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The 90% effective dose of a sufentanil bolus for the management of painful positioning in intubated patients in the ICU

Chaveron, Damien; Silva, Stein; Sanchez-Verlaan, Pascale; Conil, Jean-Marie; Sommet, Agnès; Geeraerts, Thomas; Génestal, Michèle; Minville, Vincent; Fourcade, Olivier

European Journal of Anaesthesiology: June 2012 - Volume 29 - Issue 6 - p 280–285
doi: 10.1097/EJA.0b013e328352234d

Context Pain and discomfort arising from the routine care of intubated patients in the ICU is managed by continuous infusion of narcotic and sedative drugs. There is benefit in keeping infusion rates low because lightening sedation improves clinical outcome, but this risks breakthrough pain. Management of this discomfort by bolus administration could permit lower background infusion rates, but the lowest effective bolus dose of sufentanil to achieve this is unknown.

Objective The aim of this study was to determine the effective analgesic dose in 90% of intubated patients (ED90) in the ICU given bolus sufentanil. Pain was assessed using a Behavioural Pain Scale (BPS) requiring a score of 3–4 during moving to the lateral decubitus position.

Design Prospective, dose response study.

Setting A 16-bed multidisciplinary ICU in a French university hospital. Study period was from January to June 2010.

Patients Intubated and ventilated patients were eligible for the study once they had reached a BPS of 3 or 4 and Ramsay score of 3–5 within 48 h of admission to the ICU.

Intervention The analgesic efficacy of a sufentanil bolus was measured during successive lateral decubitus positioning over a 72-h study period, using the BPS scale. The dose was increased with each subsequent turn to lateral decubitus until a BPS score of 3–4 was obtained (dose escalation, starting at zero).

Main outcome measures BPS, Ramsay score, heart rate and mean arterial pressure were collected before and during each procedure.

Results A total of 25 patients were enrolled over 6 months. The ED90 bolus for sufentanil was 0.15 μg kg−1, but 40% of the patients subsequently demonstrated increased BPS with this dose.

Conclusion The effective dose in 90% was 0.15 μg kg−1 during the first 5 days of sedation. There were no adverse effects. A pre-emptive sufentanil bolus can be used to treat anticipated pain in the ICU. Regular and frequent assessments of acute pain and sedation are essential for adjusting the dose, on a case-by-case basis. This strategy may help clinicians to keep background infusions of sedatives and narcotics as low as possible and may improve clinical outcome.

Trial registration NCT01356732.

From the Département d’Anesthésie et de Réanimation, CHU Toulouse, Université Toulouse III Paul Sabatier, Faculté de Médecine Toulouse-Rangueil, EA 4564-MATN, Institut Louis Bugnard (IFR 150) (DC, SS, PS-V, J-MC, TG, MG, VM, OF) and Laboratoire de Pharmacologie Médicale et Clinique de la Faculté de Médecine, UMR-INSERM U 1027 Equipe de Pharmacoépidémiologie, Centre Hospitalier Universitaire de Toulouse (AS) Toulouse, France

Correspondence to Damien Chaveron, Département d’Anesthésie et de Réanimation, CHU Toulouse, Université Toulouse III Paul Sabatier, Faculté de Médecine Toulouse-Rangueil, EA 4564-MATN, Institut Louis Bugnard (IFR 150), Toulouse F-31000, France E-mail:

Published online 2 March 2012

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Mechanically ventilated patients often receive both analgesic and sedative drugs to manage discomfort and pain, assist ventilator synchrony and promote safety. Nevertheless, pain in intubated patients in the ICU is still common,1,2 intense3,4 and frequently results in sleep disruption5 and post-traumatic stress disorder.6 The large doses of continuously infused sedatives and analgesics used to address this problem7,8 may be responsible for increasing the duration of mechanical ventilation and ICU stay.9–14 Although more than 80% of patients receive opioids via continuous infusion, clinical studies have indicated that less than 25% receive supplementary analgesics during painful procedures.15,16 The combination of specific tools,17 to permit early detection of pain, with standardised sedation and analgesia protocols18–21 that include supplementary boluses of analgesics during painful procedures, might improve pain management. Recent studies conclude that a more systematic pain assessment tends to improve clinical outcome of ICU patients.9,21

We therefore sought to determine the minimum dose of a sufentanil bolus required to obtain a Behavioural Pain Scale (BPS) score of 3–4 in 90% of intubated ICU patients (ED90) sedated by continuous sufentanil infusion, during brief mobilisation into the lateral decubitus position.

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Patients and methods


Approval for this study (Ethical Committee No. 09 162 02) was provided by the ‘Comité de Protection des Personnes Sud Ouest et Outre Mer 1’, France (Chairperson Dr Grandjean) on 19 October 2009. Approval was also provided by the French Health Products Safety Agency (AFSSAPS, France) on 11 September 2009.

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Study population

After informed written consent from an appropriate representative of each individual, 25 patients were enrolled in this prospective study, which was conducted in a multidisciplinary ICU with 16 beds and a ratio of one nurse per 2.5 patients. Eligible patients were intubated and ventilated adults who were sedated only with midazolam and sufentanil infusions at the minimum doses necessary to obtain Ramsay scores22 between 3 and 5 and BPS scores of 3–4. The exclusion criteria were age below 18 or over 80 years, an indication for deep sedation (e.g. the initial stage of septic shock, acute brain injury or acute respiratory distress syndrome), renal dialysis, the inability to assess pain by the BPS scale (e.g. paralysis), BMI less than 18 or more than 35 kg m−2 and preadmission use of opioid analgesic for chronic pain.

The Ramsay score assesses the level of sedation: 1 (agitated), 2 (cooperative), 3 (responding to commands), 4 (brisk response to stimulus), 5 (sluggish response to stimulus) and 6 (oversedated without any response to stimulus). The BPS assesses pain within noncommunicant sedated patients using three items, each scored from 1 to 4: facial expression (1 = relaxed, 2 = partially tightened, 3 = fully tightened, 4 = grimacing), upper limbs reactions (1 = none, 2 = partially bent, 3 = fully bent, 4 = permanently retracted) and compliance with ventilation (1 = tolerating movement, 2 = coughing but tolerant, 3 = fighting ventilator, 4 = unable to control ventilation). A score of 5 or more is considered to represent pain.

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Conditions and procedures for the assessment of analgesia

For 48 h after admission to the ICU, sedation and analgesia were managed according to a protocol intended to optimise management (Fig. 1). Midazolam was used as an intravenous sedative at an initial rate of 0.04 mg kg−1 h−1. This dose was then adjusted every 4 h until a Ramsay score between 3 and 5 was obtained with the lowest possible dose. A supplementary bolus of 0.01 mg kg−1 of midazolam could be administered as needed for agitation. Sufentanil was administered via continuous infusion at an initial rate of 0.1 μg kg−1 h−1 and adjusted until the BPS score was 3–4 at rest with the patient in the supine position.

Fig. 1

Fig. 1

Once a Ramsay score of 3–5 and BPS of 3–4 were obtained, the 72-h study period began, at which time the analgesic efficacy of a sufentanil bolus during change to the lateral decubitus position was evaluated. The ‘dose escalation starting at zero’ method was used to reach the effective dose of each patient. A single bolus was administered prior to each move to lateral decubitus and this procedure was performed every 8 h (three times per day) by our intensive care nurses.

The sufentanil bolus was injected 7 min before turning the patient and the dose (starting at 0) was increased by 0.05 μg kg−1, to a maximum of 0.4 μg kg−1, prior to each subsequent turn to lateral decubitus until a BPS score of 3–4 was obtained during mobilisation. This bolus dose was then recorded as the effective dose for that patient. For each patient, the sufentanil bolus was administered with a dedicated syringe containing sufentanil 1 μg ml−1 through peripheral or central venous access that was drug free (e.g. free of hypnotics, opioids, neuroleptics, analgesics or vasoactive medications). No other analgesic was administered during the study period.

Doses of midazolam and sufentanil, for infusion or bolus administration, were calculated using the theoretical ideal weight of the patient [ideal weight, in kg = X + 0.91 (height, in cm − 152.4), where X is 50 for men and 45.5 for women].23,24

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Data collection

For each lateral decubitus turn, Ramsay and BPS scores, heart rate and mean arterial pressure (MAP) were recorded at rest before the sufentanil bolus (T0), 7 min after administering the bolus, but before turning the patient (T1), and during lateral decubitus positioning (T2). Two independent evaluators measured the BPS value – the nurse caring for the patient and a second individual (either physician or nurse). The new Simplified Acute Physiology Score (SAPS II)25 was used to assess severity of illness.

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Statistical analysis

Statistical analyses were performed using StatView software version 5.0 (SAS Institute Inc., Cary, North Carolina, USA). Data are expressed as mean ± SD, ratio or percentage as appropriate. Comparisons of values measured at multiple time points were performed using ANOVA. Comparisons between groups were performed using Student's t-test for quantitative values and chi-squared test for qualitative values. A P value less than 0.05 was considered to be significant. The ‘dose escalation starting at zero’ method was used to find the effective dose for each patient. Strengths of the relationships between variables were calculated using the squared Pearson product moment correlation (r2).

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Over 6 months, 225 patients were admitted to the ICU, of whom 25 were included in the study (Fig. 2). Their characteristics and medical histories are summarised in Table 1. No patient had a known history of chronic intake of opioid analgesics. Patients were included in the study after an average of 24 ± 15 h of ventilation. Of those included, 24% were given propofol (2.4 ± 1.4 mg kg−1 h−1) on admission, which was discontinued before inclusion.

Fig. 2

Fig. 2

Table 1

Table 1

Figure 3 presents the dose–response curve from which the ED90 of the sufentanil bolus was obtained. A 0.15 μg kg−1 dose of sufentanil yielded a BPS score of 3–4 during lateral decubitus positioning in 23 of 25 patients (92%). The increase in the pain score between T0 and T2 without sufentanil was 2.44 ± 1.39. With regard to the T0 to T2 variations, no statistical correlation was found between BPS and heart rate (r2 = 0.09) or between BPS and MAP (r2 = 0.006). There were no significant differences in BPS score without the sufentanil bolus between moderately (Ramsay 3–4, n = 13) or deeply (Ramsay 5, n = 12) sedated patients [2.46 (±1.66) vs. 2.42 (±1.08), P = 0.94].

Fig. 3

Fig. 3

The mean BPS score at each T2 over the nine consecutive movements to lateral decubitus are presented in Fig. 4. Ten of the 25 (40%) patients experienced pain during a subsequent lateral decubitus positioning after reaching their own effective dose. This group of patients (late pain group) was not significantly different from the group without pain rebound [no late pain group (NLP)] in terms of personal characteristics, dosage criteria or sedation score (Table 1). There was no difference in the Ramsay score between T0 and T2 for the late pain group compared with the NLP group [4.2 (±0.9) vs. 4.1 (±0.9), P = 0.59].

Fig. 4

Fig. 4

The changes in MAP between T0 and T2 averaged +5% (±11), P < 0.001 (maximum decrease 23%) and the change in heart rate was +7% (±17), P < 0.001 (maximum decrease 27%). No adverse effect from the bolus was recorded (as defined by a MAP or heart rate decrease over 30% from baseline). Table 2 shows the average heart rate, MAP and Ramsay scores for each lateral decubitus turn.

Table 2

Table 2

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This study demonstrates that a sufentanil bolus of 0.15 μg kg−1 allows lateral decubitus positioning without pain in over 90% of ventilated patients already receiving a background infusion of sufentanil. To our knowledge, there is currently a lack of clinical studies concerning the treatment of brief painful stimuli associated with mobilisation of intubated and sedated patients in the ICU.

Acute pain has emerged as a major stress for ICU patients. Almost 50% of ICU patients rated their pain at rest as well as during procedures as moderate to severe4,16,26 and it has been suggested that optimising pain control could benefit clinical outcome.26,27 Chanques et al.21 demonstrated an association between systematically evaluating pain and agitation levels among ICU patients and shorter duration of mechanical ventilation, as well as lower rates of nosocomial infections. Payen et al.9 showed that pain assessment in mechanically ventilated patients is independently associated with a reduction in the duration of ventilator support and ICU stay.

Pain assessments in the ICU generally do not consider specific periods of painful stimuli and are often managed with larger doses of continuous background infusions of sedatives and narcotics. National sedation surveys have shown that a substantial proportion of patients have a deeper level of sedation than desired8,15 and this may then unnecessarily delay weaning, recovery and discharge.9–11,21

Our analysis concentrated on the brief turn to lateral decubitus because it is well known to be painful3,28 and is reproducible.17 This procedure is an essential part of care in the ICU and is performed at least three times a day by our intensive care nurses when they change the sheets. Interestingly, moving to lateral decubitus was one of the painful procedures chosen by Payen et al.17 to validate the BPS. Our study with regard to the pain intensity of lateral decubitus positioning corroborates their results.

Sufentanil is used widely in the ICU because of its rapid peak, powerful analgesic activity and short half-life. Despite the recommendations of the French Society of Anesthesia and Intensive Care (Société Française d’Anesthésie et de Réanimation, SFAR) to use an opioid bolus for analgesia during painful procedures,29 less than 25% of the patients actually receive additional analgesic.15 The only other clinical study of analgesia during short painful procedures in noncommunicating intubated patients is that of Brocas et al.,30 who gave a bolus of alfentanil (15 μg kg−1) for painful stimuli. Considering the relative analgesic potencies of opioids (morphine = 1, alfentanil = 20 and sufentanil = 1000), our dose is equivalent to about 50% of the dose used in the study by Brocas et al. The painful activity studied in their protocol was tracheal suctioning, which has been shown previously to induce a pain similar to that of moving the patient to the lateral decubitus position.17 However, pain scores are not available in the study by Brocas et al., preventing further comparisons with our data. Our finding of an ED90 for sufentanil (0.15 μg kg−1) provides a reasonable starting point for the titration of narcotic that will ultimately be adjusted according to the patient's needs. This approach has been proposed previously in nonsedated patients presenting with severe pain using morphine in doses (0.1–0.15 mg kg−1) that seem to be consistent with our results.31–33

The intensity of pain associated with positioning in lateral decubitus (as measured by BPS) in our study was not lower in patients with deep sedation levels (Ramsay 3–4 vs. 5), re-emphasising that sedation alone does not provide analgesia. Furthermore, the absence of haemodynamic changes in response to mobilisation without sufentanil showed that analgesia cannot be assumed just because there is no increase in heart rate and MAP during painful stimuli. This finding supports the use of appropriate pain scales in sedated patients.

Increased pain on subsequent positioning in lateral decubitus was observed in 40% of patients after the effective dose had been reached. However, we were not able to identify such patients in advance. Notably, the base rate of the sufentanil infusion only slightly influenced the effective dose of the bolus (r2 = 0.16). Recognising the existence of rebound pain in a significant proportion of patients underscores the need to frequently re-evaluate acute pain scores, even after obtaining initial effective pain relief. Indeed, the tachyphylaxis of opioids is well known, and this effect may explain the need for increasing doses during continuous opioid infusion. As pain intensity produced by lateral decubitus positioning without narcotics is constant over time,17 we hypothesise that the need to raise the sufentanil dose could be due to hyperalgesia.

We recognise that only approximately 11% of our ICU patients met our criteria for inclusion in our study, so that our findings may not be widely applicable. It would be worthwhile to study further dose responses among a larger sample of ICU patients.

Pre-emptive analgesia for painful stimuli in ICU patients should be integrated into a comprehensive sedation and analgesia protocol that includes multimodal analgesic therapies.34 This should require more widespread and frequent assessment of sedation and pain and an early on-demand administration of suitable narcotics for painful procedures (i.e. 0.15 μg kg−1 of sufentanil). Treating short painful interventions can provide rapid analgesia for the vast majority of patients and could avoid side effects from large doses of continuously infused sedatives and analgesics, facilitating earlier weaning from the ventilator, recovery and discharge.

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This study shows that a sufentanil bolus can work as pre-emptive treatment of acute pain in the ICU. The effective dose in 90% was found to be 0.15 μg kg−1 during the first 5 days of sedation, without adverse effects. Regular and frequent assessments of acute pain and sedation are essential for adjusting the dose, on a case-by-case basis. This strategy may help clinicians to keep background infusions of sedatives and narcotics as low as possible and may improve clinical outcome.

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We are grateful for the enthusiastic support of the nurses of the ICU at Purpan Toulouse University Hospital. We thank Dr Matt Kurrek, MD, University of Toronto, for his help in writing the manuscript.

This work was supported by the Hospitals of Toulouse, France.

Conflict of interest: none declared.

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analgesia; intensive care; nursing care; pain; pharmacology; sufentanil

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