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Canadian Journal of Anesthesia 49:1088-1094 (2002)
© Canadian Anesthesiologists' Society, 2002
Neuroanesthesia and Intensive Care

A low-dose remifentanil infusion is well tolerated for sedation in mechanically ventilated, critically-ill patients

[La perfusion d’une faible dose de rémifentanil est bien tolérée comme sédation chez des malades gravement atteints, ventilés mécaniquement]

Franco Cavaliere, MD, Massimo Antonelli, MD, Andrea Arcangeli, MD, Giorgio Conti, MD, Roberta Costa, MD, Mariano Alberto Pennisi, MD and Rodolfo Proietti, MD

From the Institute of Anaesthesia and Intensive Care, Università Cattolica del Sacro Cuore, Rome, Italy.

Address correspondence to: Dr. Franco Cavaliere, Institute of Anaesthesia and Intensive Care, Università Cattolica del Sacro Cuore, Largo Francesco Vito, 1 00168 Rome, Italy. Phone: ++39-06-30154386; Fax: ++39-06-3013450; E-mail: f.cavaliere{at}rm.unicatt.it


   Abstract
TOP
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Purpose: To study the analgesic and sedative effects of remifentanil in critically-ill patients.

Methods: Remifentanil infusion was started at 0.02 µg•kg-1•min-1 in ten mechanically ventilated critically-ill patients, and the infusion rate was increased to 0.05, 0.10, 0.15, 0.20, and 0.25 µg•kg-1•min-1 every 30 min. Basally and 25 min after each increase we measured: the Ramsey sedation score (RSS) and the respiratory response subscore of comfort scale (CSRR); the bispectral index (BIS) before and after lightly touching tracheal mucosa; heart rate and systemic arterial pressure; respiratory variables; plasma epinephrine and norepinephrine levels.

Results: Infusion rates up to 0.05 µg•kg-1•min-1 were effective against agitation and achieved a good degree of adaption to the respirator in all patients (RSS 2 or more and CSRR 3 or less); BIS decreased significantly; respiratory and circulatory variables were unaffected; mean plasma epinephrine levels decreased. At infusion rates higher than 0.05 µg•kg-1•min-1 RSS but not BIS decreased further and patient arousability caused by noxious stimuli was not prevented; respiratory drive suppression occurred at the infusion rates higher than 0.05 µg•kg-1•min-1 in four patients; bradycardia and arterial hypotension was observed in three patients; plasma epinephrine levels decreased significantly, while norepinephrine was unaffected; severe itching was experienced by one patient.

Conclusions: Low doses of remifentanil (up to 0.05 µg•kg-1•min-1) can be useful in critically-ill patients in order to achieve calm and sedation. Higher doses can inhibit respiratory drive and require controlled mechanical ventilation.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
ANALGESIA and sedation with opioids are used widely to obtain quietness and cooperation from critically ill patients as most diagnostic and therapeutic procedures performed in intensive care units (ICUs) are painful or cause psychologic distress. In this context remifentanil, a µ-agonist opioid characterized by a short blood-brain equilibration time and a rapid metabolism by non specific esterases, could be particularly useful because adjustments of the infusion rate quickly achieve correspondent and stable new plasma levels and because the short and constant context-sensitive plasma half-time allows the patient fast arousability1–3

Only few authors have investigated the safety and feasibility of remifentanil infusion for sedation in ICUs.4–6 A high incidence of undesirable effects, like respiratory depression, nausea and emesis, has been pointed out by a multicenter study focused on postoperative analgesia with remifentanil.4 However both desirable effects of remifentanil infusion, like sedation, analgesia, and decreased adrenergic tone, and undesirable effects, like respiratory drive depression, nausea, and emesis, are dose-dependent and could be obtained or prevented by choosing the appropriate dosage. The aim of this study was to investigate the safe dosage of remifentanil in patients ventilated in pressure support mode and the effects of analgesia and sedation with remifentanil on some neurological, hormonal, and cardiovascular variables.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Patients
This prospective study was performed in the 21-bed ICU of the Catholic University in Rome. After obtaining approval of the study from the local Ethics Committee and informed consent from relatives, ten patients, aged 49–80 (median 71.5 yr), five males and five females, Simplified Acute Physiology Score (SAPS) II 24–49 (median 40.5 yr), were included. Inclusion criteria were: a) age > 18 yr; b) need for mechanical ventilation; c) Glasgow coma score (GCS) > 10; d) need for sedation (Ramsey sedation score 1); e) presence of an endotracheal tube and of an arterial line. Criteria for exclusion were: a) reported allergy to opioids; b) pregnancy; c) chronic obstructive pulmonary disease; d) presence of major painful stimuli, such as recent surgical wound or trauma injuries; e) clinically relevant hepatic or renal failure.

All patients were connected to a Siemens 300 ventilator (Siemens-Elema, Sweden) in pressure support mode (18 ± 2 cm H2O). Pressure support level was adjusted to obtain a tidal volume (TV) between 8 and 10 mL•kg-1 of ideal body weight and a respiratory rate lower than 30 breaths•min-1; positive end-expiratory pressure and FIO2 were adjusted in order to obtain PaO2 values higher than 90 mmHg. No patient was under the effect of opioids, benzodiazepines, propofol, or other medications that could reasonably affect the study.

Procedure
An iv infusion of remifentanil (50 µg•mL-1, diluted in saline) was started at the rate of 0.02 µg•kg-1•min-1; the initial infusion rate was increased to 0.05, 0.10, 0.15, 0.20, up to 0.25 µg•kg-1•min-1 every 30 min, until suppression of spontaneous respiration was achieved. Spontaneous respiratory drive was considered as suppressed if no breathing activity was registered during 15 sec or a reduction of the minute ventilation to values lower than 60% of basal values was detected. Before starting the infusion and 25 min after each increase of infusion rate neurological, hormonal, respiratory, and cardiovascular variables were measured. The degree of agitation and synchrony with the ventilator was assessed by the Ramsey Sedation Score (RSS: 1: patient anxious or agitated or both; 2: patient cooperative, orientated, and tranquil; 3: the patient responds to commands only; 4: a brisk response to a light glabellar tap; 5: a sluggish response to a light glabellar tap; 6: no response)7 and by the respiratory response subscore of comfort scale (CSRR: 1: no coughing and no spontaneous respiration; 2: spontaneous respiration with little or no response to ventilation; 3: occasional cough or resistance to ventilator; 4: the patient actively breathes against ventilator or coughs regularly; 5: fights ventilator, coughing or choking).8 Patient cortical activity was determined by the bispectral index (BIS) with an A-2000 electrocardiograph monitor (Aspect Medical Systems, USA); the index was registered prior to (BIS) and immediately following (BIS1) a standard stimulus obtained by lightly touching the tracheal mucosa with a suction catheter; this maneuver was performed only after starting remifentanil infusion. Heart rate (HR) and systolic, diastolic and mean systemic arterial pressure (SAP, DAP, and MAP) were recorded. Arterial blood gas analysis was performed with a stat profile Ultra L Haemogasanalyzer (Nova Biomedical, USA). Respiratory mechanics variables were measured with a Bicore system. For this purpose, the endotracheal tube was directly connected to a differential pressure transducer for airflow and airway opening pressure recording. The transducer was connected to a Bicore CP 100 respiratory mechanics monitor (Bicore, USA). Airflow, airway opening pressure, and tidal volume obtained by airflow signal integration were digitized, stored on a personal computer via specific interface software, and analyzed with a specifically designed program (AnadatTM 5.1, Bicore CP 100 edition, Canada). The system has been already described and validated.9–11 Ten consecutive respiratory cycles were averaged to determine respiratory rate (RR), tidal volume (TV), inspiratory time (Ti), inspiratory duty cycle, i.e., the duration of a whole breathing cycle (Ttot), and mean inspiratory flow (TV/Ti). Airway occlusion pressure after 100 msec (P01) was obtained by activating the expiratory pause knob of the ventilator. With this maneuver the inspiratory valve remains closed at the end of expiration, while the expiratory valve closes, resulting in a respiratory effort against a completely closed system. After the inspiratory effort is completed, the knob is released and spontaneous respiratory rhythm continues.12 P01 was evaluated in triplicate at 20 sec intervals. This variable is an indirect index of the central respiratory drive depending on the intensity by which respiratory centres, mechano- and chemo-ceptors stimulate the inspiratory peripheral motoneurons, both in spontaneously breathing subjects13,14 and in ICU patients during assisted ventilation.15,16 Finally, the inspiratory impedance of the respiratory system was calculated as P01/[VT/Ti]; this variable represents a measure of the inspiratory mechanical transformation of the respiratory drive signal, defining the linkage between central drive (P01) and the effectiveness of airflow generation for a given level of respiratory system resistance and compliance.17 Plasma epinephrine and norepinephrine levels were also determined. Arterial heparinized blood was collected and immediately put into ice-cold water; plasma was obtained with a refrigerated centrifuge and stored at -80°C. Catecholamines were analyzed within ten days by high performance liquid chromatography with electrochemical detection (HPLC-EC) by employing the ESA plasma catecholamine analysis kit (ESA, Inc., USA).

Statistical analysis
The values of discrete variables, BIS, and BIS1 are reported as median and range. Continuous variables were graphically examined to detect major deviations from normal distribution values; values were consequently shown as mean (standard deviation) or median and range. Statistical analysis was performed with Kruskal-Wallis test and comparisons to basal values with Dunn test. P values < 0.05 were considered as statistically significant.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Main patient characteristics are presented in Table IGo. The initial infusion rates of 0.02 and 0.05 µg•kg-1•min-1 did not produce significant modifications of the respiratory variables evaluated for the purposes of this study. In more detail we did not observe variations in respiratory drive, respiratory pattern, respiratory impedance, and gas exchange (Table IIGo). The study was interrupted at the infusion rate of 0.10 µg•kg-1•min-1 in patient #10 (hypoventilation), at the rate of 0.15 in patient #3 (hypoventilation), at the rate of 0.20 in patients #1 (hypoventilation), #4 (bradycardia, HR 44 beats•min-, spontaneously resolved after ending remifentanil infusion), #8 (hypoventilation), and #9 (itching); the maximal infusion rate of 0.25 µg•kg-1•min-1 was reached in only four patients, #2, 5, 6 and 7. Three patients (#2, 4, 7) required the infusion of colloids, 500–800 mL to correct arterial hypotension (systolic pressure < 90 mmHg) at the infusion rate of 0.15 µg•kg-1•min-1. Three patients (#1,8,9) complained of itching, one of them (#9) was given an antihistaminic drug and finally required cessation of the remifentanil infusion; itching ended a few minutes after stopping the infusion.


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  		TABLE I Patient characteristics. Reasons for stopping the infusion and final rates are given. Minor side-effects did not require stopping the infusion, being slight (itching) or controlled by fluid infusion (arterial hypotension).
 

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  		TABLE II Respiratory variables during remifentanil infusion
 
Table IIIGo shows RSS, CSRR, BIS, plasma catecholamine levels, and cardiovascular variables. Remifentanil significantly decreased RSS, providing a score of 2 or more in all patients at an infusion rate of 0.05 µg•kg-1•min-1. The score was roughly proportional to the infusion rate, however some patients remained calm, but awake (RSS = 2) even at the rate of 0.15 µg•kg-1•min-1; a RSS of 5 was recorded in patient #10 at 0.05 µg•kg-1•min-1 and a RSS of 1 was recorded in patient #9 at 0.20 µg•kg-1•min-1, caused by itching. In all patients remifentanil infusion improved patient adaptation to mechanical ventilation; CSRR decreased progressively and all patients scored 3 or less, i.e., exhibited cough or only occasional ventilatory asynchrony at the rate of 0.10 µg•kg-1•min-1 or more. The BIS was also significantly lowered by remifentanil, but differed from RSS since the lowest values were observed at 0.10 µg•kg-1•min-1 and BIS did not decrease further at higher doses. Finally, remifentanil did not abolish the response to noxious stimuli; even at 0.25 µg•kg-1•min-1, tracheal stimulation elicited an increase of BIS up to values that characterize awake subjects. Remifentanil decreased epinephrine plasma levels at infusion rates higher than 0.10 µg•kg-1•min-1 and this effect was associated with a significant decrease of arterial pressure.


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  		TABLE III Neurological and circulatory variables during remifentanil infusion
 

   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
This study confirms that remifentanil infusion can provide analgesia and sedation in critically ill patients, as already reported.5,6 By increasing remifentanil doses, a state of increasing depression of the central nervous system is obtained, as reflected by clinical scores, BIS, plasma catecholamine levels, respiratory and cardiovascular variables. According to clinical needs, sedation can be titrated to different targets, such as to obtain calmness or loss of consciousness (LOC), to decrease sympathetic tone, or even to inhibit respiratory drive. In this context, remifentanil pharmacokinetics offer some advantages over other analgesics and sedatives. A constant-rate infusion of remifentanil achieves steady plasma levels in about ten minutes18 and the half-time for equilibration between plasma and its effect compartment is about 1–1.5 min.2 Therefore a stable level of sedation and analgesia is achieved in a few minutes following any infusion rate adjustment; on this basis, in this study we chose to perform the measures 25 min following each infusion rate adjustment. A further advantage of remifentanil is represented by its constant and short context-sensitive plasma half-time, which allows a prompt recovery after stopping the infusion to evaluate the neurological state of the patient.6

In our patients the neurological depression produced by remifentanil infusion was measured both with clinical and instrumental scores. From a clinical point of view, infusion rates up to 0.05 µg•kg-1•min-1 induced sedative effects without LOC, while higher rates induced LOC in most patients. Remifentanil sedation showed at least two peculiarities. Some patients were calm, but still conscious (awake, eyes open) even at high infusion rates (0.15 µg•kg-1•min-1), and a noxious stimulus caused a patient to awake promptly during remifentanil infusion at 0.20 µg•kg-1•min-1 . Our findings are consistent with those of Wilhelm et al.,5 who achieved a RSS of 4 in critically-ill patients with a mean infusion rate of 0.14 µg•kg-1•min-1, but required a propofol infusion to obtain LOC in some patients. In this study, remifentanil caused a significant decrease of BIS, however the mechanism remains unclear. Studies during anesthesia suggest that remifentanil influences BIS only in the presence of painful stimuli. Some authors observed that the increase of BIS after endotracheal intubation was significantly attenuated by infusing remifentanil and propofol rather than propofol alone, while basal values were unaffected.19 In another study, BIS was not modified by adding a remifentanil to a propofol infusion in absence of painful stimuli.20 It seems reasonable that also in critically-ill patients remifentanil could decrease BIS values only by removing pain. Patients with surgical or traumatic wounds were excluded from this study, hence the significant decrease of BIS observed suggests that the pain caused by monitoring and therapeutic procedures was not negligible. However remifentanil did not provide complete protection against painful manoeuvres since patients’ awakening caused by endotracheal suction was not prevented even at the highest infusion rate tested in this study.

Both bradycardia and arterial hypotension are well-known effects of opioids and are probably related to a vagomimetic action and to a centrally-mediated reduction in systemic vascular resistance, respectively; remifentanil, as other fentanyl analogues, probably does not cause histamine release or myocardial depression.21 In this study, remifentanil infusion caused a decrease of heart rate and blood pressure that was already clinically relevant at an infusion rate of 0.10 µg•kg-1•min-1. Arterial hypotension was observed in three patients, but was successfully treated with fluid administration. A marked, but well tolerated bradycardia was observed in one patient; however the patient recovered spontaneously and atropine administration was not necessary since heart rate increased a few minutes after ending remifentanil infusion. In this regard, remifentanil’s prompt elimination after stopping the infusion is particularly valuable to control circulatory adverse effects.

Plasma catecholamine concentration is a commonly used index of sympathetic activity in man.22–25 In healthy subjects, sleep is associated with low levels of plasma catecholamines.23 In critically ill patients, plasma epinephrine and norepinephrine have been utilized to assess sympathetic tone during sedation.24,25 We observed a significant decrease of plasma epinephrine concentration associated with increasing infusion rates of remifentanil, while norepinephrine did not change significantly since its values fell in a wider range than epinephrine and decreased only in some patients. We have no clear explanation for the different trends of epinephrine and norepinephrine. In another study performed after myocardial revascularization, deep sedation with propofol compared with intermittent administration of midazolam and morphine, decreased plasma epinephrine concentration more than norepinephrine concentration.25 These findings could possibly originate from differences between the two catecholamines. Plasma epinephrine reflects adrenomedullary release, while plasma norepinephrine mainly originates from neuronal discharge; moreover various stimuli could elicite different degrees of release of epinephrine and norepinephrine.26 Further studies are necessary to clarify this point.

Itching is a common adverse effect of opioids, probably caused by a µ-receptor mediated central mechanism.27 In our study, three patients complained of itching; in one case it caused enough discomfort to require interruption of the infusion. The association with midazolam could decrease the incidence of itching during remifentanil sedation;28 in other cases droperidol could be useful.27 Remifentanil’s prompt elimination can stop itching in patients who do not respond to pharmacological therapy.

The present study was designed also to assess the effects of increasing doses of remifentanil on several respiratory variables directly related to respiratory drive (as P0.1, TV/Ti, and RR), respiratory impedance (P0.1/[TV/Ti]), respiratory pattern (Ti/Ttot), and respiratory output (Vmin). We did not observe significant effects on respiratory drive, respiratory pattern, minute volume, and gas exchanges at the first two levels of infusion. At doses higher than 0.05 µg•kg-1•min-1, hypoventilation started to occur as demonstrated by a slight, but significant reduction of Vmin. Only when doses higher than 0.10 were administered was patient spontaneous breathing activity inhibited, as shown clearly by a reduction of P.01 and, subsequently, by the presence of respiratory pauses and by a significant reduction of spontaneous respiratory rate. Finally, the observed stability in P0.1/[TV/Ti], a reliable index of the mechanical transformation of the respiratory centre output signal,17 indirectly demonstrates the absence of effects of remifentanil on respiratory mechanics variables.

In conclusion, our observations suggest that low doses of remifentanil (up to 0.05 µg•kg-1•min-1) can be useful in patients requiring partial respiratory support (such as intermittent mandatory ventilation or pressure support ventilation) in order to achieve calm and sedation. Higher doses are necessary to obtain respiratory drive depression and to lower sympathetic tone, but require controlled mechanical ventilation and are associated with an increased incidence of adverse effects.

Revision received September 9, 2002. Accepted for publication May 23, 2002.


   References
TOP
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
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2 Glass PS, Gan TJ, Howell S. A review of the pharmacokinetics and pharmacodynamics of remifentanil. Anesth Analg 1999; 89(4 Suppl): S7–14.

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7 Ramsay MA, Savege TM, Simpson BR, Goodwin R. Controlled sedation with alphaxalone-alphadolone. Br Med J 1974; 2: 656–9.

8 Ambuel B, Hamlett KW, Marx CM, Blumer JL. Assessing distress in pediatric intensive care environments: the COMFORT scale. J Pediatr Psychol 1992; 17: 95–109.[Abstract/Free Full Text]

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21 Bowdle TA. Adverse effects of opioid agonists and agonist-antagonists in anaesthesia. Drug Saf 1998; 19: 173–89.[Medline]

22 Grassi G, Esler M. How to assess sympathetic activity in humans. J Hypertens 1999; 17: 719–34.[Medline]

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27 Kjellberg F, Tramer MR. Pharmacological control of opioid-induced pruritus: a quantitative systematic review of randomized trials. Eur J Anaesthesiol 2001; 18: 346–57.[Medline]

28 Avramov MN, Smith I, White PF. Interactions between midazolam and remifentanil during monitored anesthesia care. Anesthesiology 1996; 85: 1283–9.[Medline]




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