The effectiveness of systematic pain assessment on critically ill patient outcomes: A randomised controlled trial

Australian Critical Care xxx (xxxx) xxx

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Research paper

The effectiveness of systematic pain assessment on critically ill patient outcomes: A randomised controlled trial Evanthia Georgiou, PhD, CCRN a, * Lefkios Paikousis, MSc b, f Ekaterini Lambrinou, RN, PhD c, g Anastasios Merkouris, RN, PhD d, h Elizabeth D.E. Papathanassoglou, RN, PhD e, i a b

Еducation Sector, Nursing Services, Ministry of Health, 1 Prodromou & Chilonos Street 17, 1448 Nicosia, Cyprus

Improvast Analytical Services, 7 Arkadias, 1048, Nicosia Cyprus Department of Nursing, Cyprus University of Technology, 15, Vragadinou Str, 3041 Limassol, Cyprus d Cyprus University of Technology, Faculty of Health Sciences, Department of Nursing, 15, Vragadinou St., Limassol 3041, Cyprus e Faculty of Nursing, University of Alberta, 5-262 Edmonton Clinic Health Academy (ECHA), 11405-87th Ave. Edmonton, Alberta, T6G 1C9, Canada c

article information

a b s t r a c t

Article history: Received 27 December 2018 Received in revised form 13 September 2019 Accepted 22 September 2019

Background: Evidence suggests that critically ill patients’ pain may still be underestimated. Systematic approaches to pain assessment are of paramount importance for improving patients’ outcomes. Objectives: To investigate the effectiveness of a systematic approach to pain assessment on the incidence and intensity of pain and related clinical outcomes in critically ill patients. Methods: Randomized controlled study with consecutive critically ill patients allocated to either a standard care only or a systematic pain assessment group. The Behavioral Pain Scale (BPS) and the Critical Pain Observation Tool (C-POT) were completed twice daily for all participants. In the intervention group, clinicians were notified of pain scores. Linear Mixed Models (LMM) for the longitudinal effect of the intervention were employed. Results: A total of 117 patients were included (control: n¼61; intervention: n2¼56). The incidence of pain (C-POT >2) in the intervention group was significantly lower compared to the control group (p < .001). The intervention had a statistically significant effect on pain intensity (BPS, p ¼ 0.01). The average total morphine equivalent dose in the intervention group was higher than in the control group (p ¼ 0.045), as well as the average total dose of propofol (p ¼ 0.027). There were no statistically significant differences in ICU mortality (23.4% vs 19.3%, p¼0.38, odds ratio 0.82 [0.337-1.997]) and length of ICU stay (13.5, SD 11.1 vs 13.9, SD 9.5 days, p¼ 0.47). Conclusion: Systematic pain assessment may be associated with a decrease in the intensity and incidence of pain and influence the pharmacological management of pain and sedation of critically ill patients. © 2019 Australian College of Critical Care Nurses Ltd. Published by Elsevier Ltd. All rights reserved.

Keywords: Pain assessment Critical illness Outcomes Incidence of pain

1. Introduction Pain in the critically ill is associated with adverse physiological and psychological outcomes1 and impacts patients' quality of life

* Corresponding author. Tel.: þ35722603049, þ35799697093; fax: þ22345015. E-mail addresses: [email protected] (L. Paikousis), ekaterini.lambrinou@ cut.ac.cy (E. Lambrinou), [email protected] (A. Merkouris), [email protected] (E.D.E. Papathanassoglou). f Tel.: þ(357) 22 263418 g Tel.: þ357 25002030 h Tel.: þ35725002024; fax: þ35725002845. i Tel.: þ1 780 492-5674 (w).

after discharge from the intensive care unit (ICU).2,3 Despite notable advances in methods of pain assessment for the critically ill and in analgesia, pain in critical illness remains an unresolved challenge.4,5 The first step for adequate pain relief is a systematic assessment and documentation of pain.6 Failure to assess pain has been associated with ICU fatality,7 whereas routine pain assessment in the critically ill has been linked to improved outcomes including decreases in duration of mechanical ventilation, length of ICU stay, mortality, and complications.8 According to the latest recommendations of the Society of Critical Care Medicine, pain should be routinely monitored, and when patients are unable to self-report,

https://doi.org/10.1016/j.aucc.2019.09.004 1036-7314/© 2019 Australian College of Critical Care Nurses Ltd. Published by Elsevier Ltd. All rights reserved.

Please cite this article as: Georgiou E et al., The effectiveness of systematic pain assessment on critically ill patient outcomes: A randomised controlled trial, Australian Critical Care, https://doi.org/10.1016/j.aucc.2019.09.004

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the use of a valid behavioural pain scale is strongly recommended.1 However, data show that evidence-based practice guidelines are not fully implemented in ICUs around the world, leaving patients vulnerable to pain and related complications.5,9,10 One recent study which explored the prevalence of assessment and management practices of analgesia and sedation in New Zealand and Australian ICUs reported that only two-thirds of sedated patients had their sedation level formally assessed and that only half of patients were assessed for pain.11 Moreover, there is a lack of evidence on the effectiveness of systematic pain assessment originating from randomised controlled trials (RCTs).8 1.1. Aims Through an RCT design with consecutive ICU patients, we aimed to investigate the effect of a systematic assessment of pain on the incidence of pain episodes (primary outcome). Secondary outcomes included pain intensity, use of analgesics and sedatives, ICU length of stay, duration of mechanical ventilation, survival, and occurrence of adverse events.

2.6. Sample size Sample size calculations were performed by power analysis using G Power, version 3.1.13 Evidence from previous studies was used.14e17 The effect size appeared to differ greatly among studies, and the desired sample size ranged from 5 to 88. Taking into account an average effect size, the desired sample size was estimated at 60 participants per group, which would be sufficient to identify an effect size (d) of 0.5, for double-sided tests, alpha of 0.05, and statistical power of 80%. The sample of 120 (60/group) was powered for the primary aim only. 2.7. Randomisation, blinding, and concealment Randomisation was based on a computer-generated table of random numbers,12 and blocks of two allocations were created based on an initial Critical Care Pain Observation Tool (C-POT) score (C-POT<2 and C-POT>2). Participants and outcome assessors were blinded to group allocation, but owing to the design of the study, clinicians could not be blinded; however, they were blinded to study hypotheses. 2.8. Intervention and study arms

2. Materials and methods 2.1. Design This is a randomised, controlled, repeated-measures trial with two parallel groups (intervention and standard care group with 1:1 allocation; Fig. 1). 2.2. Setting The study was conducted in a 17-bed academic mixed medical/ surgical/trauma ICU in Cyprus, employing more than 70 registered nurses. Before the study, the unit did not use any pain assessment/ management policies.

Both groups received standard care plus additional systematic assessment of pain twice daily (between 0800-1000 and 14001600) for up to 10 consecutive days. Moreover, in the intervention group, the results of pain assessments were communicated to clinicians in a standardised way. Clinicians (including nurse or physician or both) were informed that the patient showed “some signs of pain” for C-POT of 2e3, “several signs of pain” for C-POT of 4e5, “many signs of pain” for C-POT of 6e8, “moderate pain” for Behavioral Pain Scale (BPS) of 4e6, “severe pain” for BPS of 7e9, “very severe pain” for BPS of 10e12). Any decisions regarding analgesia were independently made by clinicians without input from study personnel, and changes in analgesia or other measures were recorded. All assessments were conducted by independent assessors who were trained by the investigators to use the pain assessment tools and were blinded to group allocation.

2.3. Trial registration 2.9. Outcomes and operationalisation The Trial has been registered to the online Registry of Clinical Trials with the identification number: NCT02435589. 2.4. Ethical approval The study was approved by the Cyprus Bioethical Committee (EEBK/ЕP/2012/18). Written informed consent was obtained from surrogates before recruitment, and participant assent was sought when participants regained capacity. Confidentiality and right to withdraw at any time were assured.

2.9.1. Primary outcome The primary outcome was the incidence of pain episodes defined as a C-POT score >218,19 or a score at the 0e10 numeric rating scale (NRS) > 3.14 2.9.2. Secondary outcomes Secondary outcomes were pain intensity (C-POT, BPS, or NRS score), daily dose of opioid [morphine equivalents (mEq)] and nonopioid (mg/kg) analgesia, daily dose of sedatives (mg), ICU length of stay, duration of mechanical ventilation, survival, and occurrence of complications.

2.5. Recruitment and eligibility 2.10. Data identification Consecutive adult patients were screened daily over a 12-month period (July 2014eJuly 2015). Consented participants were randomly assigned to the intervention or control group based on a computer-generated table of random numbers.12 Exclusion criteria are as follows: Patients (a) with expected ICU stay<24 h, (b) receiving neuromuscular blockers, (c) with conditions such as Guillain-Barre, peripheral neuropathy, which modify sensory transmission of painful stimuli, and any disease or condition that complicates the assessment of pain behaviour such as decerebration or vegetative state, (d) with agitation> 3 in the Richmond Agitation-Sedation Scale (RASS), and (e) younger than 18 years.

For participants who were unable to communicate for any reason, pain was assessed by the BPS (range: 3e12) at rest and the C-POT (range: 0e8), both at rest and during turning the patient. The BPS and C-POT are considered the most valid and reliable tools for assessment of pain in adults in medical surgical and trauma ICUs;19 however, the C-POT, as opposed to the BPS, has a cut-off score (>2) for detection of pain episodes.18 Therefore, the C-POT was used for the assessment of the primary outcome as a dichotomous scale (presence or absence of pain) and for the assessment of the secondary outcome “pain intensity” as a continuous scale, in addition

Please cite this article as: Georgiou E et al., The effectiveness of systematic pain assessment on critically ill patient outcomes: A randomised controlled trial, Australian Critical Care, https://doi.org/10.1016/j.aucc.2019.09.004

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to the BPS. For participants who were able to report their pain level, we used a 0e10 NRS (with “0” indicating no pain and “10” indicating the worst pain possible). Both the BPS and C-POT have shown high correlation with self-reported pain scores.20 Interrater reliability between research assistants was tested at the pilot phase of this study, in a sample of 10 patients in the ICU. Overall, 50 pain assessments were made to check the degree of agreement. Assessments were carried out using both the C-POT and BPS. Assessments showed a Spearman correlation coefficient of 0.96 (P < 0.001) for C-POT and 0.9 (p < 0.001) for BPS ratings. Reliability assessments were repeated periodically during data collection. The level of sedation/agitation was evaluated using the RASS. All the aforementioned tools (BPS, NRS, C-POT, and RASS) have been translated and validated for use in the Greek language.21e23 The Acute Physiology and Chronic Health Evaluation II (APACHE II) score was recorded within the first 24 h of admission to the ICU, as a measure of severity of illness at admission. Opioid administration was expressed in morphine equivalents (mEq): A value derived from the combination of Fentanyl, Remyfental and Morphia. The administration of Fentanyl, Remyfentanyl and Morphia in mg/Kg of body weight/hr was combined to morphine equivalents using the following formula (Fentanyl þ Remyfentanyl)x100 þ Morphia.24 The total dose of nonopioid analgesics was calculated in mg/kg of body weight. The total dose of sedative medications (benzodiazepines, propofol) was also expressed in mg/kg of body weight. 2.11. Quality assurance A trial advisory committee supported the investigator by overseeing issues of recruitment, informed consent, randomisation, concealment, and statistical methods and by communicating with the investigator/assessors as needed. The committee assured compliance with research methodology but was not independent of the principal investigator. 2.12. Statistical methods Baseline characteristics across control and intervention groups were compared using the t test (continuous variables) and Fisher exact test (categorical variables). Association between CPOT and BPS scales was explored using the Spearman correlation coefficient. Longitudinal incidence of pain was analysed by a logistic regression model and the binary logistic link function25 based on Generalized Estimating Equations. Model fit across covariance structures was compared by the Quasi-likelihood under the Independence Model Criterion. The effect of the intervention on pain levels longitudinally was assessed by linear mixed models to account for within-subject correlation, missing data, and covariates measured in a repeated fashion.26 The covariance structure and the model fit were evaluated using the Akaike information criterion where “the lower the Akaike information criterion, the better the fit”.27,28 All models were adjusted for RASS scores as an indicator of sedation and APACHE II and Sequential Organ Failure Assessment (SOFA) as indicators of disease severity levels. Comparisons between groups were carried out using ManneWhitney U tests. Mortality rate was explored using the Fisher exact test. Time to event analysis (from ICU admission to death) was tested using the KaplaneMeier curves and the log-rank test. 3. Results 3.1. Participants and baseline characteristics During the study period, 286 patients were assessed for eligibility, of whom 117 were randomised to a control (n1 ¼ 61) and an

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intervention group (n2 ¼ 56, Fig. 1). Recruitment took place from July 2014 to July 2015. Demographic and clinical characteristics and pain scores were not statistically significantly different between the two groups at baseline, despite younger mean age in the intervention group (Table 1). Overall, 3124 CPOTC-POT, 1562 BPS, and 152 NRS pain assessments were completed for both groups. 3.2. Primary outcome: incidence of pain episodes The incidence of pain episodes (C-POT >2) during turning in the intervention group was significantly lower over time than in the control group (p < 0.001; Table 2). Incidence of pain episodes (C-POT >2) at rest, as well as the self-reported incidence of pain with NRS, was very low (<2%) across both groups; hence, no reliable models could be fitted. 3.3. Secondary outcomes 3.3.1. Pain scores The intervention appeared to have a statistically significant effect on BPS (p ¼ 0.009) but not on C-POT scores either at rest (p ¼ 0.176) or during turning (p ¼ 0.143; Table 3). The overall association between BPS and C-POT scores on the first day of the study was moderate to high (before turning: r ¼ 0.455, p < 0.001; after turning: r ¼ 0.571, p < 0.001) 3.3.2. Analgesia and sedation Fentanyl, remifentanil, and morphine were the medications used for analgesia. Overall, the percentage of patients receiving analgesia was higher in the intervention group (fentanyl ¼ 58.9%, remifentanil ¼ 33.9%, and morphine ¼ 39.3%) than in the control group (fentanyl ¼ 54.1%, remifentanil ¼ 16.4%, and morphine ¼ 29.5%). However, this difference was statistically significant only for remifentanil (p ¼ 0.024; Table 4 supplemental files). Propofol and midazolam were used for sedation. Although the percentage of patients treated with these medications was higher in the intervention group (propofol ¼ 85.7%, midazolam ¼ 33.9%) than in the control group (propofol ¼ 68.9%, midazolam ¼ 19.7%), this difference was not statistically significant (propofol: p ¼ 0.127, midazolam: p ¼ 0.062; Table 4 supplemental files). With regard to opioid medications, mean total morphine equianalgesic doses (mg/kg/study period) in the intervention group [20.72, standard deviation (SD): 24.7] were higher than in the control group (13.04, SD: 32; p ¼ 0.045). Propofol mean total doses were also higher in the intervention group (203.2, SD: 164.7) than in the control group (129.9, SD: 128.5; p ¼ 0.027), as well as the mean total dose of midazolam (p ¼ 0.252; Table 4 supplemental files). 3.3.3. Clinical outcomes Duration of mechanical ventilation (p ¼ 0.41), length of ICU stay (p ¼ 0.47), and days off ventilator (p ¼ 0.86) were not statistically significantly different between the 2 groups. The mortality rate for the intervention group was 19.3% (N ¼ 11) compared with 23.4% (N ¼ 14) in the control group (p ¼ 0.38, odds ratio: 0.82 [0.337e1997]). There was no statistically significant difference in survival (log-rank test p ¼ 0.107; Fig. 2) and in complications and adverse events between the control and intervention group. The number of patients who developed hospital-acquired pressure injuries (intervention n ¼ 11 (19.6%) vs control n ¼ 15 (24.6%), p ¼ 0.34) and nosocomial infections [intervention n ¼ 10 (17.9%) vs control n ¼ 12 (19.7%), p ¼ 0.49] was lower in the intervention group than in the control group (Table 5 supplemental files).

Please cite this article as: Georgiou E et al., The effectiveness of systematic pain assessment on critically ill patient outcomes: A randomised controlled trial, Australian Critical Care, https://doi.org/10.1016/j.aucc.2019.09.004

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Fig. 1. CONSORT 2010 flow diagram.

4. Discussion It is widely recognised that systematic assessment of pain in critically ill patients still remains infrequent and is carried out inconsistently.23,11 To our knowledge, this is the first RCT to demonstrate that the use of a structured systematic pain assessment, as an independent nursing intervention, can affect the incidence and intensity of pain episodes and administration of analgesics in critically ill patients. Previous results were mostly based on preexperimental retrospective or pre-post designs with high risk of bias.8 4.1. Effect on pain episodes and pain levels Our observation of decreased incidence and intensity of pain as a consequence of standardised pain assessment is in line with the results of an earlier nonrandomised preimplementation/postimplementation study in medical ICU patients,14 and with nonstatistically significant trends observed in another two quasiexperimental studies.15,17 A number of studies have evaluated comprehensive pain management programs which included

systematic pain assessment and reported a decrease in pain episodes.29e31 In contrast to our sample, these studies involved patients who had the ability to self-report pain. Although self-report by the patient is considered as the “gold standard” for assessing pain,32 in the present study, very few patients were able to report their pain, because of low level of consciousness, mechanical ventilation, or deep sedation. Our results are not directly comparable with results of experimental studies of pain management protocols33,34 because we implemented no such protocol, nor made recommendations for the management of pain. Considering the aforementioned studies, what this study adds is high-level evidence that systematic pain assessment can be an effective intervention on its own, even if not linked to a specific pain management protocol. It appears that increasing the awareness of clinicians about the pain a patient is experiencing can result in changes in care. There was a discrepancy noted between BPS scores, which reflected a statistically significant decrease in pain scores in the intervention group over time, and C-POT scores showing a nonstatistically significant decrease. Although this may be partially attributed to our power calculations, which were based on studies

Please cite this article as: Georgiou E et al., The effectiveness of systematic pain assessment on critically ill patient outcomes: A randomised controlled trial, Australian Critical Care, https://doi.org/10.1016/j.aucc.2019.09.004

E. Georgiou et al. / Australian Critical Care xxx (xxxx) xxx Table 1 Demographics and clinical characteristics at baseline (N ¼ 117). Demographics and clinical characteristics

Control N ¼ 61

Demographics Men 36 (59) Age 64.9 ± 14.5 Weight (kg) 76.1 ± 17.8 Diagnosis Medical 38 (62.3) Trauma 8 (13.1) Surgical 15 (24.6) History Diabetes 8 (16.3) Cardiac 29 (49.2) Respiratory 12 (20.0) Alcohol 1 (1.7) Use of opioids 0 (0.0) Neuropathic pain 0 (0.0) Stress 0 (0.0) Depression 3 (5.3) Disease severity APACHE II 20.6 ± 6.1 SAPS ІІ 53.9 ± 11.9 SOFA 7.2 ± 2.8 MODS 5.9 ± 2.8 GCS 6.5 ± 4,4 RASS 3.6 ± 2.1 LACTATE 1.59 ± 1.9 Vital sings and oxygenation *SAP 134.2 ± 21.5 *DAP 65.3 ± 13.7 *MAP 86.8 ± 15 *TEMP 36.9 ± 0.8 *HR 90.9 ± 20.2 FiO2 47.1 ± 17.1 SAPS 54 ± 11.9 SpO2 97.3 ± 3.3 Able to speak 3 (4.9) Tracheostomy 57 (95.0) Mechanical ventilation 56 (93.3)

Intervention N ¼ 56

P*

5

Table 3 Linear mixed models for the effect of the intervention on the pain levels (BPS) and indication of pain (C-POT) at rest and during turning. Dependant variable: Level of pain with BPS

33 (59) 59.5 ± 18.2 80.6 ± 16.1

0.517 0.076 0.137

28 (51.90) 11 (20.4) 15 (27.8)

0.456

15 (28.3) 35 (63.6) 11 (19.3) 1 (1.9) 1 (1.8) 1 (1.9) 1 (1.9) 0 (0.0)

0.064 0.085 0.555 0.73 0.482 0.478 0.482 0.132

21.4 ± 6.8 52.7 ± 15 7.5 ± 3 6.2 ± 2.8 5.5 ± 4.2 4.2 ± 1.8 1.27 ± 0.6

0.533 0.532 0.599 0.638 0.233 0.105 0.236

131.7 ± 19.4 64.1 ± 11.4 86.3 ± 13.2 36.7 ± 1 86.6 ± 17.3 45.5 ± 12.4 52.4 ± 15.1 97 ± 12.4 3 (5.3) 55 (98.2) 55 (98.2)

0.508 0.612 0.865 0.254 0.233 0.568 0.532 0.862 0.544 0.336 0.204

Note: Categorical variables are represented as N (%), and continuous variables are represented as mean ± standard deviation. *Fisher exact test was used for categorical variables, and independent samples t-test was used for continuous variables. *APACHE II, Acute Physiology and Chronic Health Evaluation ІІ; SAPS ІІ, Simplified Acute Physiology Score II; MODS, Multiple Organ Dysfunction System; SOFA, Sequential Organ Failure Assessment; GCS, Glasgow Coma Scale; RASS, Richmond Agitation-sedation Scale; SAP, systolic arterial pressure; DAP, diastolic arterial pressure; MAP, mean arterial pressure; TEMP, temperature; HR, heart rate.

that did not use the C-POT, it may also be attributed to clinically relevant differences between the two tools that might exist. The BPS has been used as a measure of pain intensity more often,35 and it appears to be more specific than the C-POT,20 whereas the C-POT has primarily been developed to indicate the presence of pain.18 Table 2 Generalized Estimating Equations model for the effect of the intervention on the pain incident (C-POT>2). Generalized estimating equations model

Wald Chi-square

df

Sig.

Intercept Intervention group Time Intervention group * time RASS APACHE II SOFA

20.298 6.955 2554.609 3185.275 24.823 0.109 0.53

1 1 19 18 1 1 1

<0.001 0.008 <0.001 <0.001 <0.001 0.742 0.467

QIC: 896; covariance structure: independent. Dependent variable: incident of pain (C-POT>2) during turning. *RASS, Richmond Agitation-sedation Scale; APACHE II, Acute Physiology and Chronic Health Evaluation ІІ; SOFA, Sequential Organ Failure Assessment; QIC, Quasi-likelihood under the Independence Model Criterion.

F

Sig.

320.443 260.003 224.563 263.045

1219.932 1.794 4.108 1.996

<0.001 0.024 0.044 0.009

557.357 316.667 304.993

54.147 0.146 0.993

<0.001 0.703 0.32

Source

Numerator df

Denominator df

Intercept Intervention group Time Intervention group * time RASS APACHE II SOFA

1 19 1 19 1 1 1

Dependant variable: indication of pain with C-POT at rest

F

Sig.

292.97 218.192 228.249 218.193

55.262 1.565 2.183 1.315

<0.001 0.067 0.141 0.176

524.175 282.9 274.707

111.694 <0.001 1.46 0.228 0.982 0.323

Source

Numerator df

Denominator df

Intercept Intervention group Time Intervention group * time RASS APACHE II SOFA

1 19 1 19 1 1 1

Dependant variable: indication of pain with C-POT during turning

F

Sig.

Source

Numerator df

Denominator df

Intercept Intervention group Time Intervention group * time RASS APACHE II SOFA

1 19 1 19

296.668 195.235 220.415 195.108

77.53 1.146 3.37 1.374

<0.001 0.308 0.068 0.143

1 1 1

530.281 288.56 276.225

68.134 0.012 1.223

<0.001 0.913 0.27

AIC ¼ 2721; covariance structure: heterogeneous first-order autoregressive. AIC ¼ 2794; covariance structure: heterogeneous first-order autoregressive. AIC ¼ 3589.193; covariance structure: Toeplitz. *RASS, Richmond Agitation-sedation Scale; APACHE II, Acute Physiology and Chronic Health Evaluation ІІ; SOFA, Sequential Organ Failure Assessment; C-POT, Critical Care Pain Observation Tool; BPS, Behavioral Pain Scale; AIC, Akaike information criterion.

4.2. Effect on medications Systematic pain assessment had different effects on opioid and sedative administration across the two groups. In a recent systematic review,8 8 of 10 studies reported that systematic pain assessment affected daily analgesic doses, with the majority of studies reporting better pain management and more effective use of analgesics and/or sedatives. In the present study, patients in the intervention group received significantly more total mEq dose, possibly reflecting clinicians' attempts to titrate analgesia on the basis of pain assessments. The objective of systematic pain assessment is to treat pain accurately and to avoid either overmedication or undermedication. For example, in the quasiexperimental study by Rose et al.,36 after application of the C-POT, the use of opioid analgesics increased in the mixed ICU, while it decreased in the cardiovascular surgery ICU. Shifts in the type of analgesia have also been reported in a multicentre study by Payen et al.37 because more patients with pain assessments were treated with nonopioids than those without pain assessment. The finding that a significantly higher percentage of patients in the intervention group received both propofol and aidazolam and a higher total propofol dose is worth noting. Despite controversy over the pain modulatory effects of propofol,38,39 current guidelines recommend propofol as a sedative, not analgesic.1 The observed

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Fig. 2. Survival curve for the event of death, within 15 days of ICU length of stay. KaplaneMeir survival curves for the event of death. Survival is monitored for the first 15 days in the ICU (length of ICU stay). Censored indicates length of stay of less than 15 days and no event occurred. Control group shows a “lower survival” although not statistically significant (log-rank test; c2 (1) ¼ 2.625, p ¼ 0.107). ICU, intensive care unit.

increase in propofol use could also be partly explained by the lack of sedation optimisation policies targeting an acceptable range of sedation in the ICU.40 Ideally, in accordance with the principles of analgosedation, effective use of opioid analgesics would be expected to result in decreased use of sedatives and of ensuing risks and side effects.41,42 The fact that we did not observe such trends in our unit may be indicative of the need for implementation of analgesia and sedation protocols and for personnel training. Protocols and training help minimise the effect of variables such as personal preferences, subjectivity, and nurses' level of expertise, when titrating analgesics and sedatives.43,44 It is widely accepted that critical care nurses when given the right tools such as education and support can make decisions that promote positive outcomes for patients receiving sedation and analgesia.45

4.3. Effect on clinical outcomes Although the current level of evidence emphasises the link between systematic pain assessment and improved short-term outcomes of the critically ill patients, this study did not demonstrate any significant differences between the two groups in terms of ICU length of stay, days off ventilator, and duration of mechanical ventilation. These outcomes need to be further explored in the future because our trial was not powered to detect differences in those secondary outcomes. This finding may also be understandable based on the fact that our intervention was not directly linked to prescribed pharmacological interventions. It is acknowledged that the use of integrated sedation/analgesia protocols that involve either pharmacological interventions or education of ICU health professionals is associated with improved outcomes, rather than the choice of a specific sedation/analgesia scale alone.46 In a study, in which physicians received education regarding analgesics and psychoactive drugs, a significant association with the duration of mechanical ventilation was demonstrated, although no analgesia protocol was implemented.14 Furthermore, recent evidence suggests that even when such protocols and guidelines are implemented, there is still the need to monitor the rate and the extent of their adoption, for a change in patients' outcomes.47 Therefore, systematic pain assessment may be a valuable approach to rational and effective analgesia and sedation provided that

clinicians possess adequate knowledge regarding management of pain and sedation.8 Moreover, lack of an association between systematic pain assessment and clinical outcomes may had also been partially affected by the excessive use of sedatives. Many studies have shown the negative outcomes of deep and prolonged sedation48,49 and positive results of lighter sedation in adult ICU patients.50,51 Although we did not find a statistically significant difference in complications and adverse events in the intervention group, two nonrandomised preimplementation/postimplementation studies reported a decrease in the rate of nosocomial infections (14, n ¼ 230) and complications (16, n ¼ 30) after implementation of systematic pain assessment. There was no significant effect on survival in the present study. In published studies, the effects of pain assessment on survival have been inconsistent. In one study, increased pain monitoring was independently predictive of reduced mortality in the ICU,52 whereas in other two studies, there was no significant difference in mortality.37,14,33 In the present study, detection of effects on survival would probably require a larger size because of relatively rare incidents. 5. Limitations The main limitation of the study originates from the inability to double blind the intervention and from the large number of variables considered simultaneously. Specifically, although participants and their relatives were unaware of the study group, nurses and physicians could deduct allocation because they were verbally informed of pain scores. This could have introduced sources of bias related to novelty and Hawthorne effects in nurses and/or physicians, who might have differentially modified their practice in the two groups. However, these effects may be acceptable because one of the objectives of the study was to investigate the extent to which the intervention would affect clinical practice. Nonetheless, with the present design, it is not clear whether this change in analgesia/ sedation administration would have occurred if the pain assessment information was presented as a number on a computer screen, which may be worth exploring in the future. Moreover, we cannot deduce whether the intervention affected the behaviour of nurses, physicians, or both groups. Similarly, another limitation is that research assistants who were conducting the pain assessments were aware of group allocation. Although it was initially attempted to engage independent individuals who would notify pain levels on the basis of recorded scores, it ultimately would hinder the flow of the protocol and increase the number of research assistants, thus burdening ICU procedures. Although this might have introduced bias, we considered it to be minimal, as assessors did not have any control over clinicians' decisions. Moreover, an additional limitation arose because a delirium assessment tool was not used at the unit, at the time of the study. Although evidence supports the reliability of the C-POT for patients with delirium,53 some controversy around this issue remains.54 Even though patients with agitation (RASS>3) were excluded from our sample, it is still possible that the reliability of some C-POT scores was low because of undiagnosed delirium. 6. Conclusions and recommendations This study is the first to apply an RCT methodology to investigate the efficacy of a systematic assessment of pain on outcomes of critically ill patients. The results provide strong evidence that the systematic evaluation of pain can contribute to reducing the incidence and intensity and influence the pharmacological management of pain in the ICU. However, the effects of systematic pain assessments on clinical outcomes, such as survival, length of stay, and complications, need to be evaluated further in appropriately powered RCTs.

Please cite this article as: Georgiou E et al., The effectiveness of systematic pain assessment on critically ill patient outcomes: A randomised controlled trial, Australian Critical Care, https://doi.org/10.1016/j.aucc.2019.09.004

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Funding No funding has been received for this study. CRediT authorship contribution statement Evanthia Georgiou: Conceptualization, Methodology, Project administration, Data curation, Formal analysis, Investigation, Writing - original draft, Writing - review & editing. L. Paikousis: Software, Data curation, Validation, Formal analysis. E. Lambrinou: Conceptualization, Methodology, Supervision, Validation, Visualization, Writing - review & editing. A. Merkouris: Conceptualization, Methodology, Supervision, Validation, Visualization, Writing review & editing. E.D.E. Papathanassoglou: Conceptualization, Project administration, Resources, Supervision, Validation, Visualization, Writing original draft, Writing - review & editing. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.aucc.2019.09.004. References
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Please cite this article as: Georgiou E et al., The effectiveness of systematic pain assessment on critically ill patient outcomes: A randomised controlled trial, Australian Critical Care, https://doi.org/10.1016/j.aucc.2019.09.004