), and 20 minutes after CTR (varied from 0.63-1.85). Self-reported pain scores appeared lower in Group 2 and Group 4 (but were not statistically significant). MD was 0.45 lower.Are the desirable effects large?Probably no because the MD was small. Effect size was also very small (0.03 for pain intensity).?Are the undesirable anticipated effects small?Uncertain because they were not documented in this study.Are the desirable effects large relative to undesirable effects?Uncertainty because the desirable effects were small, and undesirable effects unknown.Is there important uncertainty about how much people value the main outcomes? ● No important uncertainty or variability Are the desirable anticipated effects large? ● Probably no Are the undesirable anticipated effects small? ○ No ○ Probably no ● Uncertain Are the desirable effects large relative to undesirable effects? ○ No ○ Probably no ● Uncertain Resource useAre the resources required small? ○ No ○ Probably no ○ Uncertain ○ Probably yes ● Yes ○ Varies Yes because IV morphine and IV ketorolac are part of standard of care, and easily accessible for administration.?Is the incremental cost small relative to the net benefits? ○ No ○ Probably no ● Uncertain Probably yes because both treatments are easily accessible and seem to have similar effects. However, pain intensity was mild in all groups.JF: Both treatments are inexpensive.Paul: Benefits are uncertain.Bram: Uncertain better in this case.AcceptabilityIs the option acceptable to key stakeholders? ○ No ○ Probably no ○ Uncertain ○ Probably yes ● Yes Yes because these drugs are already part of ICU standard of care.FeasibilityIs the option feasible to implement? ○ No ○ Probably no ○ Uncertain ● Probably yes Probably yes because to time the peak effect of medication with CTR can be difficult in practice (i.e., uncertainty about the time of CTR procedure).Recommendation Should a narcotic vs. an NSAID be used for critically ill adults undergoing a procedure (2.1)?Balance of consequences Undesirable consequences clearly outweigh desirable consequences in most settingsUndesirable consequences probably outweigh desirable consequences in most settingsThe balance between desirable and undesirable consequences is closely balanced or uncertainDesirable consequences probably outweigh undesirable consequences in most settingsDesirable consequences clearly outweigh undesirable consequences in most settings○○●○○Type of recommendation We recommend against offering this optionWe suggest not offering this optionWe suggest offering this optionWe recommend offering this option○○●○Recommendation We suggest offering either IV morphine or IV ketorolac prior to a procedure (i.e., CTR) for pain management in ICU patients (+2C).?should we keep general terms (opioid, NSAID)?for procedures, can we extrapolate to any procedure?question of interest to clinicians (for any procedure).Justification The study findings did not confirm the relative superiority of either morphine or ketorolac as an analgesic prior to CTR. Pain intensity was mild in all groups.?Subgroup considerations CTR in cardiac surgery ICU patientsImplementation considerations Timing the administration of analgesia (peak effect) prior to the procedure is a key aspect to maximize effective pain reduction. Coordination with the care team is important (and can be challenging).Monitoring and evaluation Pain assessment pre and post procedure to allow the evaluation of the effectiveness of analgesia.; monitoring of adverse events is also important to plan.Research possibilities Include a control group and larger sample size; investigate other procedures and other medication (opioids, NSAID) in various ICU patient groups.Implementation studies are also neededComments during electronic voting by entire panelThe recommendation’s wording differs from the question – realizing it’s hard to make firm statements with low quality of evidence. Please qualify for "patients with normal kidney function not at risk of AKI" Recommendation & e to d table inconsistent; e to d recommends narcotic not nsaid; Recommendation based on one study with ketorolac, generalizing it to all NSAIDS and all procedures. Question: NSAID gel compared to placebo for critically ill adults undergoing a procedure (2.1) Setting: Bibliography: Quality assessment№ of patientsEffectQualityImportance№ of studiesStudy designRisk of biasInconsistencyIndirectnessImprecisionOther considerationsNSAID gelplaceboRelative(95% CI)Absolute(95% CI)Pain Score1 randomised trials not serious not serious not serious serious anone 53 53 - MD 3 lower(3.56 lower to 2.44 lower) ????MODERATE CRITICAL CI: Confidence interval; MD: Mean differenceExplanations a. Lowered for small number of patients despite tight confidence intervals showing benefit. QuestionShould NSAID gel vs. placebo be used for critically ill adults undergoing a procedure (2.1)? Population: critically ill adults undergoing a procedure (2.1) Background: Intervention: NSAID gel Comparison: placebo Main outcomes: Pain ScoreAssessmentCriteria Judgements Research evidence Additional considerations ProblemIs there a problem priority? ● Yes Benefits & harms of the optionsWhat is the overall certainty of this evidence? ● Moderate The relative importance or values of the main outcomes of interest: OutcomeRelative importance Certainty of the evidence (GRADE) Pain ScoreCRITICAL????MODERATESingh study ADDIN EN.CITE <EndNote><Cite><Author>Singh</Author><Year>2005</Year><RecNum>1918</RecNum><DisplayText>[24]</DisplayText><record><rec-number>1918</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232813">1918</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Singh, Madhavi</author><author>Gopinath, Ramachandran</author></authors></contributors><auth-address>Department of Anesthesia, Nizams Institute of Medical Sciences, Andhra Pradesh, India. madhavidev@</auth-address><titles><title>Topical analgesia for chest tube removal in cardiac patients</title><secondary-title>J. Cardiothorac. Vasc. Anesth.</secondary-title></titles><periodical><full-title>J. Cardiothorac. Vasc. Anesth.</full-title></periodical><pages>719-722</pages><volume>19</volume><number>6</number><dates><year>2005</year><pub-dates><date>2005/12</date></pub-dates></dates><isbn>1053-0770</isbn><urls><related-urls><url>(05)00300-9</url></related-urls><pdf-urls><url>All Papers/S/Singh and Gopinath 2005 - Topical analgesia for chest tube removal in cardiac patients.pdf</url></pdf-urls></urls><electronic-resource-num>10.1053/j.jvca.2005.07.024</electronic-resource-num></record></Cite></EndNote>[24] : ?Doubleblind RCT of cardiac patients with mediastinal and pleural chest tubes. Control: ?paraffin gel around chest tubes (either mediastinal or pleural) (n=53) vs. 50 mg?valdecoxib around chest tubes (either mediastinal or pleural) (n=53) at least 30 minutes prior to CTR (median 45 minutes).0-10 VAS scores: ?control 5 +1.48 vs valdecoxib 2 + 1.48 (p<0.05)SMD: -3 [-3.56, -2.44]Desirable effects large? ?clinically significant differences in pain scoresUndesirable effects small? ?no differences in HR, BP and other ?"adverse effects" such as skin irritation.Is there important uncertainty about how much people value the main outcomes? ● No important uncertainty or variability Are the desirable anticipated effects large? ● Yes Are the undesirable anticipated effects small? ● Yes Are the desirable effects large relative to undesirable effects? ● Yes Resource useAre the resources required small? ● Varies Application of NSAID around tube 30 minutes prior to CTR should not be too time intensive. ?Probably more costly than opioids, although authors said cost for 10 g Valdecoxib would cost US $0.50.- No gel available at the bedside in the US. - very expensive ($200/patient).-: How to address availability issues? To be discussed in a larger forum. US cost to consider?What is the cost of voltaren local analgesic gel?-: Varies based on availability issues in different countries.?Is the incremental cost small relative to the net benefits? ● Varies Net benefits were large, availability and costs will vary.AcceptabilityIs the option acceptable to key stakeholders? ● Varies Stakeholders could accept depending on availability and cost.FeasibilityIs the option feasible to implement? ○ No ○ Probably no ○ Uncertain ○ Probably yes ○ Yes ● Varies With time, practice of applying NSAID gel would become routinized.-: Varies based on options available in hospitals.-: Initially Probably yes if available and at low cost, but varies is acceptable.Recommendation Should NSAID gel vs. placebo be used for critically ill adults undergoing a procedure (2.1)?Balance of consequences Undesirable consequences clearly outweigh desirable consequences in most settingsUndesirable consequences probably outweigh desirable consequences in most settingsThe balance between desirable and undesirable consequences is closely balanced or uncertainDesirable consequences probably outweigh undesirable consequences in most settingsDesirable consequences clearly outweigh undesirable consequences in most settings○○○○●Type of recommendation We recommend against offering this optionWe suggest not offering this optionWe suggest offering this optionWe recommend offering this option○○●○Recommendation Study results show clinically significant effects on CTR pain. ?Application to practice is recommended.We suggest offering using NSAID gel (if available) over placebo prior to CTR.Small sample size + uncertainty, change for "we suggest offering this option". Vote to come Very expensive product; no direct comparison besides placebo.?NSAID gel available available over the counter in France (not in the USA - Paul).Justification CTR pain is substantial and needs effective interventionOne study from India with a product not available in the US.?Subgroup considerations Study conducted in India; needs replication in heterogeneous group of patients elsewhere and in patients with chest tubes after thoracic surgery or trauma, and in larger sample sizes.Implementation considerations Gel needs to be applied long enough prior to procedure (30 to 60 minutes) to get peak effect.Availability and costs to be taken into consideration.Monitoring and evaluation Systematic assessment of pain scores before and during/after CTR.Research possibilities See subgroup considerations. Other studies testing other products available in other ments during electronic Voting by Entire panelThe recommendation is inconsistent with the e to d profile, which recommends nsaid gelQuestion: Cold therapy compared to no cold therapy for critically ill adults undergoing a procedure (2.2) Quality assessment№ of patientsEffectQualityImportance№ of studiesStudy designRisk of biasInconsistencyIndirectnessImprecisionOther considerationscold therapyno cold therapyRelative(95% CI)Absolute(95% CI)Pain Intensity during Procedure (assessed with: 2 mins post procedure)2 randomised trials not serious not serious serious aserious bnone 65 65 - MD 1.91 lower(5.34 lower to 1.52 higher) ????LOW CRITICAL CI: Confidence interval; MD: Mean differenceExplanationsa. Multiple time points after chest tube removal studied and only 2 mins post was significantly different (these are results presented here). b. Small number of patients and confidence intervals do not rule out harm. QuestionShould cold therapy vs. no cold therapy be used for critically ill adults undergoing a procedure (2.2)? Population: critically ill adults undergoing a procedure (2.2) Background: Intervention: cold therapy Comparison: no cold therapy Main outcomes: Pain Intensity during ProcedureAssessmentCriteria Judgements Research evidence Additional considerations ProblemIs there a problem priority? ○ No ○ Probably no ○ Uncertain ○ Probably yes ● Yes ○ Varies 10/12/16Dear MA Heidari Gorji,?I am a member of a Guidelines panel on Pain, Agitation , Delirium, Early Mobilization and Sleep for the Society of Critical Care Medicine.? I read your report on ice packs for chest tube removal pain with great interest, and we would like to include it in our evidence results.? However, we have some questions about your study that I hope you can answer.??1)????? ?Can you present the numbers in your sample?? We are confused as to whether 80 post-cardiac surgery patients were in the study (abstract).? Under Materials and Methods, you write that the sample size of 30 patients in each group (intervention and control) was increased to 40 in each group.? In this same section, in the paragraph that begins with “On the first day after operation”,? you describe assignment of patients to groups which is confusing to me.? Under Statistical Analysis, you say there were 90 patients for whom data were available.? Earlier you had said there were 80 patients.? In Table 1, I count 40 (male and female) patients in the experimental group and 40 (male and female)patients in the control group.? Regarding Table 2, how many patients were in each of the three groups:? control, cold application, and relaxation?2)????? Regarding the pain measurement tool that you used:? Under Materials and Methods, in the paragraph that begins with “Data collection tools…”, you write that you used a 0 – 100 mm Visual Analogue Scale.? However, in Table 2, you report pain severity scores as 4.6+0.66 (control) vs 2.4+0.52 (cold application) vs 2.3+0.35 (relaxation).? Are those scores on a 0 – 100 VAS or a 0 – 10 numeric rating scale (NRS)?? In Figure 1, your “y” axis is 0 – 5.? Was that per a 0 – 100 VAS or a 0 – 10 NRS?3)????? Do you provide differences in pain scores according to the type of chest tube removed, mediastinal or pleural??Thank you for your help with this. ? Non-pharmacological interventions for pain management ?are important in the ICU and could contribute to reduce pain and to improve pain control in patients.Benefits & harms of the optionsWhat is the overall certainty of this evidence? ○ No included studies ○ Very low ● Low ○ Moderate ○ High The relative importance or values of the main outcomes of interest: OutcomeRelative importance Certainty of the evidence (GRADE) Pain Intensity during ProcedureCRITICAL????LOWOverall Certainty: ?2 studies were in data abstraction. 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ADDIN EN.CITE.DATA [25] was true RCT and Sauls 2002 ADDIN EN.CITE <EndNote><Cite><Author>Sauls</Author><Year>2002</Year><RecNum>1919</RecNum><DisplayText>[26]</DisplayText><record><rec-number>1919</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232813">1919</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sauls, Jenny</author></authors></contributors><auth-address>Middle Tennessee State University, Murfreesboro, TN 37130, USA. jsauls@mtsu.edu</auth-address><titles><title>The use of ice for pain associated with chest tube removal</title><secondary-title>Pain Manag. Nurs.</secondary-title></titles><periodical><full-title>Pain Manag. Nurs.</full-title></periodical><pages>44-52</pages><volume>3</volume><number>2</number><dates><year>2002</year><pub-dates><date>2002/6</date></pub-dates></dates><isbn>1524-9042</isbn><urls><related-urls><url> Papers/S/Sauls 2002 - The use of ice for pain associated with chest tube removal.pdf</url></pdf-urls></urls></record></Cite></EndNote>[26] was before and after study. The results were different (Gorji showed benefit whereas Sauls did not).?In GorjiPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Hb3JqaTwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [25] , for intervention group #1, iced packs wound around chest tube x 10 minutes until temperature 13 degrees; for intervention group #2, relaxation: calm and deep breathing for 5 minutes, then 10 minutes more; control group#3 received no intervention. ?Used 0 - 100 VAS but must have reported on a 0 - 10 scale. ?Pain intensity scores immediately after CTR:cold application group = 2.4 +?0.52control group = 4.6 + 0.66Size of each of the groups unknown. ?See email.Gorji: ?SMD?3.67 [-4.40, -2.94] lower for cold therapy; SignificantIn Sauls ADDIN EN.CITE <EndNote><Cite><Author>Sauls</Author><Year>2002</Year><RecNum>1919</RecNum><DisplayText>[26]</DisplayText><record><rec-number>1919</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232813">1919</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sauls, Jenny</author></authors></contributors><auth-address>Middle Tennessee State University, Murfreesboro, TN 37130, USA. jsauls@mtsu.edu</auth-address><titles><title>The use of ice for pain associated with chest tube removal</title><secondary-title>Pain Manag. Nurs.</secondary-title></titles><periodical><full-title>Pain Manag. Nurs.</full-title></periodical><pages>44-52</pages><volume>3</volume><number>2</number><dates><year>2002</year><pub-dates><date>2002/6</date></pub-dates></dates><isbn>1524-9042</isbn><urls><related-urls><url> Papers/S/Sauls 2002 - The use of ice for pain associated with chest tube removal.pdf</url></pdf-urls></urls></record></Cite></EndNote>[26] , for intervention group, ice pack on either side of chest tube for 10 minutes; for control group,?tepid water pack on either side of chest tube. Used 0 - 10 NRS. ?Pain intensity scores immediately after CTR:Control group (n=25): ?6.34 ?+ 2.52experimental group (n=25): ?5.86 + 2.82Sauls: ?SMD -0.17 lower for cold therapy [-0.72, 0.39] NSAre the desirable anticipated effects large?The overall SMD is -1.91 [-5.34, 1.52]Therefore, the desirable anticipated effects are probably large because a NRS pain intensity difference greater than 1.7 - 2 is assessed as clinically significant. ?However, this was from only 1 study with a questionable sample size.?Group consensuAre the undesirable anticipated effects small? There was no mention in either study of side effects associated with the use of cold packs. ?But it is possible that patients could have skin burns from cold packs if applied directly to skin for too long.No evidence of side effects, so uncertain. Burn injury not negligable.- UncertainAre the desirable effects large relative to undesirable effects? There was a significant decrease in pain in Gorji's cold pack group, with no reports of undesirable effects.Is there important uncertainty about how much people value the main outcomes? ○ Important uncertainty or variability ○ Possibly important uncertainty or variability ○ Probably no important uncertainty or variability ● No important uncertainty or variability Are the desirable anticipated effects large? ○ No ○ Probably no ○ Uncertain ● Probably yes Are the undesirable anticipated effects small? ○ No ○ Probably no ● Uncertain Are the desirable effects large relative to undesirable effects? ○ No ○ Probably no ○ Uncertain ● Probably yes Resource useAre the resources required small? ○ No ○ Probably no ● Uncertain No description of resources besides the gel packs in studies.Three cooling gel packs (8 × 10 cm) twisted in gauze were used to wrap around each chest tube for 10 minutes prior to tube removal. ? These packs would have to be purchased and stored in a freezer in the ICU. ?Having enough room for more than one set may pose a problem.Is the incremental cost small relative to the net benefits? ○ No ○ Probably no ○ Uncertain ● Probably yes The overall costs of the gel cooling packs should be incidental if the benefits to patients were decreased pain associated with a procedure known to cause substantial pain. ?Patients who had received opioid analgesic during less than 4 hours before the?intervention were excluded from the study. ?However, costs of an analgesic intervention, if needed to augment cold therapy, would be low.AcceptabilityIs the option acceptable to key stakeholders? ○ No ○ Probably no ○ Uncertain ● Probably yes Key stakeholders should be committed to a relatively low cost, non-pharmacological approach to pain relief.FeasibilityIs the option feasible to implement? ○ No ○ Probably no ○ Uncertain ● Probably yes Implementation would require a practice change and development of a written protocol for use of the gel packs, as well as purchase and storing of the gel packs.-Uncertain: only 2 studies with contradictory results. In one study, patients did not receive opioids.- Probably yes; question on feasibility of implementing of the intervention.- Feasible to implement considering the low amount of resources needed compared to other interventions.Recommendation Should cold therapy vs. no cold therapy be used for critically ill adults undergoing a procedure (2.2)?Balance of consequences Undesirable consequences clearly outweigh desirable consequences in most settingsUndesirable consequences probably outweigh desirable consequences in most settingsThe balance between desirable and undesirable consequences is closely balanced or uncertainDesirable consequences probably outweigh undesirable consequences in most settingsDesirable consequences clearly outweigh undesirable consequences in most settings○○○●○Type of recommendation We recommend against offering this optionWe suggest not offering this optionWe suggest offering this optionWe recommend offering this option○○●○Recommendation We suggest to offer cold therapy during chest tube removal for ICU pain management (to be confirmed).More research is needed, with inclusion of larger samples, before the use of cold gel packs is determined to be efficacious for pain relief during chest tube removal.Note: Still waiting to hear from Gorji to answer our questions.?Justification Chest tube removal pain was decreased in one study of cold packs.Subgroup considerations These 2 studies were conducted with cardiac surgery patients. ?In Gorji study, patients had 1 mediastinal tube and 1 left pleural tube. ?Differences in pain between the 2 types of tubes were not reported. ?In previous research, (Puntillo & Weiss, 1994) ADDIN EN.CITE <EndNote><Cite><Author>Puntillo</Author><Year>1994</Year><RecNum>1774</RecNum><DisplayText>[27]</DisplayText><record><rec-number>1774</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232805">1774</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Puntillo, K.</author><author>Weiss, S. J.</author></authors></contributors><auth-address>Department of Physiological Nursing, School of Nursing, University of California, San Francisco.</auth-address><titles><title>Pain: its mediators and associated morbidity in critically ill cardiovascular surgical patients</title><secondary-title>Nurs. Res.</secondary-title></titles><periodical><full-title>Nurs. Res.</full-title></periodical><pages>31-36</pages><volume>43</volume><number>1</number><dates><year>1994</year><pub-dates><date>1994/1</date></pub-dates></dates><isbn>0029-6562</isbn><urls><related-urls><url>;[27], pleural chest tubes were significantly more painful than mediastinal tubes. ?So, type of tube should be analyzed.?Implementation considerations Implementation would require a practice change in a particular ICU.Monitoring and evaluation Pre and post pain assessments to evaluate impact of the intervention. 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ADDIN EN.CITE.DATA [25] study. ?Those patients could be included in future studies and, if they are unable to self-report pain, a pain behavior scale could be used to assess pain. ?These steps could increase generalizability of study results. ?If patients reported pain prior to the procedure, they could be medicated with analgesic drugs, and the effect of these drugs, as well as the ice, could be examinedComments during electronic voting by entire panelUnclear whether cold/ music therapy offered as sole pain management strategy or considered adjuncts from the question.Evidence poor; RCT study= beneficial, pre-post negative, gaps in methods/ results and methods.Question: Relaxation with pharmacotherapy compared to no relaxation for critically ill pain management (5.4) Quality assessment№ of patientsEffectQualityImportance№ of studiesStudy designRisk of biasInconsistencyIndirectnessImprecisionOther considerationsRelaxation with pharmacotherapyno relaxationRelative(95% CI)Absolute(95% CI)Pain Intensity immediately after Chest Tube Removal (VAS cm)2 observational studies not serious aserious b,cnot serious very serious d,enone 31 33 - MD 0.32 higher(0.67 lower to 1.31 higher) ????VERY LOW CRITICAL Pain intensity 15 minutes after Chest tube removal (VAS cm)1 observational studies not serious not serious not serious serious d,fnone 19 21 - MD 2.5 lower(4.18 lower to 0.82 lower) ????VERY LOW CRITICAL CI: Confidence interval; MD: Mean differenceExplanationsa. 1 study indicated low risk of bias; 2nd study indicated high ROB due to variable co-interventions between groups and no adjustment for group differences b. 1 study showed variable results based on gender and age; results not consistent amongst groups c. I2 = 80% d. Low sample size e. mean difference crosses line of no effect f. Despite CI that do not cross 'no effect', imprecision lowered for sample size QuestionShould Relaxation with pharmacotherapy vs. no relaxation be used for critically ill pain management (5.4)? Population: critically ill pain management (5.4) Background: Intervention: Relaxation with pharmacotherapy Comparison: no relaxation Main outcomes: Pain Intensity immediately after Chest Tube Removal (VAS cm)Pain intensity 15 minutes after Chest tube removal (VAS cm)Setting: Perspective: AssessmentCriteria Judgements Research evidence Additional considerations ProblemIs there a problem priority? ○ No ○ Probably no ○ Uncertain ○ Probably yes ● Yes Non-pharmacological interventions for pain management?are important in the ICU and could contribute to reduce pain and to improve pain control in patients.Benefits & harms of the optionsWhat is the overall certainty of this evidence? ○ No included studies ● Very low The relative importance or values of the main outcomes of interest: OutcomeRelative importance Certainty of the evidence (GRADE) Pain Intensity immediately after Chest Tube Removal (VAS cm)CRITICAL????VERY LOWPain intensity 15 minutes after Chest tube removal (VAS cm)CRITICAL????VERY LOWSummary of overall evidence on pain scores:2 matched cohort studies (Friesner et al. 2006; Houston & Jesurum, 1999) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Gcmllc25lcjwvQXV0aG9yPjxZZWFyPjIwMDY8L1llYXI+
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ADDIN EN.CITE.DATA [28, 29] in which pain scores were higher immediately after CTR with a MD of 0.32, and then decreased with a MD of 2.5 15 minutes after CTR. However, the quality of evidence was very low. Small samples were used in both studies (n=40 and 24, respectively).In Friesner et al. (2006) (n=40), relaxation consisted of deep-breathing exercises. Immediately after CTR, mean pain scores were 6.57 (SD=2.61) for the intervention group, and 8.61 for the control group (SD=2.96). Mean pain scores decreased to 3.07 (SD=2.45) and to 5.57 (SD=2.96) in the intervention group, and the control group respectively. Significant decreases in pain scores with relaxation were found immediately after, and 15 minutes post CTR (F tests, p<0.01) (p. 273).In Houston & Jesurum (1999) ADDIN EN.CITE <EndNote><Cite><Author>Houston</Author><Year>1999</Year><RecNum>1922</RecNum><DisplayText>[29]</DisplayText><record><rec-number>1922</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232813">1922</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Houston, S.</author><author>Jesurum, J.</author></authors></contributors><auth-address>St. Luke's Episcopal Hospital, Cardiovascular Recovery Unit, Houston, TX 77030, USA. shouston@</auth-address><titles><title>The quick relaxation technique: effect on pain associated with chest tube removal</title><secondary-title>Appl. Nurs. Res.</secondary-title></titles><periodical><full-title>Appl. Nurs. Res.</full-title></periodical><pages>196-205</pages><volume>12</volume><number>4</number><dates><year>1999</year><pub-dates><date>1999/11</date></pub-dates></dates><isbn>0897-1897</isbn><urls><related-urls><url>;[29] (n=24), the quick relaxation technique (QRT) consisted of clenching fists, deep breathing, go limp as a rag doll, and yawning. Strange results were obtained and were presented by age and gender. In summary, pain scores were not significantly different between groups (p=0.062). Men older than 70 yo in the control group showed almost twice more pain than those of the intervention group. The situation was reversed in older women (p.202).?Are the desirable anticipated effects large?Likely uncertain, 2 non RCTs with small samples and very low quality of evidence. Opioid administration was variable between patients.Are the undesirable anticipated effects large?No mention of adverse events in both studies.?Are the desirable effects large relative to undesirable effects?Uncertain based on very low evidence and no information on adverse events (although they appear to be very unlikely).Is there important uncertainty about how much people value the main outcomes? ● No important uncertainty or variability Are the desirable anticipated effects large? ○ No ○ Probably no ● Uncertain Are the undesirable anticipated effects small? ● Probably yes Are the desirable effects large relative to undesirable effects? ○ No ○ Probably no ● Uncertain Resource useAre the resources required small? ○ No ○ Probably no ○ Uncertain ○ Probably yes ● Yes ○ Varies Instructions clearly described in both studies.?Short instructions which can be taught to ICU patients at the bedside.Is the incremental cost small relative to the net benefits? ○ No ○ Probably no ○ Uncertain ● Probably yes Is relaxation worth the benefit?The net benefits remain to be demonstrated, but appear promising. Relaxation does not involve any cost.AcceptabilityIs the option acceptable to key stakeholders? ○ No ○ Probably no ○ Uncertain ● Probably yes I would believe that the vast majority would likely approve this intervention.?Patient's preference to take into consideration.FeasibilityIs the option feasible to implement? ○ No ○ Probably no ○ Uncertain ● Probably yes No implementation studies available.?In Friesner et al. (2006) ADDIN EN.CITE <EndNote><Cite><Author>Friesner</Author><Year>2006</Year><RecNum>1923</RecNum><DisplayText>[28]</DisplayText><record><rec-number>1923</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232813">1923</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Friesner, Stacy A.</author><author>Curry, Donna Miles</author><author>Moddeman, Gail R.</author></authors></contributors><auth-address>College of Nursing and Health, Wright State University, Dayton, Ohio 45435, USA.</auth-address><titles><title>Comparison of two pain-management strategies during chest tube removal: relaxation exercise with opioids and opioids alone</title><secondary-title>Heart Lung</secondary-title></titles><periodical><full-title>Heart Lung</full-title></periodical><pages>269-276</pages><volume>35</volume><number>4</number><dates><year>2006</year><pub-dates><date>2006/7</date></pub-dates></dates><isbn>0147-9563</isbn><urls><related-urls><url>(05)00196-2</url></related-urls><pdf-urls><url>All Papers/F/Friesner et al. 2006 - Comparison of two pain-management strategies during chest tube removal - relaxation exercise with opioids and opioids alone.pdf</url></pdf-urls></urls><electronic-resource-num>10.1016/j.hrtlng.2005.10.005</electronic-resource-num></record></Cite></EndNote>[28] , the relaxation techinique was initiated by patients 5 minutes before CTR.In Houston & Jesurum (1999) ADDIN EN.CITE <EndNote><Cite><Author>Houston</Author><Year>1999</Year><RecNum>1922</RecNum><DisplayText>[29]</DisplayText><record><rec-number>1922</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232813">1922</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Houston, S.</author><author>Jesurum, J.</author></authors></contributors><auth-address>St. Luke's Episcopal Hospital, Cardiovascular Recovery Unit, Houston, TX 77030, USA. shouston@</auth-address><titles><title>The quick relaxation technique: effect on pain associated with chest tube removal</title><secondary-title>Appl. Nurs. Res.</secondary-title></titles><periodical><full-title>Appl. Nurs. Res.</full-title></periodical><pages>196-205</pages><volume>12</volume><number>4</number><dates><year>1999</year><pub-dates><date>1999/11</date></pub-dates></dates><isbn>0897-1897</isbn><urls><related-urls><url>;[29] , the quick relaxation technique was taught to patients the day prior to CTR, and participated in two practice sessions (one immediately prior to CTR).Little resource and time needed to perform a brief relaxation technique during procedural pain.?Minimal training required.Nursing training? ?Will depend on relaxation technique.Recommendation Should Relaxation with pharmacotherapy vs. no relaxation be used for critically ill pain management (5.4)?Balance of consequences Undesirable consequences clearly outweigh desirable consequences in most settingsUndesirable consequences probably outweigh desirable consequences in most settingsThe balance between desirable and undesirable consequences is closely balanced or uncertainDesirable consequences probably outweigh undesirable consequences in most settingsDesirable consequences clearly outweigh undesirable consequences in most settings○○●○○Type of recommendation We recommend against offering this optionWe suggest not offering this optionWe suggest offering this optionWe recommend offering this option○○●○Recommendation We suggest offering relaxation during procedural pain as a complementary intervention to ICU pain management (+2C).Can we still suggest an intervention if the benefits and consequences are balanced or uncertain? ?Do we change to probably outweigh?Justification Although evidence is of very low quality, relaxation remains a safe and quick intervention to use. However, the benefits remain to be demonstrated. Worth mentioning, various relaxation techniques were used in included studies.Subgroup considerations Both included studies were performed in cardiac surgery (CABG) ICU patients during CRT (chest tube removal).Implementation considerations No specific resources needed to apply this intervention. Minimal training required. Written information could also be provided to patients to get familiar with relaxation.Monitoring and evaluation Pre and post pain assessments to evaluate impact of the intervention. Patient's preference and satisfaction could also be considered.Research possibilities Experimental studies (RCT) are clearly needed to demonstrate the benefits of relaxation. Implementation studies are also lacking.?Question: Standardized and/or protocol-based analgesia/analgosedation programs compared to no standardized programs for critical care pain management (4) Setting: Critical Care ICU Bibliography: Quality assessment№ of patientsEffectQualityImportance№ of studiesStudy designRisk of biasIncon-sistencyIndirect-nessImprec-isionOther considerationsstandardized and/or protocol-based analgesia/analgosedation programsno standardized programsRelative(95% CI)Absolute(95% CI)Nosocomial infection2 randomised trials serious anot serious not serious bserious c,dnone 6/112 (5.4%) 10/106 (9.4%) RR 0.62(0.25 to 1.56) 36 fewer per 1,000(from 53 more to 71 fewer) ????LOW CRITICAL Duration of MV3 randomised trials serious enot serious not serious not serious none 313 326 - MD 1.26 lower(1.8 lower to 0.73 lower) ????MODERATE CRITICAL ICU LOS3 randomised trials serious enot serious not serious not serious none 313 326 - MD 2.27 lower(2.96 lower to 1.58 lower) ????MODERATE CRITICAL Constipation1 observational studies not serious not serious not serious serious dnone 18/50 (36.0%) 15/50 (30.0%) RR 1.20(0.68 to 2.11) 60 more per 1,000(from 96 fewer to 333 more) ????VERY LOW IMPORTANT Cardiovascular Adverse Drug Reaction2 randomised trials serious fnot serious not serious bserious dnone 4/153 (2.6%) 4/157 (2.5%) RR 0.90(0.26 to 3.14) 3 fewer per 1,000(from 19 fewer to 55 more) ????LOW CRITICAL Sedatives Exposure1 randomised trials serious gnot serious not serious serious cnone 110 116 - SMD 0.57 lower(0.84 lower to 0.31 lower) ????LOW CRITICAL Opioid Exposure1 randomised trials serious gnot serious not serious serious cnone 55 58 - MD 0.06 SD higher(0.31 lower to 0.42 higher) ????LOW CRITICAL Pain intensity VAS (cm)4 observational studies not serious not serious not serious not serious none 747 780 - MD 0.35 lower(0.49 lower to 0.22 lower) ????LOW CRITICAL CI: Confidence interval; RR: Risk ratio; MD: Mean difference; SMD: Standardised mean differenceExplanationsa. 1 study reports no blinding of participants or outcome assessors; the other study does not report randomization or blinding processes b. Note: only includes remifentanil based analgosedation protocols c. Small sample size d. Unclear if benefit or harm e. Two studies report randomization; 1 study did not report randomization; no studies had adequate blinding of participants or outcome assessors f. 1 study did not clearly report randomization or blinding of participants/assessors; 2nd study did not randomize or blind participants/assessors g. Appropriate randomization and intention-to-treat, however inadequate or lack of randomization QuestionShould standardized and/or protocol-based analgesia/analgosedation programs vs. no standardized programs be used for critical care pain management (4)? Population: critical care pain management (4) Background: Intervention: standardized and/or protocol-based analgesia/analgosedation programs Comparison: no standardized programs Main outcomes: Nosocomial infectionDuration of MVICU LOSConstipationCardiovascular Adverse Drug ReactionSedatives ExposureOpioid ExposurePain intensity VAS (cm)Setting: Critical Care ICU AssessmentCriteria Judgements Research evidence Additional considerations ProblemIs there a problem priority? ● Yes Benefits & harms of the optionsWhat is the overall certainty of this evidence? ○ No included studies ○ Very low ● Low The relative importance or values of the main outcomes of interest: OutcomeRelative importance Certainty of the evidence (GRADE) Nosocomial infectionCRITICAL????LOWDuration of MVCRITICAL????MODERATEICU LOSCRITICAL????MODERATEConstipationIMPORTANT????VERY LOWCardiovascular Adverse Drug ReactionCRITICAL????LOWSedatives ExposureCRITICAL????LOWOpioid ExposureCRITICAL????LOWare the desirable anticipated effects large?reduction in duration of MV and?reduction in ICU LOS(data from 3 RCTs)?Duration of MV = MD - 1.26 (-1.8 to -0.73)ICU LOS = MD -2.27 (-2.96 to -1.58)Rozendaal FW, Spronk PE, Snellen FF, et al: Remifentanil-propofol analgo-sedation shortens duration of ventilation and length of ICU stay compared to a conventional regimen: A centre randomised, cross-over, open-label study in the netherlands. Intensive Care Med 2009;35:291-298 ADDIN EN.CITE <EndNote><Cite><Author>Rozendaal</Author><Year>2009</Year><RecNum>2160</RecNum><DisplayText>[30]</DisplayText><record><rec-number>2160</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232827">2160</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rozendaal, F. Willem</author><author>Spronk, Peter E.</author><author>Snellen, Ferdinand F.</author><author>Schoen, Adri</author><author>van Zanten, Arthur R. H.</author><author>Foudraine, Norbert A.</author><author>Mulder, Paul G. H.</author><author>Bakker, Jan</author><author>Ulti, Safe investigators</author></authors></contributors><auth-address>Jeroen Bosch Hospital, 's-Hertogenbosch, The Netherlands.</auth-address><titles><title>Remifentanil-propofol analgo-sedation shortens duration of ventilation and length of ICU stay compared to a conventional regimen: a centre randomised, cross-over, open-label study in the Netherlands</title><secondary-title>Intensive Care Med.</secondary-title></titles><periodical><full-title>Intensive Care Med.</full-title></periodical><pages>291-298</pages><volume>35</volume><number>2</number><dates><year>2009</year><pub-dates><date>2009/2</date></pub-dates></dates><isbn>0342-4642</isbn><urls><related-urls><url> Papers/R/Rozendaal et al. 2009 - Remifentanil-propofol analgo-sedation shortens d ... a centre randomised, cross-over, open-label study in the Netherlands.pdf</url></pdf-urls></urls><electronic-resource-num>10.1007/s00134-008-1328-9</electronic-resource-num></record></Cite></EndNote>[30]Brook AD, Ahrens TS, Schaiff R, et al: Effect of a nursing-implemented sedation protocol on the duration of mechanical ventilation. Crit Care Med 1999;27:2609-2615 . ADDIN EN.CITE <EndNote><Cite><Author>Brook</Author><Year>1999</Year><RecNum>2108</RecNum><DisplayText>[31]</DisplayText><record><rec-number>2108</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232824">2108</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Brook, A. D.</author><author>Ahrens, T. S.</author><author>Schaiff, R.</author><author>Prentice, D.</author><author>Sherman, G.</author><author>Shannon, W.</author><author>Kollef, M. H.</author></authors></contributors><auth-address>Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, MO, USA.</auth-address><titles><title>Effect of a nursing-implemented sedation protocol on the duration of mechanical ventilation</title><secondary-title>Crit. Care Med.</secondary-title></titles><periodical><full-title>Crit. Care Med.</full-title></periodical><pages>2609-2615</pages><volume>27</volume><number>12</number><dates><year>1999</year><pub-dates><date>1999/12</date></pub-dates></dates><isbn>0090-3493</isbn><urls><related-urls><url>;[31]Strom T, Martinussen T, Toft P: A protocol of no sedation for critically ill patients receiving mechanical ventilation: A randomised trial. Lancet 2010;375:475-480Pain intensity - "reduced" 4 cohort trials NRS (0-10) - pooarburns. Burns 2010;36:639-646 ADDIN EN.CITE <EndNote><Cite><Author>Berger</Author><Year>2010</Year><RecNum>1913</RecNum><DisplayText>[32]</DisplayText><record><rec-number>1913</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232813">1913</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Berger, Mette M.</author><author>Davadant, Maryse</author><author>Marin, Christian</author><author>Wasserfallen, Jean-Blaise</author><author>Pinget, Christophe</author><author>Maravic, Philippe</author><author>Koch, Nathalie</author><author>Raffoul, Wassim</author><author>Chiolero, René L.</author></authors></contributors><auth-address>Service of Intensive Care Medicine & Burns Centre, University Hospital (CHUV), Lausanne, Switzerland. Mette.Berger@chuv.ch</auth-address><titles><title>Impact of a pain protocol including hypnosis in major burns</title><secondary-title>Burns</secondary-title></titles><periodical><full-title>Burns</full-title></periodical><pages>639-646</pages><volume>36</volume><number>5</number><dates><year>2010</year><pub-dates><date>2010/8</date></pub-dates></dates><isbn>0305-4179</isbn><urls><related-urls><url>(09)00454-9</url></related-urls><pdf-urls><url>All Papers/B/Berger et al. 2010 - Impact of a pain protocol including hypnosis in major burns.pdf</url></pdf-urls></urls><electronic-resource-num>10.1016/j.burns.2009.08.009</electronic-resource-num></record></Cite></EndNote>[32]undergoing cardiac surgery after implementation of a quality improvement postoperative pain treatment program. J Crit Care 2008;23:359-371 ADDIN EN.CITE <EndNote><Cite><Author>Diby</Author><Year>2008</Year><RecNum>1927</RecNum><DisplayText>[33]</DisplayText><record><rec-number>1927</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232813">1927</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Diby, Marc</author><author>Romand, Jacques-André</author><author>Frick, Sonia</author><author>Heidegger, Claudia Paula</author><author>Walder, Bernhard</author></authors></contributors><auth-address>Nursing Directorate, University Hospitals of Geneva, Rue Micheli-du-Crest 24, CH-1211 Geneva 14, Switzerland.</auth-address><titles><title>Reducing pain in patients undergoing cardiac surgery after implementation of a quality improvement postoperative pain treatment program</title><secondary-title>J. Crit. Care</secondary-title></titles><periodical><full-title>J. Crit. Care</full-title></periodical><pages>359-371</pages><volume>23</volume><number>3</number><dates><year>2008</year><pub-dates><date>2008/9</date></pub-dates></dates><isbn>0883-9441</isbn><urls><related-urls><url>(07)00189-X</url><url>(07)00189-X</url></related-urls><pdf-urls><url>All Papers/D/Diby et al. 2008 - Reducing pain in patients undergoing cardiac surgery ... entation of a quality improvement postoperative pain treatment program.pdf</url></pdf-urls></urls><electronic-resource-num>10.1016/j.jcrc.2007.11.005</electronic-resource-num></record></Cite></EndNote>[33]?Egerod I, Jensen MB, Herling SF, et al: Effect of an analgo-sedation protocol for neurointensive patients: A two-phase interventional non-randomized pilot study. Crit Care 2010;14:R71 ADDIN EN.CITE <EndNote><Cite><Author>Egerod</Author><Year>2010</Year><RecNum>1928</RecNum><DisplayText>[34]</DisplayText><record><rec-number>1928</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232813">1928</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Egerod, Ingrid</author><author>Jensen, Malene Brorsen</author><author>Herling, Suzanne Forsyth</author><author>Welling, Karen-Lise</author></authors></contributors><auth-address>Copenhagen University Hospital, Rigshospitalet, Department 7331, UCSF, Blegdamsvej 9, Copenhagen O, Denmark. ie@ucsf.dk</auth-address><titles><title>Effect of an analgo-sedation protocol for neurointensive patients: a two-phase interventional non-randomized pilot study</title><secondary-title>Crit. Care</secondary-title></titles><periodical><full-title>Crit. Care</full-title></periodical><pages>R71</pages><volume>14</volume><number>2</number><dates><year>2010</year><pub-dates><date>2010/4/19</date></pub-dates></dates><isbn>0270-7462</isbn><urls><related-urls><url> Papers/E/Egerod et al. 2010 - Effect of an analgo-sedation protocol for neurointensive patients - a two-phase interventional non-randomized pilot study.pdf</url></pdf-urls></urls><electronic-resource-num>10.1186/cc8978</electronic-resource-num></record></Cite></EndNote>[34]Skrobik Y, Ahern S, Leblanc M, et al: Protocolized intensive care unit management of analgesia, sedation, and delirium improves analgesia and subsyndromal delirium rates. Anesth Analg 2010;111:451-463 ADDIN EN.CITE <EndNote><Cite><Author>Skrobik</Author><Year>2010</Year><RecNum>2016</RecNum><DisplayText>[35]</DisplayText><record><rec-number>2016</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232819">2016</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Skrobik, Yoanna</author><author>Ahern, Stéphane</author><author>Leblanc, Martine</author><author>Marquis, Fran?ois</author><author>Awissi, Don Kelena</author><author>Kavanagh, Brian P.</author></authors></contributors><auth-address>H?pital Maisonneuve-Rosemont, 5415 Blvd. De l'Assomption, Montreal, QC, Canada H1T 2M4. skrobik@sympatico.c</auth-address><titles><title>Protocolized intensive care unit management of analgesia, sedation, and delirium improves analgesia and subsyndromal delirium rates</title><secondary-title>Anesth. Analg.</secondary-title></titles><periodical><full-title>Anesth. Analg.</full-title></periodical><pages>451-463</pages><volume>111</volume><number>2</number><dates><year>2010</year><pub-dates><date>2010/8</date></pub-dates></dates><isbn>0003-2999</isbn><urls><related-urls><url> Papers/S/Skrobik et al. 2010 - Protocolized intensive care unit management of ana ... tion, and delirium improves analgesia and subsyndromal delirium rates.pdf</url></pdf-urls></urls><electronic-resource-num>10.1213/ANE.0b013e3181d7e1b8</electronic-resource-num></record></Cite></EndNote>[35]nosocomial infection?- no difference combining 2 RCT?RR 0.62 (0.25 to 1.56)36 fewer per 1000 patients?Breen D, Karabinis A, Malbrain M, et al: Decreased duration of mechanical ventilation when comparing analgesia-based sedation using remifentanil with standard hypnotic-based sedation for up to 10 days in intensive care unit patients: A randomised trial [ISRCTN47583497]. Crit Care 2005;9:R200-10 ADDIN EN.CITE <EndNote><Cite><Author>Breen</Author><Year>2005</Year><RecNum>2158</RecNum><DisplayText>[36]</DisplayText><record><rec-number>2158</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232827">2158</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Breen, Des</author><author>Karabinis, Andreas</author><author>Malbrain, Manu</author><author>Morais, Rex</author><author>Albrecht, Sven</author><author>Jarnvig, Inge-Lise</author><author>Parkinson, Pauline</author><author>Kirkham, Andrew J. T.</author></authors></contributors><auth-address>Anaesthesia and Intensive Care, Royal Hallamshire Hospital, Sheffield, UK. des.breen@sth.nhs.uk</auth-address><titles><title>Decreased duration of mechanical ventilation when comparing analgesia-based sedation using remifentanil with standard hypnotic-based sedation for up to 10 days in intensive care unit patients: a randomised trial [ISRCTN47583497]</title><secondary-title>Crit. Care</secondary-title></titles><periodical><full-title>Crit. Care</full-title></periodical><pages>R200-10</pages><volume>9</volume><number>3</number><dates><year>2005</year><pub-dates><date>2005/6</date></pub-dates></dates><isbn>0270-7462</isbn><urls><related-urls><url> Papers/B/Breen et al. 2005 - Decreased duration of mechanical ventilation when co ... edation for up to 10 days in intensive care unit patients - a ra[...].pdf</url></pdf-urls></urls><electronic-resource-num>10.1186/cc3495</electronic-resource-num></record></Cite></EndNote>[36]?Strom T, ?Martinussen T, Toft P: A protocol of no sedation for critically ill patients receiving mechanical ventilation: A randomised trial. Lancet 2010;375:475-480) ADDIN EN.CITE <EndNote><Cite><Author>Str?m</Author><Year>2010</Year><RecNum>219</RecNum><DisplayText>[37]</DisplayText><record><rec-number>219</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232711">219</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Str?m, Thomas</author><author>Martinussen, Torben</author><author>Toft, Palle</author></authors></contributors><auth-address>Department of Anesthesia and Intensive Care Medicine, Odense University Hospital, University of Southern Denmark, Denmark. t.s@dadlnet.dk</auth-address><titles><title>A protocol of no sedation for critically ill patients receiving mechanical ventilation: a randomised trial</title><secondary-title>Lancet</secondary-title></titles><periodical><full-title>Lancet</full-title></periodical><pages>475-480</pages><volume>375</volume><number>9713</number><keywords><keyword>ICU Rehab 2015</keyword></keywords><dates><year>2010</year><pub-dates><date>2010/2/6</date></pub-dates></dates><isbn>0140-6736</isbn><urls><related-urls><url>(09)62072-9</url><url>(09)62072-9</url></related-urls><pdf-urls><url>All Papers/S/Str?m et al. 2010 - A protocol of no sedation for critically ill patients receiving mechanical ventilation - a randomised trial.pdf</url></pdf-urls></urls><electronic-resource-num>10.1016/S0140-6736(09)62072-9</electronic-resource-num></record></Cite></EndNote>[37]Discussion:JF: Yes considering effects on MV duration and ICU LOSCeline + Kathleen: Probably yes considering no clinical significance on pain scores (refer to question)Gerald: Yes - protocol with sedatives which impact on patient's LOC so more impact on other outcomes than pain intensityUse of sedatives and analgesics will influence pain scores - Berger trial (1.4 control vs 0.9 intervention), 2.7 control vs 1.4 protocol, ?1.61 control vs 1.15 protocol, 1.5 vs 0.6So pain scores were low (average over the ICU LOS) in both groups and the differences was still significant - could change to Yes based on this informationare the undesirable anticipated effects small?constipation ?- no difference?(although only 1 cohort trial assessed it - Bowel movement at 48 hours)RR 1.20 (0.68 to 2.11)60 more per 1000 ptTedders KM, McNorton KN, Edwin SB: Efficacy and safety of analgosedation with fentanyl compared with traditional sedation with propofol. Pharmacotherapy 2014;34:643-647Cardiovascular ADR?no difference (2RCT)RR 0.90 (0.26 to 3.14)3 fewer per 1000 ptBreen D, Karabinis A, Malbrain M, et al: Decreased duration of mechanical ventilation when comparing analgesia-based sedation using remifentanil with standard hypnotic-based sedation for up to 10 days in intensive care unit patients: A randomised trial [ISRCTN47583497]. Crit Care 2005;9:R200-10 ADDIN EN.CITE <EndNote><Cite><Author>Breen</Author><Year>2005</Year><RecNum>2158</RecNum><DisplayText>[36]</DisplayText><record><rec-number>2158</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232827">2158</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Breen, Des</author><author>Karabinis, Andreas</author><author>Malbrain, Manu</author><author>Morais, Rex</author><author>Albrecht, Sven</author><author>Jarnvig, Inge-Lise</author><author>Parkinson, Pauline</author><author>Kirkham, Andrew J. T.</author></authors></contributors><auth-address>Anaesthesia and Intensive Care, Royal Hallamshire Hospital, Sheffield, UK. des.breen@sth.nhs.uk</auth-address><titles><title>Decreased duration of mechanical ventilation when comparing analgesia-based sedation using remifentanil with standard hypnotic-based sedation for up to 10 days in intensive care unit patients: a randomised trial [ISRCTN47583497]</title><secondary-title>Crit. Care</secondary-title></titles><periodical><full-title>Crit. Care</full-title></periodical><pages>R200-10</pages><volume>9</volume><number>3</number><dates><year>2005</year><pub-dates><date>2005/6</date></pub-dates></dates><isbn>0270-7462</isbn><urls><related-urls><url> Papers/B/Breen et al. 2005 - Decreased duration of mechanical ventilation when co ... edation for up to 10 days in intensive care unit patients - a ra[...].pdf</url></pdf-urls></urls><electronic-resource-num>10.1186/cc3495</electronic-resource-num></record></Cite></EndNote>[36]Rozendaal FW, Spronk PE, Snellen FF, et al: Remifentanil-propofol analgo-sedation shortens duration of ventilation and length of ICU stay compared to a conventional regimen: A centre randomised, cross-over, open-label study in the netherlands. Intensive Care Med 2009;35:291-298 ADDIN EN.CITE <EndNote><Cite><Author>Rozendaal</Author><Year>2009</Year><RecNum>2160</RecNum><DisplayText>[30]</DisplayText><record><rec-number>2160</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232827">2160</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rozendaal, F. Willem</author><author>Spronk, Peter E.</author><author>Snellen, Ferdinand F.</author><author>Schoen, Adri</author><author>van Zanten, Arthur R. H.</author><author>Foudraine, Norbert A.</author><author>Mulder, Paul G. H.</author><author>Bakker, Jan</author><author>Ulti, Safe investigators</author></authors></contributors><auth-address>Jeroen Bosch Hospital, 's-Hertogenbosch, The Netherlands.</auth-address><titles><title>Remifentanil-propofol analgo-sedation shortens duration of ventilation and length of ICU stay compared to a conventional regimen: a centre randomised, cross-over, open-label study in the Netherlands</title><secondary-title>Intensive Care Med.</secondary-title></titles><periodical><full-title>Intensive Care Med.</full-title></periodical><pages>291-298</pages><volume>35</volume><number>2</number><dates><year>2009</year><pub-dates><date>2009/2</date></pub-dates></dates><isbn>0342-4642</isbn><urls><related-urls><url> Papers/R/Rozendaal et al. 2009 - Remifentanil-propofol analgo-sedation shortens d ... a centre randomised, cross-over, open-label study in the Netherlands.pdf</url></pdf-urls></urls><electronic-resource-num>10.1007/s00134-008-1328-9</electronic-resource-num></record></Cite></EndNote>[30]Sedation exposure -reduced (1 RCT) - reducedSMD - 0.57 (-0.84 to -0.31)?Strom T, ?Martinussen T, Toft P: A protocol of no sedation for critically ill patients receiving mechanical ventilation: A randomised trial. Lancet 2010;375:475-480) ADDIN EN.CITE <EndNote><Cite><Author>Str?m</Author><Year>2010</Year><RecNum>219</RecNum><DisplayText>[37]</DisplayText><record><rec-number>219</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232711">219</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Str?m, Thomas</author><author>Martinussen, Torben</author><author>Toft, Palle</author></authors></contributors><auth-address>Department of Anesthesia and Intensive Care Medicine, Odense University Hospital, University of Southern Denmark, Denmark. t.s@dadlnet.dk</auth-address><titles><title>A protocol of no sedation for critically ill patients receiving mechanical ventilation: a randomised trial</title><secondary-title>Lancet</secondary-title></titles><periodical><full-title>Lancet</full-title></periodical><pages>475-480</pages><volume>375</volume><number>9713</number><keywords><keyword>ICU Rehab 2015</keyword></keywords><dates><year>2010</year><pub-dates><date>2010/2/6</date></pub-dates></dates><isbn>0140-6736</isbn><urls><related-urls><url>(09)62072-9</url><url>(09)62072-9</url></related-urls><pdf-urls><url>All Papers/S/Str?m et al. 2010 - A protocol of no sedation for critically ill patients receiving mechanical ventilation - a randomised trial.pdf</url></pdf-urls></urls><electronic-resource-num>10.1016/S0140-6736(09)62072-9</electronic-resource-num></record></Cite></EndNote>[37]Opioid exposure - (1 RCT) no difference+0.06 (-0.31 to +0.42)?Strom T, ?Martinussen T, Toft P: A protocol of no sedation for critically ill patients receiving mechanical ventilation: A randomised trial. Lancet 2010;375:475-480) ADDIN EN.CITE <EndNote><Cite><Author>Str?m</Author><Year>2010</Year><RecNum>219</RecNum><DisplayText>[37]</DisplayText><record><rec-number>219</rec-number><foreign-keys><key app="EN" db-id="v9razzrwmtv29zeet5tvadzm9d5dffdd0s55" timestamp="1507232711">219</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Str?m, Thomas</author><author>Martinussen, Torben</author><author>Toft, Palle</author></authors></contributors><auth-address>Department of Anesthesia and Intensive Care Medicine, Odense University Hospital, University of Southern Denmark, Denmark. t.s@dadlnet.dk</auth-address><titles><title>A protocol of no sedation for critically ill patients receiving mechanical ventilation: a randomised trial</title><secondary-title>Lancet</secondary-title></titles><periodical><full-title>Lancet</full-title></periodical><pages>475-480</pages><volume>375</volume><number>9713</number><keywords><keyword>ICU Rehab 2015</keyword></keywords><dates><year>2010</year><pub-dates><date>2010/2/6</date></pub-dates></dates><isbn>0140-6736</isbn><urls><related-urls><url>(09)62072-9</url><url>(09)62072-9</url></related-urls><pdf-urls><url>All Papers/S/Str?m et al. 2010 - A protocol of no sedation for critically ill patients receiving mechanical ventilation - a randomised trial.pdf</url></pdf-urls></urls><electronic-resource-num>10.1016/S0140-6736(09)62072-9</electronic-resource-num></record></Cite></EndNote>[37]Is there important uncertainty about how much people value the main outcomes? ● No important uncertainty or variability Are the desirable anticipated effects large? ● Yes Are the undesirable anticipated effects small? ● Probably yes ○ Yes ○ Varies Are the desirable effects large relative to undesirable effects? ○ No ○ Probably no ○ Uncertain ● Probably yes ○ Yes ○ Varies Resource useAre the resources required small? ○ No ● Probably no ○ Uncertain ○ Probably yes ○ Yes ○ Varies can be a big practice change to end users. May require more resourcesimplementing protocols can be time consuming and maintaining the quality is challenging: agree: Probably no or varies - resources are variable from an ICU to another?Is the incremental cost small relative to the net benefits? ○ No ○ Probably no ○ Uncertain ● Probably yes ○ Yes ○ Varies Reduction in ICU LOS drives economics, however it is important to note the ?implementation typically requires dedicated support.?there MAY be an increase need for 1:1 nursing care (or use of sitters - leave out?)In addition, ?it is important to note some of the cohort trials and some of the RCT utilize remifentanil. This question does not cull out individual medications; therefore the cost of specific medication should not influence cost.?comment on use of sitters (could be seen as a cost barrier) - may be related to more agitation less sedatives, more awake patients may lead to increased presence at the bedsideIn some countries the ratio of nurse-pt is 1:1 (nurse also manage the ventilator); more mobilization too specific to one study?AcceptabilityIs the option acceptable to key stakeholders? ○ No ○ Probably no ○ Uncertain ● Probably yes Standardized and/or protocol-based analgesia/analgosedation programs can be polarizing topic. Some multi-professional ICU leaders are very supportive and others are not.?Change to Probably yes - although we know that not all opioids are easily available in all countries-Nurse satisfaction increased after implementation of such a protocol – prob.yesFeasibilityIs the option feasible to implement? ● Probably yes it's been done in several real-life cohort examples, therefore likely feasible (but not easy) Group agrees!Recommendation Should standardized and/or protocol-based analgesia/analgosedation programs vs. no standardized programs be used for critical care pain management (4)?Balance of consequences Undesirable consequences clearly outweigh desirable consequences in most settingsUndesirable consequences probably outweigh desirable consequences in most settingsThe balance between desirable and undesirable consequences is closely balanced or uncertainDesirable consequences probably outweigh undesirable consequences in most settingsDesirable consequences clearly outweigh undesirable consequences in most settings○○○●○Type of recommendation We recommend against offering this optionWe suggest not offering this optionWe suggest offering this optionWe recommend offering this option○○●○Recommendation We suggest standardized and/or protocol-based analgesia/analgosedation programs should be utilized for critical care pain management. (+2C)*3 RCTs with consistent results; suggest to change with "recommend" (Kathleen agrees)*refer to 2013 guidelines (suggest) because it was a +2B*C for low quality of evidence so should be +2C*Recommend has a stronger impact on policy makers - it would require that all ICUs have protocols for their patients - does not mean that pain not be managed it can be done individually*agrees with "recommend" but also with consistency with previous guidelinesPaul: stay with "suggest"*analgosedation defined as "analgosedation?refers to the use of opioids for pain control and sedation purposes." by the groupJustification Reduction in ICU LOS and MV with no apparent increase in ADE (adverse drug events) compared to standard of care.?Subgroup considerations Many subgroups have been studied, however much more research in need (see research possibilities below) in specific ICU population. Neuro ICU, Trauma ICU, Cardiac Surgery ICU.?Implementation considerations Institutions should have have frequent assessment (multiple times a day) of pain via validated tools as a standard of care (patient report and behavioral pain scores). Leaders need to be willing to champion the effort to embrace the challenges of implementing clinical practice change.?Monitoring and evaluation Important to monitor process measures (e.g. quality of pain assessment documentation, compliance with frequency, opioid/sedation mediation utilization) and clinical outcomes (e.g. pain scores, ICU LOS, length of MV) as well as economic impact.?Research possibilities is one opioid better than another for standardized and/or protocol-based analgesia/analgosedation programs ? Gerald - clearly define analgesia-based sedation Is there an ICU setting (ICU patient population) most appropriate for standardized and/or protocol-based analgesia/analgosedation programs?Is the benefit of standardized and/or protocol-based analgesia/analgosedation programs reduction in pain or is it avoidance of harmful sedatives?More in depth look at the adverse effects, opioid withdrawal and post-hospital opioid use disorder associated with standardized and/or protocol-based analgesia/analgosedation programs.?Comments during electronic voting by entire panelHesitant about strong recommendation; moderate evidence on ICU LOS and MV duration. With validated pain assessment tools available, it is time to move forward and implement structured pain management approaches. Comparative group needs to be added into the recommendation. 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