Prescribing nonopioids in mechanically ventilated critically ill patients

Journal of Critical Care (2013) 28, 534.e7–534.e12

Prescribing nonopioids in mechanically ventilated critically ill patients☆,☆☆ Jean-Francois Payen MD, PhD a,⁎, Celine Genty BSc b , Olivier Mimoz MD, PhD c , Jean Mantz MD, PhD d , Jean-Luc Bosson MD, PhD b , Gerald Chanques MD, PhD e a

Pôle d'Anesthésie-Réanimation, Hôpital Michallon, et UJF-Grenoble 1, INSERM U836, Grenoble Institut des Neurosciences, Grenoble, France b Centre de Recherche Clinique, INSERM 003, Hôpital Michallon, et UJF-Grenoble 1, CNRS, TIMC-IMAG, UMR-CNRS 5525, Grenoble, France c Département d'Anesthésie-Réanimation, Centre Hospitalier Universitaire, Université de Poitiers, et INSERM ERI 23, Poitiers, France d Département d'Anesthésie-Réanimation, Hôpital Beaujon, Assistance Publique des Hôpitaux de Paris, Clichy, France e Département d'Anesthésie-Réanimation B, Hôpital Saint Eloi, Montpellier, France

Keywords: Intensive care unit; Analgesia; Sedation; Opioids; Paracetamol

Abstract Purpose: We searched for factors independently associated with the prescription of multimodal (balanced) analgesia in mechanically ventilated critically ill patients. Methods: In this post hoc analysis of a cohort study, 172 patients who received a combination of 1 opioid with nonopioids, that is, paracetamol and/or nefopam, (multimodal analgesia), were compared with 302 patients who received opioid only on day 2 of their stay in the intensive care unit. Results: Patients given multimodal analgesia were more likely to have fewer organ failures and received fewer hypnotics compared with patients who received opioid only. They self-reported more frequently their pain level. There were no differences in the daily dose of opioids between the 2 groups. A low illness severity score, no more than 1 organ failure on day 2, the ability to self-rate pain, and a moderate-to-severe pain rated on day 2 were factors independently associated with the prescription of multimodal analgesia on day 2 (all P b .01). Conclusions: In mechanically ventilated patients, the addition of nonopioids to opioids is mostly prescribed for patients with lower illness severity scores and who are able to self-rate their pain intensity. These findings suggest that the concept of multimodal analgesia must be promoted in the intensive care unit. © 2013 Elsevier Inc. All rights reserved.

☆ Competing interests: This work was supported by an unrestricted grant from Biocodex, Paris, France, for the Centre de Recherche Clinique, INSERM 003, Hôpital Michallon, Grenoble, France, to conduct an extraction from the Dolorea database and perform data analysis. The study sponsor had no role in the design and conduct of the study, its management, analysis, data interpretation, and preparation, review, or manuscript approval. All opinions, results, and conclusions are those of the authors. There are no financial or other relationships that might lead to conflict of interests. ☆☆ Author contributions: J.F.P., G.C., O.M., and J.M. designed the research; J.F.P., G.C., O.M., and J.M. performed the research; J.F.P., G.C., C.G., and J.L.B. analyzed the data; and J.F.P., G.C., O.M., and J.M. wrote the manuscript. All authors attest to having reviewed the original study data and data analysis. Dr Jean-François Payen is the guarantor of the study, taking responsibility for the integrity of the work as a whole, from inception to published article. ⁎ Corresponding author. Pôle d'Anesthésie-Réanimation, Hôpital Albert Michallon, BP 217, 38043 Grenoble, France. Tel.: +33 4 76 76 56 35; fax: +33 4 76 76 51 83. E-mail address: [email protected] (J.-F. Payen).

0883-9441/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jcrc.2012.10.006

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1. Introduction Pain in the intensive care unit (ICU) is frequent and often rated as moderate to severe in intensity, challenging its management [1]. The use of opioids is extensive in the ICU, and national surveys have reported either no alternative to opioids [2] or restricted use of nonsteroidal anti-inflammatory drugs (NSAIDs) and regional analgesia to a small number of selected patients [3,4]. In our prospective multicenter study based on data obtained from 1381 mechanically ventilated patients, nonopioids were prescribed for only 33% of patients on day 2 (D2) of their ICU stay [5]. However, the combination of opioids with nonopioids according to the concept of multimodal (balanced) analgesia introduced 2 decades ago is widely practiced for treating postoperative pain [6]. The use of multimodal analgesia after major surgery has been declared by 71% of respondents in a European survey [7]. This modality has been shown to provide improved analgesia, a sparing effect on morphine consumption, and reduced opioid-related adverse effects in the postoperative setting [8,9]. However, no data exist concerning how multimodal analgesia is considered in the ICU. In a post hoc analysis of the Dolorea study, we found that mechanically ventilated ICU patients assessed for pain on D2 of their ICU stay had marked differences in sedation and analgesia management compared with patients who were not assessed for pain [10]. They had more frequent sedation level evaluations and were given fewer hypnotics, lower daily midazolam doses, and more nonopioids. Whether this prescription of nonopioids in combination with opioids was related to pain intensity, daily dose of opioids, and/or the patient's ability to self-rate pain was undetermined. We hypothesized that verbally able patients may be more likely to receive nonopioids in addition to opioids because they can self-rate their pain intensity even on D2 of their ICU stay. To verify this hypothesis, we conducted a post hoc analysis from the Dolorea database to describe factors independently associated with the prescription of multimodal analgesia, that is, a combination of opioid with nonopioids, in mechanically ventilated ICU patients assessed for pain. Data were compared according to whether patients received either multimodal analgesia or opioid only.

2. Materials and methods The Dolorea study was conducted from January 2004 until January 2005 in 43 ICUs in France and 1 ICU in Luxembourg [5]. Patients 15 years or older were enrolled in the study if admitted to the ICU for a foreseeable length of mechanical ventilation exceeding 24 hours. Patients were excluded if they had severe brain injury on admission (defined by a Glasgow Coma Scale score b9), or if mechanical ventilation was delayed for more than 24 hours after admission to the ICU. For the purpose of this post hoc

J.-F. Payen et al. analysis, we excluded from the Dolorea database those patients who had not received opioids and were not assessed for pain on D2 of their ICU stay. A detailed description of data collection and quality control procedures is available elsewhere [5]. Briefly, each site had a dedicated individual who entered raw data into an electronic case report form (ClinInfo SA, Lyon, France). For each patient, a set of variables was collected that included demographic characteristics, illness severity on admission as defined by the Simplified Acute Physiology Score II and an individual Sequential Organ Failure Assessment (SOFA) score of 3 or 4 (ie, moderate-to-severe organ failure) [11], and ICU resources. For each patient, we recorded the instrument used to assess sedation and pain levels on D2 of the ICU stay, the type of sedative and opioid drug used, the cumulative amounts of these drugs administered over the previous 24 hours, the use of nonopioids, and the management of procedural pain (endotracheal suctioning, mobilization) on D2. Physicians were also asked to describe the reason(s) for prescribing analgesia to each patient. Descriptive statistics were frequencies and percentages for categorical variables and medians (25th-75th percentiles) for continuous variables. Characteristics of the 2 groups of patients were compared using χ2 or Fisher tests for categorical variables and the Mann-Whitney test for continuous variables (Stata 11.0; StataCorp, College Station, Tex). Variables with a P value of less than .20 and no interaction between each other were subjected to a stepwise logistic regression model to investigate possible factors associated with the prescription of multimodal analgesia. A P value less than .05 was considered statistically significant.

3. Results Of the 447 patients in the Dolorea database who were given nonopioids on D2, 396 received paracetamol (88%) and 175 received nefopam (39%). The prescription of other nonopioids (NSAIDs, regional analgesia, other drugs) accounted for less than 5% of patients in total. Therefore, multimodal analgesia was defined as the combination of one opioid with paracetamol and/or nefopam. Of the 1381 patients registered in the database, 474 satisfied the inclusion criteria on D2, including 302 patients who received opioid only and 172 patients who intravenously received a combination of one opioid with paracetamol (n = 96 patients), nefopam (n = 15 patients), both drugs (n = 51 patients), or each drug with ketoprofen as NSAID (n = 10 patients) (Fig. 1). Table 1 shows the baseline characteristics of the 2 groups of patients according to whether they received multimodal analgesia or opioid only on D2. Patients who received multimodal analgesia were more likely those having been admitted after trauma or elective surgery, with lower illness

Prescribing nonopioids in mechanically ventilated patients

534.e9

1381 patients admitted to ICU

907 patients excluded for post-hoc analysis: 631 were not assessed for pain on D2 125 did not receive analgesic drug on D2 89 were extubated within 48 hrs of admission 36 did not receive opioid drug on D2 10 died within 48 hrs of admission 10 stayed in ICU less than 48 hrs 6 patients – data not available

474 mechanically-ventilated patients who received opoid drug and assessed for pain on D2

172 (36%) who received multimodal analgesia on D2 302 (64%) who received one opioid on D2

Fig. 1 Patient flow diagram showing the number of identified, excluded, and analyzed patients receiving either multimodal analgesia or opioid only.

severity scores on admission, and fewer organ failures on D2 compared with patients receiving opioids only (P b .01). In this population of patients assessed for pain on D2, the instruments used for measuring pain were either self-report intensity scales such as the visual analog scale (VAS), the numeric rating scale (NRS), the verbal descriptor scale (VDS), or behavioral pain scales such as the behavioral pain scale (BPS) [12] and the Harris scale [13] (Table 2). The proportion of patients verbally able to self-rate their pain was higher in the group treated with multimodal analgesia, with a more frequent use of VAS and VDS compared with behavioral pain scales. Moderate-to-severe pain at baseline and during painful procedures was significantly more frequent in this group of patients. The daily dose of opioids on D2 was comparable between the 2 groups. Patients with multimodal analgesia were also more likely to have received a dedicated pain treatment with opioids during procedural pain events (Table 2). The reasons for prescribing multimodal analgesia were significantly more frequently to treat baseline pain (53% vs 23%, P b .01), procedural pain (77% vs 40%, P b .01), and pain related to the patient's disease (63% vs 44%, P b .01) and were significantly less often to treat discomfort associated with mechanical ventilation (79% vs 91%, P b .01). We also noticed marked differences in sedation management between the 2 groups. Patients receiving multimodal analgesia were less likely treated with sedatives (hypnotics), midazolam in particular, and they received lower daily doses of midazolam (Table 3). They were even less likely deeply sedated. Consequently, fewer patients were assessed for sedation (consciousness) in this group.

In multivariate analysis, there were 6 factors independently associated with the prescription of multimodal analgesia (all P b .01): a low Simplified Acute Physiology Score II on admission (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.96-0.99), an admission source other than medicine (OR, 3.92; 95% CI, 2.01-7.66), no more than 1 organ failure on D2 (OR, 2.56; 95% CI, 1.55-4.21), ability to self-rate pain (OR, 2.85; 95% CI, 1.65-4.91), moderate-to-severe pain rated on D2 (OR, 4.89; 95% CI, 1.69-14.12), and pain during procedure as the main reason to prescribe this modality (OR, 2.49; 95% CI, 1.46-4.25). The area under the curve of the model was 0.85 (95% CI, 0.810.88; P b .01).

4. Discussion In this cohort study of mechanically ventilated critically ill patients assessed for pain, we found paracetamol and/or nefopam to be the most frequently prescribed nonopioids in association with opioids on D2 of the ICU stay. This modality was prescribed mostly for patients with lower illness severity scores and able to self-rate their pain intensity. Overall, our study suggests that the concept of multimodal analgesia applied in the postoperative setting remains to be extended to all patients in the ICU. The analgesic efficacy of nonopioids combined with opioids has already been investigated in the ICU, mostly after major surgery. Ketamine, gabapentin, and epidural analgesia were among the techniques postulated as improving analgesia and decreasing the morphine consumption for

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J.-F. Payen et al.

Table 1 Baseline characteristics of the 474 mechanically ventilated patients according to the modality of analgesia: a combination of opioid with paracetamol and/or nefopam (multimodal analgesia) or opioid only

Age (y), median (IQR) Male sex, n (%) Admission source, n (%) Elective surgery Emergency surgery Trauma Medicine Others SAPS II, median (IQR) SOFA score 3 or 4 on D2 a, n (%) Respiratory Cardiovascular Renal Neurological Coagulation Hepatic Organ failures N 1 on D2, n (%)

Opioid only (n = 302)

Multimodal analgesia (n = 172)

P

61 (48-73) 195 (65)

57 (38-71) 115 (67)

.02 .61 b .01

28 (9) 100 (33) 25 (8) 140 (47) 9 (3) 46 (37-60)

184 (61) 217 (72) 81 (27) 45 (15) 40 (13) 30 (10) 195 (65)

46 (27) 75 (44) 28 (16) 15 (9) 8 (5) 38 (26-46)

75 (44) 82 (48) 21 (12) 10 (6) 9 (5) 8 (5) 59 (34)

together, these data indicate that there may be some value in using paracetamol and/or nefopam in association with opioids in the ICU. Whether these nonopioids might be effective at reducing opioid dose and related adverse events, for example, impaired vigilance status, delirium, and withdrawal syndrome, warrants further investigation. Nevertheless, our findings show that the rationale for prescribing

Table 2 Analgesia management and pain assessment on D2 of the ICU stay according to the modality of analgesia: a combination of opioid with paracetamol and/or nefopam (multimodal analgesia) or opioid only Opioid only (n = 302)

b .01 b .01 b .01 b .01 b .01 b .01 .04 b .01

Quantitative data are expressed as median and IQR, that is, 25th and 75th percentiles. IQR indicates interquartile range; SAPS, Simplified Acute Physiology Score. a The number of individual organ failures (SOFA score 3 or 4) exceeds the total number of included patients.

ICU patients [14–16]. In routine practice, however, continuous administration of opioids as the sole source of analgesia remains the most popular technique in unselected mechanically ventilated ICU patients [2,3,5]. In the present study, paracetamol and nefopam were found as the 2 most frequently used nonopioids that were given to only 33% of ICU patients. In a French survey of practices in the postoperative setting, however, paracetamol was prescribed for 90% of patients who received concomitantly opioids [17]. A systematic review found a 30% morphine-sparing effect within the 4 hours after administration of paracetamol postoperatively, although there was no associated decrease of analgesic-related adverse events [18]. In the ICU, no serious adverse events have been reported for paracetamol use apart from a few cases of arterial hypotension [19]. Nefopam is a centrally acting nonopioid agent that has been proposed as an adjuvant to opioid-analgesia to treat moderate postoperative pain. Postoperative morphine consumption and pain intensity at 24 hours were significantly decreased with nefopam [20]. In the ICU, single-dose nefopam for 30 minutes was effective at relieving moderate-to-severe pain with no respiratory or neurologic adverse effects [21]. Taken

Pain assessment, n (%) VAS 17 (6) VDS 14 (5) NRS 10 (3) BPS 169 (57) Other a 89 (30) Moderate-to-severe pain 7/296 (2) at baseline b, n/N (%) Type of opioids, n (%) Morphine 8 (3) Sufentanil 107 (35) Fentanyl 156 (52) Remifentanil 25 (8) Other 6 (2) Daily dose of opoid, median (IQR) Morphine 0.3 (0.2-1.5) (mg kg− 1 24 h− 1) 8.0 (4.5-11.2) Sufentanil (μg kg− 1 24 h− 1) 40 (28-63) Fentanyl (μg kg− 1 24 h− 1) Remifentanil 109 (76-150) (μg kg− 1 24 h− 1) 36/294 (12) High dosages of opioids c, n/N (%) Procedural pain 206 (68) assessment, n (%) 37/203 (18) Moderate-to-severe pain during procedure b, n/N (%) 40 (13) Procedural pain treatment with opioids, n (%)

Multimodal analgesia (n = 172)

P

b .01 41 (24) 39 (23) 8 (5) 74 (43) 9 (5) 35/169 (21)

b .01 b .01

44 (26) 71 (41) 27 (16) 23 (13) 7 (4) 0.4 (0.3-0.7)

.87

6.4 (3.3-10.0)

.18

31 (20-60)

.08

114 (75-218)

.81

16/164 (10)

.42

113 (66)

.57

51/111 (46)

b .01

59 (34)

b .01

Quantitative data are expressed as median and IQR, that is, 25th and 75th percentiles. IQR indicates interquartile range; VAS, Visual Analog Scale; VDS, Verbal Descriptor Scale; NRS, Numerical Rating Scale; BPS, Behavioral Pain Scale. a Corresponds to the Harris scale mainly. b Corresponds to a VAS or NRS score of more than 3 of 10 mm, a VDS score of more than 1 of 4, a BPS score of more than 4 of 12, and a Harris scale score of more than 5 of 8. c Corresponds to daily doses exceeding 90th percentile for each drug.

Prescribing nonopioids in mechanically ventilated patients Table 3 Sedation management and sedation assessment on D2 of the ICU stay according to the modality of analgesia: a combination of opioid with paracetamol and/or nefopam (multimodal analgesia) or opioid only

Sedation assessment, n (%) Sedation scale, n (%) Ramsay SAS RASS Other Deep sedation state a, n/N (%) Sedative use, n (%) Type of sedative, n (%) Propofol Midazolam Other Daily dose of sedative, median (IQR) Propofol (mg kg −1 24 h −1) Midazolam (mg kg −1 24 h −1) High dosages of sedatives b, n/N (%)

Opioid only (n = 302)

Multimodal analgesia (n = 172)

P

247 (82)

106 (62)

b .01

98 (40) 33 (13) 53 (21) 63 (26) 133/183 (73)

57 (54) 12 (11) 17 (16) 20 (19) 39/86 (45)

267 (88)

103 (60)

41 (15) 219 (82) 7 (3)

32 (31) 70 (68) 1 (1)

28 (10-42)

23 (7-40)

1.2 (0.8-2.1)

0.6 (0.4-1.3)

19/260 (7)

3/100 (3)

.11

b .01 b .01 b .01

.47 b .01 .13

Quantitative data are expressed as median and IQR, that is, 25th and 75th percentiles. IQR indicates interquartile range; SAS, Sedation Assessment Scale; RASS, Richmond Agitation Sedation Scale. a Corresponds to a Ramsay score of 5 or 6, a SAS score of 1 or 2, or a RASS score of − 5 or − 4. b Corresponds to daily doses exceeding 90th percentile for each drug.

nonopioids in the ICU is inconsistent with the concept of multimodal analgesia applied in the postoperative setting. We found that nonopioids were more often prescribed for verbally able patients and patients with lower severity illness. In this cohort of patients with no severe brain injury on admission, the verbally able condition was most probably related to the limited prescription of hypnotics and to the lower daily dose of midazolam (see Table 3). Although the medical reasons for prescribing hypnotics were not explored in this study, a limited use of hypnotics may account, in part, for fewer patients with drug-related cardiovascular failure and/or respiratory failure as assessed by the SOFA score, as we suggested previously [5]. Moreover, this finding suggests that despite efforts to promote the use of instruments to assess pain in nonverbal critically ill patients [22], efforts to improve pain management within the ICU remain remarkably dependent on the ability of patients to self-express their pain. Many caregivers consider the measurement of sedation (consciousness) as the prerequisite to managing both

534.e11 sedation and analgesia for nonverbal patients [23]. Conversely, the duality between hypnosis and analgesia has been practiced for years in the operating room, and efforts are constantly being made to develop instruments able to monitor pain during general anesthesia [24,25]. It is noticeable that our patients admitted from other sources than medicine, that is, elective and emergency surgery, were more likely to receive nonopioids, suggesting that such prescription was initiated in the operating room before transfer to the ICU. It is, however, possible to assess pain using patient self-report pain instruments in the ICU, provided the patients are awake and communicative [26]. Overall, these findings strongly encourage the assessment of pain with self-reporting tools in communicative patients, even during mechanical ventilation. Moreover, there is a current trend to question the systematic use of hypnotics within the ICU and to encourage the concept of sedationbased analgesia [1,27]. Our study suggests that patients able to communicate and express their pain intensity are more likely to receive additional analgesics to treat baseline and procedural pain. There are some limitations in this study. First, this is a post hoc analysis of the Dolorea study. However, our objective was to describe, for the first time, the profile of patients who were given multimodal analgesia in the ICU. Our findings should provide a better knowledge on how the addition of nonopioids to opioids is considered in medical practice. Second, we did not compare the 2 groups of patients regarding classical patient outcomes, for example, mortality rate and duration of mechanical ventilation. Our study population size was small, which precluded the use of sophisticated method, that is, propensity-adjusted score analysis, to correct unadjusted comparisons of outcomes [10]. In conclusion, this post hoc analysis shows that the combination of opioids with nonopioid analgesic drugs, that is, paracetamol and/or nefopam, on D2 of the ICU stay, is more likely prescribed for verbally able patients. Our findings indicate that the concept of multimodal analgesia applied in the postoperative setting should be encouraged in the ICU.

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