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From the Department of Anesthesia and Intensive Care, Università Cattolica del S. Cuore, Policlinico A. Gemelli, Rome, Italy.
Address correspondence to: Dr. Giorgio Conti, Department of Anesthesia and Intensive Care, Università Cattolica del S. Cuore, Policlinico A. Gemelli, Largo A. Gemelli 8,00168 Rome, Italy. Phone: + 39 06 30154386; Fax: + 39 06 3013450; E-mail: g.conti{at}rm.unicatt.it
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Abstract |
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Methods: In this prospective observational cohort study, we observed 12 adult patients receiving partial ventilatory support for acute respiratory failure. Each subject received a continuous infusion of sufentanil at 0.2 to 0.3 µg•kg–1•hr–1 to obtain a modified Ramsay sedation score between 2 and 3. In basal conditions and at variable distance from the beginning of the sufentanil infusion (10’, 30’, 60’, 120’, 24 hr) we evaluated gas exchange, hemodynamic variables, respiratory rate (RR), tidal volume (TV), respiratory pattern, respiratory drive (P0.1) and inspiratory impedance of the respiratory system [P0.1/TV/inspiratory time (Ti)].
Results: The continuous iv administration of 0.2 to 0.3 µg•kg–1•hr–1 of sufentanil resulted in the desired level of sedation. No significant heart rate, heart rhythm and blood pressure changes were observed. Sufentanil infusion did not affect TV, minute volume, Ti/inspiratory duty cycle, RR, P0.1, P0.1/TV/Ti and gas exchange did not change significantly over the study period.
Conclusion: A continuous infusion of sufentanil induces "awake" sedation with no detectable effects on respiratory variables in critically ill patients during partial ventilatory support.
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Introduction |
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TOPAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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Critically ill patients often experience stressful maneuvers such as endotracheal intubation and mechanical ventilation, suctioning or painful diagnostic and therapeutic interventions. The net effect is an increase in catecholamine secretion and oxygen demand with further systemic and coronary vasoconstriction.1 An adequate level of analgesia and sedation (analgesia-sedation) is thus a precious tool to control the patient’s pain and anxiety by modulating the response to stress.
Among the large variety of sedatives and analgesics commonly available,2 opioids, especially morphine and fentanyl, are widely used because of their efficacy in pain control and psychological discomfort mitigation. However, their well known side effects such as constipation, possible dependence, difficult arousal, and, principally, respiratory depression3 in response to the doses normally utilized have often restricted their use only to patients undergoing controlled mechanical ventilation.
The introduction into clinical use of new synthetic opioids with limited adverse effects particularly on the respiratory system has offered an option for the analgesia-sedation of critically ill patients. Sufentanil is a potent opioid with remarkable sedative properties,4 tenfold more powerful than fentanyl. Its high liposolubility results in a faster passage through the blood-brain barrier with an easier titration, a better clearance and a shorter duration of action compared to previous opioids.4 Experimental data in patients undergoing general anesthesia have shown that sufentanil has a lower incidence of respiratory depression and cardiovascular instability.5
This drug could therefore represent a good choice for critically ill patients requiring long-term analgesia-sedation, especially during partial ventilatory support techniques (i.e., ventilatory support modes preserving spontaneous breathing activity) where analgesia-sedation with minimal effects on spontaneous respiratory drive is required. Unfortunately few data are available regarding the respiratory effects of analgesia-sedation with sufentanil in patients during partial ventilatory support modes.6
We conducted a prospective physiologic pilot study aimed at evaluating the effects of the continuous infusion of a single sedative, sufentanil, at 0.2 to 0.3 µg•kg–1•hr–1 on central respiratory drive, gas exchanges, respiratory pattern and inspiratory impedance of the respiratory system in a group of 12 patients during pressure support ventilation (PSV).
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Patients and methods |
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At the time of inclusion the patients had received mechanical ventilation for an average of 7 ± 5 days. Enrollment criteria were as follows: i) ventilation with pressure support mode; and ii) presence of agitation, anxiety or restlessness requiring pharmacological sedation (a modified Ramsay Score = 1).7 The modified Ramsay sedation score (Table I
) is commonly and widely used to measure sedation on a scale ranging from 1 to 6 (where 6 = patient asleep and completely unresponsive to stimuli).
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All patients were ventilated with a Siemens 300 ventilator (Siemens Elema, Sweden) in PSV mode (mean values of pressure support: 17 ± 3 cm H2O) and received different levels of positive end-expiratory pressure according to their clinical requirements (mean values 7 ± 2 cm H2O, range 5–9 cm H2O). The FIO2 ranged between 0.4 and 0.5. The pressure trigger was set at –1 cm H2O, checking the absence of auto-trigger effect.
For the purposes of this study, the endotracheal tube was connected directly to a differential pressure transducer for airflow (V’) and airway opening pressure (Pao) recording. The V’ and Pao transducers were connected to a Bicore CP 100 respiratory mechanics monitor (Bicore, CA, USA), where tidal volume (TV) is obtained by V’ signal integration on time.
V’, Pao and TV recording can be immediately printed on paper or digitized and stored on a personal computer via specific interface software and analyzed with a specifically designed program (AnadatTM 5.1, Bicore CP 100 edition, Montreal, QC, Canada). This system to evaluate respiratory mechanics has already been described and validated.8,9
Airway occlusion pressure after 100 msec (P0.1)10 was measured by activating the expiratory pause knob of the ventilator to obtain a brief occlusion of the system (inspiratory and expiratory valves close simultaneously); as a consequence the patient’s inspiratory effort occurs against a completely closed system, allowing the indirect evaluation of the central respiratory drive.11
Study protocol
In basal conditions, arterial blood was sampled for blood gas analysis (Stat Profile, Nova Biomedical, USA) and ten consecutive respiratory cycles were averaged to determine: respiratory rate (RR), TV, inspiratory and expiratory time (Ti, Te), inspiratory duty cycle (Ttot) and mean inspiratory flow (TV/Ti). The whole breathing cycle and its inspiratory and expiratory components were expressed as Ttot, Ti and Te, respectively.
Basal P0.1 (i.e., airway occlusion pressure at 0.1 sec) was evaluated in triplicate, at 20 sec intervals. The inspiratory impedance of the respiratory system was also calculated as P0.1/(TV/Ti).
After the basal measurements, an infusion of sufentanil was started, using a syringe pump, via a central vein at the initial dose of 0.3 µg•kg–1•hr–1; this dose was chosen following our previous clinical experience and reduced at 0.2 µg•kg–1•hr–1 at T1 if a modified Ramsay sedation score of 2 was obtained. No medication with possible interaction with opioids was administered concomitantly.
The above-mentioned variables were again evaluated after ten minutes (T1), 30 min (T2), 60 min (T3), 120 min (T4) and 24 hr (T5). Arterial blood was sampled at T2 and T5 for blood gas analysis. At the same time intervals, the level of sedation was evaluated using the modified Ramsay sedation score; the desired modified Ramsay sedation score was between 2 and 3.
During the course of the study the electrocardiogram, invasive blood pressure and pulse oximetry were monitored continuously.
Statistical analysis
All results are expressed as mean ± standard deviation. Comparisons were performed with the one-way analysis of variance for repeated measures. Ramsay sedation score at different times was compared with Chi squared test. Significance was defined as a P value lower than 0.05.
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Results |
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TOPAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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along with their admission diagnosis, severity score and outcome.
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No significant heart rate, heart rhythm and arterial blood pressure changes were observed during the study period (Table III). All the patients included had a mean Glasgow coma scale of 14 (range 12–15).
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) show that sufentanil had no significant effects on the respiratory variables evaluated. In particular, TV, minute volume, Ti/Ttot, RR, P0.1 and 0.1/TV/Ti remained stable during the entire study, as well as gas exchange (Table III
).
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Sufentanil administration was continued after the end of the study for a mean time of 5 ± 1.9 days without clinical side effects; nine out of 12 patients where discharged from the ICU, while three patients died (two of septic shock and multiple organ failure, one of cardiogenic shock).
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Discussion |
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TOPAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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Despite their clinical efficacy in terms of pain control and sedation, the use of opioids as single sedatives has been restricted in the past, especially in patients receiving partial ventilatory support,3 by their well-known effects on respiratory drive, sometimes manifest even at low doses.
The analgesic action of opioids seems to be mainly due to an activation of µ1-receptor with, eventually, a mild effect on µ2 and 
-receptors, by contrast considered the receptors mostly involved in the depression of respiratory drive.12
Morphine and fentanyl act on all receptor subtypes, providing effective analgesia at the price of a marked respiratory drive reduction. Moreover, their accumulation effect, particularly evident after long-term continuous infusion, may exacerbate respiratory depression.
Sufentanil, a more recent synthetic opioid, possesses attractive properties for continuous infusion in ICU patients, acting almost exclusively on µ1-receptors. Moreover, its context-sensitive half-life (i.e., the time required to obtain a 50% reduction in the plasma drug concentration after the end of the infusion) is sevenfold lower that of fentanyl with, consequently, a reduced risk of accumulation.4,12,13
Our data confirm and expand the finding of Prause et al.,6 who retrospectively evaluated the charts of 211 critically ill patients receiving a continuous infusion of sufentanil at different doses (range 0.075–1.22 µg•kg–1•hr–1) to obtain a modified Ramsay sedation score between 2 and 4 during various partial respiratory support modes (continuous positive airway pressure, synchronized intermittent mandatory ventilation or PSV). These authors observed only a modest increase of PaCO2 from 39.5 ± 7.3 mmHg (before initiating sedation) to 42.7 ± 6.8 mmHg during the continuous infusion of sufentanil. Unfortunately, in their retrospective study, the authors did not perform measurements of respiratory drive or respiratory pattern variables but major modifications were considered unlikely, in view of the stability of PaCO2 values.
To our best knowledge this is the first study assessing the effects of sufentanil on respiratory drive, respiratory pattern and gas exchanges in critically ill patients receiving partial ventilatory support. At the doses used and for the short period of time considered, our data support the absence of major effects on respiratory drive, even when respiratory drive is evaluated with a precise and very sensitive variable such as P0.1, for a relatively prolonged period of time.10,11,14
P0.1 is an indirect parameter of central respiratory drive depending on the intensity by which respiratory centres, mechano, and chemoreceptors stimulate the inspiratory motoneurons.10 P0.1 has been confirmed to be a reliable indicator of the activity of respiratory centres, both in spontaneously breathing subjects10,14 and in ICU patients during assisted mechanical ventilation.11,15,16
Furthermore, the absence of significant modifications of the inspiratory impedance of the respiratory system [P0.1/(TV/Ti)] suggests that, at least with the doses used, other respiratory adverse effects such as chest-wall rigidity or alterations of respiratory mechanics were avoided. P0.1/(TV/Ti) measures the inspiratory mechanical transformation of the respiratory drive signal and defines the relation between central drive (P0.1) and the efficacy of V’ generation for a given level of respiratory system resistances and compliance.17
A sufentanil infusion allowed us to maintain our patients in a condition of "awake sedation," free from pain and anxiety, well responsive to orders and, above all, breathing in partial ventilatory support mode, with all the consequent advantages related to the preservation of spontaneous breathing activity in terms of lung mechanics, hemodynamics and prevention of respiratory muscle atrophy.18
A major point to underline is that we always avoided the administration of an initial iv bolus dose of sufentanil. According to our previous clinical experience, administration of a bolus results in a high incidence of side effects (mainly consisting of transitory hypotension).
Notwithstanding our positive results, the relatively small number of patients studied and the short duration of the study may not have allowed us to detect small differences or long term adverse effects such as delirium. However, this pilot study of physiologic variables can represent the basis for larger clinical trials, assessing the safety of sufentanil as a single sedative in unselected critically ill patients.
In conclusion, the results of our pilot study suggest that, in critically ill patients breathing on a partial respiratory support mode, a continuous infusion of sufentanil at 0.2 to 0.3 µg•kg–1•hr–1 may produce adequate "awake" analgesia-sedation, with no detectable effects on respiratory drive, respiratory pattern, and inspiratory impedance of the respiratory system and gas exchange.
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Footnotes |
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References |
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2 Fruh B. A comparison of propofol and midazolam for long-term sedation of mechanically ventilated patients: a cross-over study (Italian). J Drug Devel 1989; 2(suppl 2): 45–7.
3 Arunasalam K, Davenport HT, Painter S, Jones JG. Ventilatory response to morphine in young and old subjects. Anaesthesia 1983; 38: 529–33.[Medline]
4 Monk JP, Beresford R, Ward A. Sufentanil. A review of its pharmacological properties and therapeutic use. Drugs 1988; 36: 286–313.[Medline]
5 Bailey PL, Streisand JB, East KA, et al. Differences in magnitude and duration of opioid-induced respiratory depression and analgesia with fentanyl and sufentanil. Anesth Analg 1990; 70: 8–15.
6 Prause A, Wappler F, Scholz J, Bause H, Schulte am Esch J. Respiratory depression under long-term sedation with sufentanil, midazolam and clonidine has no clinical significance. Intensive Care Med 2000; 26: 1454–61.[Medline]
7 Ramsay MA, Savage TM, Simpson BR, Goodwin R. Controlled sedation with alphaxalone-alphadolone. BMJ 1974; 2: 656–9.
8 Petros AJ, Lamond CT, Bennett D. The Bicore pulmonary monitor. A device to assess the work of breathing while weaning from mechanical ventilation. Anaesthesia 1993; 48: 985–8.[Medline]
9 Kirton OC, Banner MJ, Axelrad A, Drugas G. Detection of unsuspected imposed work of breathing: case reports. Crit Care Med 1993; 21: 790–5.[Medline]
10 Whitelaw WA, Derenne JP, Milic-Emili J. Occlusion pressure as a measure of respiratory center output in conscious man. Respir Physiol 1975; 23: 181–99.[Medline]
11 Perrigault PF, Pouzeratte YH, Jaber S, et al. Changes in occlusion pressure (P0.1) and breathing pattern during pressure support ventilation. Thorax 1999; 54: 119–23.
12 Hughes MA, Glass PS, Jacobs JR. Context-sensitive half-time in multicompartment pharmacokinetic models for intravenous anesthetic drugs. Anesthesiology 1992; 76: 334–41.[Medline]
13 Shook JE, Watkins WD, Camporesi EM. Differential roles of opioid receptors in respiration, respiratory disease, and opiate-induced respiratory depression. Am Rev Respir Dis 1990; 142: 895–909.[Medline]
14 Rosa G, Conti G, Orsi P, et al. Effects of low-dose propofol administration on central respiratory drive, gas exchanges and respiratory pattern. Acta Anaesthesiol Scand 1992; 36: 128–31.[Medline]
15 Conti G, De Blasi R, Pelaia P, et al. Early prediction of successful weaning during pressure support ventilation in chronic obstructive pulmonary disease patients. Crit Care Med 1992; 20: 366–71.[Medline]
16 Conti G, Cinnella G, Barboni E, Lemaire F, Harf A, Brochard L. Estimation of occlusion pressure during assisted ventilation in patients with intrinsic PEEP. Am J Respir Crit Care Med 1996; 154: 907–12.[Abstract]
17 Hussain SN, Pardy RL, Dempsey JA. Mechanical impedance as determinant of inspiratory neural drive during exercise in humans. J Appl Physiol 1985; 59: 365–75.
18 Brochard S, Pluskwa F, Lemaire F. Improved efficacy of spontaneous breathing with inspiratory pressure support. Am Rev Respir Dis 1987; 136: 411–5.[Medline]
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