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Future Perspectives
Abstract
The increasing number of published studies on inhaled sedation from groups all over the world as well as the sales figures of AnaConDa (personal communication) indicate that inhaled sedation is used in some hospitals in everyday practice worldwide. This is remarkable, as there is no explicit approval for long-term ICU sedation with volatile anaesthetic by any authority and this application differs considerably from that in the operating theatre. A multicentre study with the title “a randomized controlled open-label study to confirm the efficacy and safety of sedation with isoflurane in invasively ventilated ICU patients using the AnaConDa administration system” (Acronym: Isoconda; EudraCT number: 2016-004551-67) is now under way to put things straight.
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AnaConDa-100 ml (ACD-100, Sedana Medical, Uppsala, Sweden) is well established for inhalation sedation in the intensive care unit. But because of its large dead space, the system can retain carbon dioxide (CO2) and increase ventilatory demands. We therefore evaluated whether AnaConDa-50 ml (ACD-50), a device with half the internal volume, reduces CO2 retention and ventilatory demands during sedation of invasively ventilated, critically ill patients. Ten patients participated in this cross-over protocol. After sedation with isoflurane via ACD-100 for 24 h, the 5-h observation period started. During the first hour, ACD-100 was used; for the next 2 h, ACD-50; and for the last 2 h, ACD-100 was used again. Sedation was titrated to Richmond Agitation and Sedation Scale (RASS) score − 3 to − 4 and a processed electroencephalogram (Narcotrend Index, Narcotrend-Gruppe, Hannover, Germany) was recorded. Minute ventilation, CO2 elimination, and isoflurane consumption were compared. All patients were deeply sedated (Narcotrend Index, mean ± SD: 38 ± 10; RASS scores − 3 to − 5) and breathed spontaneously with pressure support throughout the observation period. Infusion rates of isoflurane and opioid, either remifentanil or sufentanil, as well as ventilator settings were unchanged. Minute ventilation and end-tidal CO2 were significantly reduced with the ACD-50, respiratory rate remained unchanged, and tidal volume decreased by 66 ± 43 ml. End-tidal isoflurane concentrations were also slightly reduced while haemodynamic measures remained constant. The ACD-50 reduces the tidal volume needed to eliminate carbon dioxide without augmenting isoflurane consumption.
Inhalation sedation is increasingly performed in intensive care units. For this purpose, two anaesthetic reflectors, AnaConDa™ and Mirus™ are commercially available. However, their internal volume (100 ml) and possible carbon dioxide reflection raised concerns. Therefore, we compared carbon dioxide elimination of both with a heat moisture exchanger (HME, 35 ml) in a test lung model. A constant flow of carbon dioxide was insufflated into the test lung, ventilated with 500 ml, 10 breaths per minute. HME, MIRUS and AnaConDa were connected successively. Inspired (insp-CO2) and end-tidal carbon dioxide concentrations (et-CO2) were measured under four conditions: ambient temperature pressure (ATP), body temperature pressure saturated (BTPS), BTPS with 0.4 Vol% (ISO-0.4), and 1.2 Vol% isoflurane (ISO-1.2). Tidal volume increase to maintain normocapnia was also determined. Insp-CO2 was higher with AnaConDa compared to MIRUS and higher under ATP compared to BTPS. Isoflurane further decreased insp-CO2 and abolished the difference between AnaConDa and MIRUS. Et-CO2 showed similar effects. In addition to volumetric dead space, reflective dead space was determined as 198 ± 6/58 ± 6/35 ± 0/25 ± 0 ml under ATP/BTPS/ISO-0.4/ISO-1.2 conditions for AnaConDa, and 92 ± 6/25 ± 0/25 ± 0/25 ± 0 ml under the same conditions for MIRUS, respectively. Under BTPS conditions and with the use of moderate inhaled agent concentrations, reflective dead space is small and similar between the two devices.
The circle system has been in use for more than a 100 years, whereas the first clinical application of an anaesthetic reflector was reported just 15 years ago. Its functional basis relies on molecular sieves such as zeolite crystals or activated carbon. In a circle system, the breathing gas is rebreathed after carbon dioxide absorption; a reflector on the other hand specifically retains the anaesthetic during expiration and resupplies it during the next inspiration. Reflection systems can be used in conjunction with intensive care ventilators and do not need the permanent presence of trained qualified staff. Because of easy handling and better ventilatory capabilities of intensive care ventilators, reflection systems facilitate the routine use of volatile anaesthetics in intensive care units. Until now, there are three reflection systems commercially available: the established AnaConDa™ (Sedana Medical, Uppsala, Sweden), the new smaller AnaConDa-S™, and the Mirus™ (Pall Medical, Dreieich, Germany). The AnaConDa consists only of a reflector which is connected to a syringe pump for infusion of liquid sevoflurane or isoflurane. The Mirus represents a technical advancement; its control unit includes a gas and ventilation monitor as well as a gas dispensing unit. The functionality, specific features, advantages and disadvantages of both systems are discussed in the text.
Background:
A volatile anaesthetic (VA) reflector can reduce VA consumption (VAC) at the cost of fine control of its delivery and CO2 accumulation. A digital in-line vaporizer and a second CO2 absorber circumvent both of these limitations. We hypothesized that the combination of a VA reflector with an in-line vaporizer would yield substantial VA conservation, independent of fresh gas flow (FGF) in a circle circuit, and provide fine control of inspired VA concentrations.
Method:
Prospective observational study on six Yorkshire pigs. A secondary anaesthetic circuit consisting of a Y-piece with 2 one-way valves, an in-line vaporizer and a CO2 absorber in the inspiratory limb was connected to the patient's side of the VA reflector. The other side was connected to the Y-piece of a circle anaesthetic circuit. In six pigs, an inspired concentration of sevoflurane of 2.5% was maintained by the in-line vaporizer. We measured VAC at FGF of 1, 4 and 10 l/min.
Results:
With the secondary circuit, VAC was 55% less than with the circle system alone at FGF 1 l/min, and independent of FGF over the range of 1-10 l/min. Insertion of a CO2 absorber in the secondary circuit reduced Pet CO2 by 1.3-2.0 kpa (10-15 mmHg).
Conclusion:
A secondary circuit with reflector and in-line vaporizer provides highly efficient anaesthetic delivery, independent of FGF. A second CO2 absorber was necessary to scavenge the CO2 reflected by the anaesthetic reflector. This secondary circuit may turn any open circuit ventilator into an anaesthetic delivery unit.
During patient sedation with liquid volatile anaesthetic, some problems may occur through a process called auto-pumping, defined as an expansion of bubbles inside the syringe, which can lead to uncontrolled anaesthetic delivery. The study examined how the temperature of liquid volatile anaesthetics (sevoflurane and isoflurane) and the presence of gas bubbles in the syringe affect the occurrence of auto-pumping when using the anaesthetic conserving device (ACD, AnaConDa™, Sedana Medical, Uppsala, Sweden). Four different circumstances for each volatile anaesthetic were tested with a bench study: volatile anaesthetic at room temperature or precooled with and without the presence of gas bubbles in the syringe. Liquid volatile anaesthetic was infused into the ACD via a syringe pump at a fixed rate and heated gradually until the temperature of the syringe surface reached 50 °C. A main-stream gas monitor was used to measure the expired fraction of volatile anaesthetic (FE vol%). The occurrence of auto-pumping was observed only in the subgroups containing gas bubbles, with both anaesthetics. In these subgroups, the values of the expired anaesthetic gas fraction increased dramatically with the expansion of gas bubbles in the syringe (ΔFE ranged from +1.6 to 2.4 vol% for sevoflurane and +2.3 to 3.4 vol% for isoflurane). Furthermore, when the heat source was removed, a substantial decline in anaesthetic agent values below the baseline was observed with both anaesthetics. The presence of gas bubbles in the syringe, especially when exposed to a heat source, may provoke auto-pumping with uncontrolled excessive anaesthetic delivery. If auto-pumping is suspected, the syringe pump must be stopped and the ACD removed from the breathing circuit at once.
Background:
Inhalation agents are being used in place of intravenous agents to provide sedation in some intensive care units. We performed a systematic review and meta-analysis of prospective randomized controlled trials, which compared the use of volatile agents versus intravenous midazolam or propofol in critical care units.
Methods:
A search was conducted using MEDLINE (1946-2015), EMBASE (1947-2015), Web of Science index (1900-2015), and Cochrane Central Register of Controlled Trials. Eligible studies included randomized controlled trials comparing inhaled volatile (desflurane, sevoflurane, and isoflurane) sedation to intravenous midazolam or propofol. Primary outcome assessed the effect of volatile-based sedation on extubation times (time between discontinuing sedation and tracheal extubation). Secondary outcomes included time to obey verbal commands, proportion of time spent in target sedation, nausea and vomiting, mortality, length of intensive care unit, and length of hospital stay. Heterogeneity was assessed using the I statistic. Outcomes were assessed using a random or fixed-effects model depending on heterogeneity.
Results:
Eight trials with 523 patients comparing all volatile agents with intravenous midazolam or propofol showed a reduction in extubation times using volatile agents (difference in means, -52.7 minutes; 95% confidence interval [CI], -75.1 to -30.3; P < .00001). Reductions in extubation time were greater when comparing volatiles with midazolam (difference in means, -292.2 minutes; 95% CI, -384.4 to -200.1; P < .00001) than propofol (difference in means, -29.1 minutes; 95% CI, -46.7 to -11.4; P = .001). There was no significant difference in time to obey verbal commands, proportion of time spent in target sedation, adverse events, death, or length of hospital stay.
Conclusions:
Volatile-based sedation demonstrates a reduction in time to extubation, with no increase in short-term adverse outcomes. Marked study heterogeneity was present, and the results show marked positive publication bias. However, a reduction in extubation time was still evident after statistical correction of publication bias. Larger clinical trials are needed to further evaluate the role of these agents as sedatives for critically ill patients.
With the AnaConDa™ and the MIRUS™ system, volatile anesthetics can be administered for inhalation sedation in intensive care units. Instead of a circle system, both devices use anesthetic reflectors to save on the anesthetic agent. We studied the efficiency of desflurane reflection with both devices using different tidal volumes (VT), respiratory rates (RR), and ‘patient’ concentrations (CPat) in a bench study. A test lung was ventilated with four settings (volume control, RR × VT: 10 × 300 mL, 10 × 500 mL, 20 × 500 mL, 10 × 1000 mL). Two different methods for determination of reflection efficiency were established: First (steady state), a bypass flow carried desflurane into the test lung (flowin), the input concentration (Cin) was varied (1–17 vol%), and the same flow (flowex, Cex) was suctioned from the test lung. After equilibration, CPat was stored online and averaged; efficiency [%] was calculated \((100 \times \left( {1 - \left( {{\text{flow}}_{\text{in}} \times \left( {{\text{C}}_{\text{in}} - {\text{C}}_{\text{ex}} } \right)/{\text{C}}_{\text{Pat}} \times {\text{RR}} \times {\text{V}}_{\text{T}} } \right)} \right)\). Second (washout), flowin and flowex were stopped, the decline of CPat was measured; efficiency was calculated from the decay constant of the exponential regression equation. Both measurement methods yielded similar results (Bland–Altman: bias: −0.9 %, accuracy: ±5.55 %). Efficiencies higher than 80 % (>80 % of molecules exhaled are reflected) could be demonstrated in the clinical range of CPat and VT. Efficiency inversely correlates with the product of CPat and VT which can be imagined as the volume of anesthetic vapor exhaled by the patient in one breath, but not with the respiratory frequency. Efficiency of the AnaConDa™ was higher for each setting compared with the MIRUS™. Desflurane is reflected by both reflectors with efficiencies high enough for clinical use.
Introduction:
With the AnaConDa™ system, inhalational sedation in the intensive care unit has become popular. The device can be used with common intensive care unit ventilators and is inserted between the Y-piece and the patient. Liquid isoflurane or sevoflurane are delivered by a syringe pump. 90 % of anesthetic exhaled by the patient is absorbed by a reflector and resupplied during the next inspiration. The new Mirus™ system also uses a reflector. Its control unit identifies end-tidal concentrations from the flow, injects anesthetics during early inspiration, controls anesthetic concentrations automatically, and can also apply desflurane. The AnaConDa™ and Mirus™ system are certified 'conformité établi', however, little is known about the Mirus™ and case reports are still lacking.
Case description:
We used the Mirus™ with desflurane for 24 h in a patient suffering from acute respiratory distress syndrome. The patient was treated with kinetic lateral rotational therapy. While deeply sedated, our patient breathed 9.0-12.0 l min(-1) spontaneously. Thereafter, awakening and wash-out were considerably shorter than after isoflurane in the same patient with AnaConDa™. There were no major problems during the sedation. However, consumption of desflurane was high.
Conclusion:
Desflurane sedation with the Mirus™ seems promising, but the reflector should be improved to absorb and resupply more of the anesthetic agent.
The Anaconda(™) system is used to deliver inhalational sedation in the intensive care unit in mainland Europe. The new Mirus(™) system also uses a reflector like the Anaconda; however, it also identifies end-tidal concentrations from the gas flow, injects anaesthetics during early inspiration, controls anaesthetic concentrations automatically, and can be used with desflurane, which is not possible using the Anaconda. We tested the Mirus with desflurane in the laboratory. Compared with an external gas monitor, the bias (two standard deviations) of the end-tidal concentration was 0.11 (0.29)% volume. In addition, automatic control was reasonable and maximum concentration delivered was 10.2%, which was deemed to be sufficient for clinical use. Efficiency was > 80% and was also deemed to be acceptable, but only when delivering a low concentration of desflurane (≤ 1.8%). By modifying the reflector, we improved efficiency up to a concentration of 3.6%. The Mirus appears to be a promising new device for long-term sedation with desflurane on the intensive care unit, but efficiency must be improved before routine clinical use becomes affordable.
Background
The anaesthetic conserving device AnaConDa® (ACD) reflects exhaled anaesthetic agents thereby facilitating the use of inhaled anaesthetic agents outside operating theatres. Expired CO2 is, however, also reflected causing a dead space effect in excess of the ACD internal volume. CO2 reflection from the ACD is attenuated by humidity. This study tests the hypothesis that sevoflurane further attenuates reflection of CO2. An analysis of clinical implications of our findings was performed.
Methods
Twelve postoperative patients received mechanical ventilation using a conventional heat and moisture exchanger (HME, internal volume 50 ml) and an ACD (100 ml), the latter with or without administration of sevoflurane. The ACD was also studied with a test lung at high sevoflurane concentrations. Reflection of CO2 and dead space effects were evaluated with the single-breath test for CO2.
Results
Sevoflurane reduced but did not abolish CO2 reflection. In patients, the mean dead space effect with 0.8% sevoflurane was 88 ml larger using the ACD compared with the HME (P
The anesthetic conserving device (ACD) reduces consumption of volatile anesthetic drug by a conserving medium adsorbing exhaled drug during expiration and releasing it during inspiration. Elevated arterial CO2 tension (PaCO2) has been observed in patients using the ACD, despite tidal volume increase to compensate for larger apparatus dead space. In a test lung using room temperature dry gas, this was shown to be due to adsorption of CO2 in the ACD during expiration and release of CO2 during the following inspiration. The effect in the test lung was higher than in patients. We tested the hypothesis that a lesser dead space effect in patients is due to higher temperature and/or moisture attenuating rebreathing of CO2.
The lungs of 6 postoperative cardiac surgery patients were ventilated using a conventional heat and moisture exchanger (HME) or an ACD. The ACD was studied with a test lung at varying temperatures and moistures. Infrared spectrometry was used to measure apparent dead space by the single-breath test for CO2 as well as rebreathing of CO2.
In patients, the median apparent dead space was 136 mL (95% confidence interval [CI,] 120-167) larger using the ACD compared with an HME (after correction for difference in internal volume 100 and 50 mL, respectively). Median rebreathing of CO2 using the ACD was 53% (range 48-58) of exhaled CO2 compared with 29% (range 27-32) with an HME. The median difference in CO2 rebreathing was 23% (95% CI, 18-27). In the test lung apparent dead space using ACD was unaffected by body temperature but decreased from 360 to 260 mL when moisture was added. This decreased rebreathing of CO2 from 62% to 48%.
The use of an ACD increases apparent dead space to a greater extent than can be explained by its internal volume. This is caused by adsorption of CO2 in the ACD during expiration and release of CO2 during inspiration. Rebreathing of CO2 was attenuated by moisture. The dead space effect of the ACD could be clinically relevant in acute respiratory distress syndrome and other diseases associated with ventilation difficulties, but investigations with larger sample sizes would be needed to determine the clinical importance.
Purpose:
The use of volatile-based sedation within critical care environments has been limited by difficulties of drug administration and safety concerns over environment pollution and staff exposure in an intensive care unit (ICU) with no scavenging. The aim of this study was to develop a simple scavenging system to be used with the Anesthesia Conserving Device (AnaConDa(®)) and to determine whether or not ambient concentrations of residual anesthetic are within current acceptable limits.
Technical features:
The scavenging system consists of two Deltasorb(®) canisters attached to the ICU ventilator in series. AnaConDa is a miniature vaporizer designed to provide volatile-based sedation within an ICU. The first ten patients recruited into a larger randomized trial assessing outcomes after elective coronary graft bypass surgery were sedated within the cardiac ICU using either isoflurane or sevoflurane. Sedation was guided by the Sedation Agitation Scale, resulting in an end-tidal minimum anesthetic concentration of volatile agent ranging from 0.1-0.3. At one hour post ICU admission, infrared photometric analysis was used to assess environmental contamination at four points along the ventilator circuit and scavenging system and around the patient's head. All measurements taken within the patient's room were below 1 part per million, which satisfies criteria for occupational exposure.
Conclusions:
This study shows that volatile agents can be administered safely within critical care settings using a simple scavenging system. Our scavenging system used in conjunction with the AnaConDa device reduced the concentration of environmental contamination to a level that is acceptable to Canadian standards and standards in most Western countries and thus conforms to international safety standards. The related clinical trial was registered at www.clinicaltrials.gov (NCT01151254).
Rationale:
Choice and intensity of early (first 48 h) sedation may affect short- and long-term outcome.
Objectives:
To investigate the relationships between early sedation and time to extubation, delirium, and hospital and 180-day mortality among ventilated critically ill patients in the intensive care unit (ICU).
Methods:
Multicenter (25 Australia and New Zealand hospitals) prospective longitudinal (ICU admission to 28 d) cohort study of medical/surgical patients ventilated and sedated 24 hours or more. We assessed administration of sedative agents, ventilation time, sedation depth using Richmond Agitation Sedation Scale (RASS, four hourly), delirium (daily), and hospital and 180-day mortality. We used multivariable Cox regression to quantify relationships between early deep sedation (RASS, -3 to -5) and patients' outcomes.
Measurements and main results:
We studied 251 patients (mean age, 61.7 ± 15.9 yr; mean Acute Physiology and Chronic Health Evaluation [APACHE] II score, 20.8 ± 7.8), with 21.1% (53) hospital and 25.8% (64) 180-day mortality. Over 2,678 study days, we completed 14,736 RASS assessments. Deep sedation occurred in 191 (76.1%) patients within 4 hours of commencing ventilation and in 171 (68%) patients at 48 hours. Delirium occurred in 111 (50.7%) patients with median (interquartile range) duration of 2 (1-4) days. After adjusting for diagnosis, age, sex, APACHE II, operative, elective, hospital type, early use of vasopressors, and dialysis, early deep sedation was an independent predictor of time to extubation (hazard ratio [HR], 0.90; 95% confidence interval [CI], 0.87-0.94; P < 0.001), hospital death (HR, 1.11; 95% CI, 1.02-1.20; P = 0.01), and 180-day mortality (HR, 1.08; 95% CI, 1.01-1.16; P = 0.026) but not delirium occurring after 48 hours (P = 0.19).
Conclusions:
Early sedation depth independently predicts delayed extubation and increased mortality, making it a potential target for interventional studies.
The anaesthetic conserving device (ACD) AnaConDa(®) was developed to allow the reduced use of inhaled agents by conserving exhaled agent and allowing rebreathing. Elevated has been observed in patients when using this ACD, despite tidal volume compensation for the larger apparatus dead space. The aim of the present study was to determine whether CO(2), like inhaled anaesthetics, adsorbs to the ACD during expiration and returns to a test lung during the following inspiration.
The ACD was attached to an experimental test lung. Apparent dead space by the single-breath test for CO(2) and the amount of CO(2) adsorbed to the carbon filter of the ACD was measured with infrared spectrometry.
Apparent dead space was 230 ml larger using the ACD compared with a conventional heat and moisture exchanger (internal volumes 100 and 50 ml, respectively). Varying CO(2) flux to the test lung (85-375 ml min(-1)) did not change the measured dead space nor did varying respiratory rate (12-24 bpm). The ACD contained 3.3 times more CO(2) than the predicted amount present in its internal volume of 100 ml.
Our measurements show a CO(2) reservoir effect of 180 ml in excess of the ACD internal volume. This is due to adsorption of CO(2) in the ACD during expiration and return of CO(2) during the following inspiration.
Long-term sedation with midazolam or propofol in intensive care units (ICUs) has serious adverse effects. Dexmedetomidine, an α(2)-agonist available for ICU sedation, may reduce the duration of mechanical ventilation and enhance patient comfort.
To determine the efficacy of dexmedetomidine vs midazolam or propofol (preferred usual care) in maintaining sedation; reducing duration of mechanical ventilation; and improving patients' interaction with nursing care.
Two phase 3 multicenter, randomized, double-blind trials carried out from 2007 to 2010. The MIDEX trial compared midazolam with dexmedetomidine in ICUs of 44 centers in 9 European countries; the PRODEX trial compared propofol with dexmedetomidine in 31 centers in 6 European countries and 2 centers in Russia. Included were adult ICU patients receiving mechanical ventilation who needed light to moderate sedation for more than 24 hours (midazolam, n = 251, vs dexmedetomidine, n = 249; propofol, n = 247, vs dexmedetomidine, n = 251).
Sedation with dexmedetomidine, midazolam, or propofol; daily sedation stops; and spontaneous breathing trials.
For each trial, we tested whether dexmedetomidine was noninferior to control with respect to proportion of time at target sedation level (measured by Richmond Agitation-Sedation Scale) and superior to control with respect to duration of mechanical ventilation. Secondary end points were patients' ability to communicate pain (measured using a visual analogue scale [VAS]) and length of ICU stay. Time at target sedation was analyzed in per-protocol population (midazolam, n = 233, vs dexmedetomidine, n = 227; propofol, n = 214, vs dexmedetomidine, n = 223).
Dexmedetomidine/midazolam ratio in time at target sedation was 1.07 (95% CI, 0.97-1.18) and dexmedetomidine/propofol, 1.00 (95% CI, 0.92-1.08). Median duration of mechanical ventilation appeared shorter with dexmedetomidine (123 hours [IQR, 67-337]) vs midazolam (164 hours [IQR, 92-380]; P = .03) but not with dexmedetomidine (97 hours [IQR, 45-257]) vs propofol (118 hours [IQR, 48-327]; P = .24). Patients' interaction (measured using VAS) was improved with dexmedetomidine (estimated score difference vs midazolam, 19.7 [95% CI, 15.2-24.2]; P < .001; and vs propofol, 11.2 [95% CI, 6.4-15.9]; P < .001). Length of ICU and hospital stay and mortality were similar. Dexmedetomidine vs midazolam patients had more hypotension (51/247 [20.6%] vs 29/250 [11.6%]; P = .007) and bradycardia (35/247 [14.2%] vs 13/250 [5.2%]; P < .001).
Among ICU patients receiving prolonged mechanical ventilation, dexmedetomidine was not inferior to midazolam and propofol in maintaining light to moderate sedation. Dexmedetomidine reduced duration of mechanical ventilation compared with midazolam and improved patients' ability to communicate pain compared with midazolam and propofol. More adverse effects were associated with dexmedetomidine.
clinicaltrials.gov Identifiers: NCT00481312, NCT00479661.
To evaluate efficacy and adverse events related to inhaled sevoflurane for long-term sedation compared with standard intravenous (i.v.) sedation with propofol or midazolam.
Randomized controlled trial. Sixty intensive care unit (ICU) patients expected to require more than 24 h sedation were randomly assigned to one of three groups: group S, inhaled sevoflurane; group P, i.v. propofol; group M, i.v. midazolam. All patients also received i.v. remifentanil for goal-directed sedation (Ramsay scale and pain score) until extubation or for a maximum of 96 h. Primary end points were wake-up times and extubation delay from termination of sedative administration. Proportion of time within Ramsay score 3-4, i.v. morphine consumption at 24 h post extubation, hallucination episodes after end of sedation, adverse events, inorganic fluoride plasma levels, and ambient sevoflurane concentrations were recorded.
Forty-seven patients were analyzed. Wake-up time and extubation delay were significantly (P<0.01) shorter in group S (18.6 ± 11.8 and 33.6 ± 13.1 min) than in group P (91.3 ± 35.2 and 326.11 ± 360.2 min) or M (260.2 ± 150.2 and 599.6 ± 586.6 min). Proportion of time within desired interval of sedation score was comparable between groups. Morphine consumption during the 24 h following extubation was lower in group S than in groups P and M. Four hallucination episodes were reported in group P, five in group M, and none in group S (P=0.04). No hepatic or renal adverse events were reported. Mean plasma fluoride value was 82 μmol l(-1) (range 12-220 μmol l(-1)), and mean ambient sevoflurane concentration was 0.3 ± 0.1 ppm.
Long-term inhaled sevoflurane sedation seems to be a safe and effective alternative to i.v. propofol or midazolam. It decreases wake-up and extubation times, and post extubation morphine consumption, and increases awakening quality.
Increased inorganic fluoride levels after methoxyflurane exposure in the 1970s and prolonged intraoperative sevoflurane use have been suggested to be potentially nephrotoxic. In the intensive care unit we evaluated the effect on renal integrity of short-term inhaled postoperative sedation with sevoflurane using the Anesthetic Conserving Device (ACD) compared with propofol.
In this prospective, randomized, single-blinded study, after major abdominal, vascular or thoracic surgery 125 patients were allocated to receive either sevoflurane (n = 64) via the ACD (end-tidal 0.5-1 vol%) or i.v. propofol (n = 61) for postoperative sedation up to 24 h. Urinary alpha-glutathione-s-transferase as primary outcome variable, urinary N-acetyl-glucosaminidase, serum creatinine, and inorganic fluoride concentrations, urine output and fluid management were measured preoperatively, at the end of surgery, and at 24 and 48 h postoperatively.
The sedation time in the intensive care unit was comparable between the sevoflurane (9.2 +/- 4.3 h) and the propofol (9.3 +/- 4.7 h) group. Alpha-glutathione-s-transferase levels were significantly increased at 24 and 48 h postoperatively compared with preoperative values in both groups, without significant differences between the groups. N-acetyl-glucosaminidase and serum creatinine remained unchanged in both study groups, and urine output and creatinine clearance were comparable between the groups throughout the study period. Inorganic fluoride levels increased significantly (P < 0.001) at 24 h after sevoflurane exposure (39 +/- 25 micromol/L) compared with propofol (3 +/- 6 micromol/L) and remained elevated 48 h later (33 +/- 26 vs 3 +/- 5 micromol/L). One patient in each group suffered from renal insufficiency, requiring intensive diuretic therapy, but not dialysis, during hospital stay.
Short-term sedation with either sevoflurane using ACD or propofol did not negatively affect renal function postoperatively. Although inorganic fluoride levels were elevated after sevoflurane exposure, glomerular and tubular renal integrity were preserved throughout the hospital stay.
The anaesthetic conserving device (AnaConDa), Sedana Medical, Sundbyberg, Sweden) facilitates administration of isoflurane or sevoflurane by liquid infusion. An anaesthetic reflector inside the device conserves exhaled anaesthetic and re-supplies it during inspiration. In this bench study, we examined the influence of infusion rates and ventilatory settings on the resulting anaesthetic concentrations on patient (C(pat)) and ventilator side of the reflector (C(loss)) to describe its technical performance.
A Puritan Bennett 840 ICU ventilator (Pleasanton, US), AnaConDa, and a test lung (3 l-chloroprene-bag) were assembled. Infusion rates (IR, 0.2-50 ml h(-1)), respiratory rates (RR, 5-40 breaths min(-1)), and tidal volumes (V(T), 0.3, 0.5, and 1.0 l) were varied. C(pat) was measured via a thin catheter in the middle of the 3 l-bag in steady state (online data storage and averaging over >10 min). C(loss) was calculated from IR (to yield the volume of vapour per unit of time), and expired minute volume (in which the vapour is diluted) on the assumption that, in the steady state, input by liquid infusion equals output through the reflector.
At lower concentrations (C(pat) < 1 vol%) the ratio C(loss)/C(pat) was constant (R(C) = 0.096 +/- 0.012) for all combinations of IR, RR and V(T), both for isoflurane and sevoflurane. The device could efficiently reflect up to 10 ml vapour per breath (e.g. 2 vol% in 0.5 l). When exceeding this capacity, surplus vapour "spilled over" and R(C) markedly increased indicating decreased performance.
The triple product minute volume times R(C) times C(pat) describes anaesthetic losses through the reflector. It can easily be calculated as long as the 10 ml reflection capacity is not exceeded and thus R(C) is constant. Increased minute ventilation necessitates increasing the IR to keep C(pat) constant. When using large V(T) and high C(pat) "spill over" occurs. This effect offers some protection against an inadvertent overdose.
To examine the possible contribution of sedation with propofol in the deaths of children who were intubated and required intensive care.
Case note review.
Three intensive care units.
Five children with upper respiratory tract infections aged between 4 weeks and 6 years.
Four patients had laryngotracheo-bronchitis and one had bronchiolitis. All were sedated with propofol. The clinical course in all five cases was remarkably similar: an increasing metabolic acidosis was associated with brady-arrhythmia and progressive myocardial failure, which did not respond to resuscitative measures. All children developed lipaemic serum after starting propofol. These features are not usually associated with respiratory tract infections. No evidence was found of viral myocarditis, which was considered as a possible cause of death.
Although the exact cause of death in these children could not be defined, propofol may have been a contributing factor.
Background:
Volatile anesthetics are increasingly used for sedation in intensive care units. The most common administration system is AnaConDa-100 mL (ACD-100; Sedana Medical, Uppsala, Sweden), which reflects volatile anesthetics in open ventilation circuits. AnaConDa-50 mL (ACD-50) is a new device with half the volumetric dead space. Carbon dioxide (CO2) can be retained with both devices. We therefore compared the CO2 elimination and isoflurane reflection efficiency of both devices.
Methods:
A test lung constantly insufflated with CO2 was ventilated with a tidal volume of 500 mL at 10 breaths/min. End-tidal CO2 (EtCO2) partial pressure was measured using 3 different devices: a heat-and-moisture exchanger (HME, 35 mL), ACD-100, and ACD-50 under 4 different experimental conditions: ambient temperature pressure (ATP), body temperature pressure saturated (BTPS) conditions, BTPS with 0.4 Vol% isoflurane (ISO-0.4), and BTPS with 1.2 Vol% isoflurane. Fifty breaths were recorded at 3 time points (n = 150) for each device and each condition. To determine device dead space, we adjusted the tidal volume to maintain normocapnia (n = 3), for each device. Thereafter, we determined reflection efficiency by measuring isoflurane concentrations at infusion rates varying from 0.5 to 20 mL/h (n = 3), for each device.
Results:
EtCO2 was consistently greater with ACD-100 than with ACD-50 and HME (ISO-0.4, mean ± standard deviations: ACD-100, 52.4 ± 0.8; ACD-50, 44.4 ± 0.8; HME, 40.1 ± 0.4 mm Hg; differences of means of EtCO2 [respective 95% confidence intervals]: ACD-100 - ACD-50, 8.0 [7.9-8.1] mm Hg, P < .001; ACD-100 - HME, 12.3 [12.2-12.4] mm Hg, P < .001; ACD-50 - HME, 4.3 [4.2-4.3] mm Hg, P < .001). It was greatest under ATP, less under BTPS, and least with ISO-0.4 and BTPS with 1.2 Vol% isoflurane. In addition to the 100 or 50 mL "volumetric dead space" of each AnaConDa, "reflective dead space" was 40 mL with ACD-100 and 25 mL with ACD-50 when using isoflurane. Isoflurane reflection was highest under ATP. Under BTPS with CO2 insufflation and isoflurane concentrations around 0.4 Vol%, reflection efficiency was 93% with ACD-100 and 80% with ACD-50.
Conclusions:
Isoflurane reflection remained sufficient with the ACD-50 at clinical anesthetic concentrations, while CO2 elimination was improved. The ACD-50 should be practical for tidal volumes as low as 200 mL, allowing lung-protective ventilation even in small patients.
Introduction:
Isoflurane has shown better sedation control and potential benefits in patients with ARDS compared to propofol or midazolam, but the practical use during continuous lateral rotational therapy remains unknown. We therefore compared isoflurane with propofol and midazolam regarding sedation depth (per the Richmond Agitation-Sedation Scale), opioid consumption, lung function, and hemodynamics in patients treated with continuous lateral rotational therapy.
Methods:
38 consecutive critically ill surgical subjects were retrospectively studied using a hospital database. All subjects suffered from ARDS and were treated with continuous lateral rotational therapy between May 2010 and September 2013. Nineteen subjects were sedated with propofol or midazolam and compared with 19 subjects sedated with isoflurane using the AnaConDa-system.
Results:
Isoflurane sedation resulted in significantly lower Richmond Agitation-Sedation Scale scores compared with propofol or midazolam. Despite deep isoflurane sedation, opioid consumption could be significantly reduced. Spontaneous breathing was possible in 90% of the subjects on isoflurane sedation compared with 16% of the subjects sedated with propofol or midazolam. The difference between peak inspiratory pressure and PEEP was significantly decreased after 24 h of isoflurane sedation. Oxygenation (PaO2 /FIO2 ) improved in both groups. Hemodynamics and need for vasopressor therapy were comparable between groups.
Conclusions:
This study supports the feasibility of isoflurane sedation using continuous lateral rotational therapy.
Background:
Use of Anesthetic Conserving Devices (ACD) for inhalational isoflurane sedation in intensive care units (ICU) has grown in recent years, and healthcare professionals are concerned about isoflurane pollution and exposure-related health risks. Real-time measurements to determine isoflurane exposure in ICU personnel during short-term patient care procedures and ACD handling have not yet been performed.
Methods:
Isoflurane concentrations in the breathing zones of ICU staff (25 cm around the nose and mouth) were measured, by photoacoustic gas monitoring, during daily practice including tracheal suctioning, oral hygiene, body care, and patient positioning. Isoflurane pollution was further determined during ACD replacement, syringe filling, and after isoflurane spillages.
Results:
The average mean isoflurane concentration 25 cm above patients' tracheostoma was 0.3 ppm. Mean (mean) and maximum (max) isoflurane exposure in personnel's breathing zones during patient care ranged from 0.4 to 1.9 ppm and 0.7 to 6.6 ppm, respectively. Isoflurane exposure during ACD replacement was mean 0.5 to 17.4 ppm and max 0.8 to 114.3 ppm. Isoflurane concentrations during ACD syringe filling ranged from 2.4 to 9.1 ppm. The maximum isoflurane concentrations after spillage were dose-dependent.
Conclusions:
Use of ACDs and patient physical manipulation are accompanied by isoflurane pollution. Baseline concentrations did not exceed long-term exposure limits, but short-term limits were occasionally exceeded during patient care procedures and ACD handling. Spillages should be avoided, especially when air-conditioning and scavenging systems are unavailable.
Six patients suffering from acute respiratory distress syndrome with the need for extracorporeal membrane oxygenation (ECMO) therapy in deep sedation were included. Isoflurane sedation with the AnaConDa system was initiated within 24 hours after initiation of ECMO therapy and resulted in a satisfactory sedation (Richmond Agitation-Sedation Scale -4 to -5). Despite deep sedation, spontaneous breathing was possible in 6 of 6 patients. We observed a reduced need for vasopressor therapy and improved lung function (PaO2, PaCO2, delta P, and tidal volume) during isoflurane sedation. Opioid consumption could be reduced, and only very low doses of isoflurane were needed (1 mL/h to 3 mL/h). This small case series supports the feasibility of sedation using inhaled anesthetics concurrently with venovenous ECMO.
Seit über hundert Jahren verwenden wir das Kreisteil in Narkosegeräten. Dabei wird die gesamte Ausatemluft nach Kohlendioxidabsorption rückgeatmet. Vor 15 Jahren erfolgte die erste klinische Anwendung eines Anästhetikareflektors. Ein Reflektor arbeitet mit Pendelluft, hält spezifisch nur das Anästhetikum bei der Ausatmung fest und gibt es bei der Einatmung wieder ab. Eine hohe Reflexionseffizienz (Anzahl wieder eingeatmeter/Anzahl ausgeatmeter Anästhetikamoleküle, RE 80–90 %) bedingt einen niedrigen Verbrauch. Analog zum Frischgasfluss beim Kreisteil beschreibt die pulmonale Clearance ((1-RE) × Atemminutenvolumen) die Opposition zwischen Verbrauch und Steuerbarkeit. Erst die Vorteile der Reflexionssysteme ermöglichten den routinemäßigen Einsatz volatiler Anästhetika auf Intensivstationen. Einfache Handhabung sowie bessere Beatmungseigenschaften von Intensiv- versus Anästhesierespiratoren sind Grundvoraussetzungen hierfür. Neben AnaConDa™ (Sedana Medical, Uppsala, Schweden) ist mit MIRUS™ (Pall Medical, Dreieich, Deutschland) nun ein zweites, technisch weiterentwickeltes Reflexionssystem kommerziell erhältlich. Die Ausnutzung organprotektiver Effekte, die exzellente Steuerbarkeit sowie eine dosisabhängige tiefe Sedierung bei erhaltener Spontanatmung ohne nennenswerte Kumulation und Toleranzentwicklung lassen volatile Anästhetika als interessante Alternative erscheinen, insbesondere für Patienten, die eine tiefe Sedierung benötigen oder bei denen intravenöse Sedativa nicht mehr anschlagen. Erste Untersuchungen zum Langzeitüberleben deuten darauf hin, dass tiefe intravenöse Sedierungen nachteilig sind, inhalative Sedierungen hingegen mit Vorteilen verbunden sein könnten. Prospektive Studien zur Mortalität, aber auch zum psychologischen Outcome stehen allerdings noch aus.
Background: The aim of this study was to evaluate the efficacy and safety of isoflurane as a postoperative sedative following coronary artery bypass grafting (CABG) surgery. Methods: Twenty four patients scheduled for CABG were randomized to either isoflurane group (number= 12) which received isoflurane for postoperative sedation via the Anesthesia Conserving Device (ACD) to obtain an end tidal concentration of 0.5% or midazolam group (number= 12) which received midazolam as a conventional method of postoperative sedation in a dose of 0.02-0.05 mg/kg/h. Study started when patients arrived to surgical coronary care unit and Ramsay sedation score became 4 and continued for 24 hours or until extubation. All patients received standard anaesthetic regimen during surgery and postoperatively analgesia was achieved by morphine infusion 0.02 mg/kg/h. Postoperative haemodynamic variables, Ramsay sedation score, total morphine used, liver enzymes, renal functions, cardiac enzymes were calculated and recorded. Results: Wake-up times were significantly shorter in the isoflurane group where time to extubation [mean (SD)] was 15.2 (5.3) min and in the midazolam group 120.1 (30.3) min, P value = 0.01. Time to follow verbal command was 16.3 (3.2) min versus 60.4 (20.4) min for the isoflurane group and midazolam group, respectively, P value = 0.03. Patients in the isoflurane group were mobilized significantly earlier from bed 8 (1.8) h, compared to 14 (3.3) h in midazolam group, P value < 0.05. No serious complications related to either sedative drug occurred. Conclusion: Administration of isoflurane via ACD following CABG is a safe and efficacious method for sedation with short wake- up time facilitating the growing up fast track CABG surgery.
Isoflurane may be protective in preclinical models of lung injury, but its use in patients with lung injury remains controversial and the mechanism of its protective effects remains unclear. The authors hypothesized that this protection is mediated at the level of alveolar tight junctions and investigated the possibility in a two-hit model of lung injury that mirrors human acute respiratory distress syndrome.
Wild-type mice were treated with isoflurane 1 h after exposure to nebulized endotoxin (n = 8) or saline control (n = 9) and then allowed to recover for 24 h before mechanical ventilation (MV; tidal volume, 15 ml/kg, 2 h) producing ventilator-induced lung injury. Mouse lung epithelial cells were similarly treated with isoflurane 1 h after exposure to lipopolysaccharide. Cells were cyclically stretched the following day to mirror the MV protocol used in vivo.
Mice treated with isoflurane following exposure to inhaled endotoxin and before MV exhibited significantly less physiologic lung dysfunction. These effects appeared to be mediated by decreased vascular leak, but not altered inflammatory indices. Mouse lung epithelial cells treated with lipopolysaccharide and cyclic stretch and lungs harvested from mice after treatment with lipopolysaccharide and MV had decreased levels of a key tight junction protein (i.e., zona occludens 1) that was rescued by isoflurane treatment.
Isoflurane rescued lung injury induced by a two-hit model of endotoxin exposure followed by MV by maintaining the integrity of the alveolar-capillary barrier possibly by modulating the expression of a key tight junction protein.
Isoflurane has shown better control of intensive care sedation than propofol or midazolam and seems to be a useful alternative. However, its effect on survival remains unclear.
The objective of this study is to compare mortality after sedation with either isoflurane or propofol/midazolam.
A retrospective analysis of data in a hospital database for a cohort of consecutive patients.
Sixteen-bed interdisciplinary surgical ICU of a German university hospital.
Consecutive cohort of 369 critically ill surgical patients defined within the database of the hospital information system. All patients were continuously ventilated and sedated for more than 96 h between 1 January 2005 and 31 December 2010. After excluding 169 patients (93 >79 years old, 10 <40 years old, 46 mixed sedation, 20 lost to follow-up), 200 patients were studied, 72 after isoflurane and 128 after propofol/midazolam.
Sedation with isoflurane using the AnaConDa system compared with intravenous sedation with propofol or midazolam.
Hospital mortality (primary) and 365-day mortality (secondary) were compared with the Kaplan-Meier analysis and a log-rank test. Adjusted odds ratios (ORs) [with 95% confidence interval (95% CI)] were calculated by logistic regression analyses to determine the risk of death after isoflurane sedation.
After sedation with isoflurane, the in-hospital mortality and 365-day mortality were significantly lower than after propofol/midazolam sedation: 40 versus 63% (P = 0.005) and 50 versus 70% (P = 0.013), respectively. After adjustment for potential confounders (coronary heart disease, chronic obstructive pulmonary disease, acute renal failure, creatinine, age and Simplified Acute Physiology Score II), patients after isoflurane were at a lower risk of death during their hospital stay (OR 0.35; 95% CI 0.18 to 0.68, P = 0.002) and within the first 365 days (OR 0.41; 95% CI 0.21 to 0.81, P = 0.010).
Compared with propofol/midazolam sedation, long-term sedation with isoflurane seems to be well tolerated in this group of critically ill patients after surgery.
Status asthmaticus is an acute, intractable asthma attack refractory to standard interventions that can lead to progressive respiratory failure. Successful management requires a fundamental understanding of the disease process, its clinical presentation, and proper evaluation. Treatment must be instituted early and is aimed at reversing the airway inflammation, bronchoconstriction, and hyper-reactivity that often lead to lower airway obstruction, impaired ventilation, and oxygenation. Most patients are effectively treated with standard therapy including beta2-adrenergic agonists and corticosteroids. Others necessitate adjunctive therapies and escalation to noninvasive ventilation or intubation. We will review the pathophysiology, evaluation, and treatment options for pediatric patients presenting with status asthmaticus with a particular focus on refractory status asthmaticus treated with volatile anesthetics. In addition, we include a proven approach to the management of these patients in the critical care setting, which requires close coordination between critical care and anesthesia providers. We present a case series of three patients, two of which have the longest reported cases of continuous isoflurane use in status asthmaticus. This series was obtained from a retrospective chart review and highlights the efficacy of the volatile anesthetic, isoflurane, in three pediatric patients with refractory life-threatening status asthmaticus.
Background:
Sevoflurane sedation in the intensive care unit is possible with a special heat and moisture exchanger called the Anesthetic Conserving Device (ACD) (AnaConDa; Sedana Medical AB, Uppsala, Sweden). The ACD, however, may corrupt ventilatory mechanics when used during the weaning process of intensive care unit patients. The authors compared the ventilatory effects of light-sedation with sevoflurane administered with the ACD and those of classic management, consisting of a heated humidifier and intravenous sedation, in intensive care unit patients receiving pressure-support ventilation.
Methods:
Fifteen intensive care unit patients without chronic pulmonary disease were included. A target Richmond Agitation Sedation Scale level of -1/-2 was obtained with intravenous remifentanil (baseline 1-condition). Two successive interventions were tested: replacement of the heated humidifier by the ACD without sedation change (ACD-condition) and sevoflurane with the ACD with an identical target level (ACD-sevoflurane-condition). Patients finally returned to baseline (baseline 2-condition). Work of breathing, ventilatory patterns, blood gases, and tolerance were recorded. A steady state of 30 min was achieved for each experimental condition.
Results:
ACD alone worsened ventilatory parameters, with significant increases in work of breathing (from 1.7 ± 1.1 to 2.3 ± 1.2 J/l), minute ventilation, P0,1, intrinsic positive end-expiratory pressure (from 1.3 ± 2.6 to 4.7 ± 4.2 cm H2O), inspiratory pressure swings, and decreased patient comfort. Sevoflurane normalized work of breathing (from 2.3 ± 1.2 to 1.8 ± 1 J/l), intrinsic positive end-expiratory pressure (from 4.7 ± 4.2 to 1.8 ± 2 cm H2O), inspiratory pressure swings, other ventilatory parameters, and patient tolerance.
Conclusions:
ACD increases work of breathing and worsens ventilatory parameters. Sevoflurane use via the ACD (for a light-sedation target) normalizes respiratory parameters. In this patient's population, light-sedation with sevoflurane and the ACD may be possible during the weaning process.
Sepsis remains a leading cause of death in intensive care units. There is growing evidence that volatile anesthetics have beneficial immunomodulatory effects on complex inflammation-mediated conditions. The authors investigated the effect of volatile anesthetics on the overall survival of mice in a sepsis model of cecal ligation and puncture (CLP).
Mice (N = 12 per treatment group) were exposed to anesthetic concentrations of desflurane, isoflurane, and sevoflurane either during induction of sepsis or when the mice showed pronounced symptoms of inflammation. Overall survival, as well as organ function and inflammation was compared with the CLP group without intervention.
With desflurane and sevoflurane conditioning (1.2 minimal alveolar concentration for 2 h immediately after induction of CLP) overall survival was improved to 58% and 83% compared with 17% in the untreated CLP group, respectively. Isoflurane did not significantly affect outcome. Application of sevoflurane 24 h after sepsis induction significantly improved overall survival to 66%.
Administration of the volatile anesthetics desflurane and sevoflurane reduced CLP-induced mortality. Anesthesia may be a critical confounder when comparing study data where different anesthesia protocols were used.
The intensive care unit (ICU) environment is often perceived to be hostile and frightening by patients due to unfamiliar surroundings coupled with presence of numerous personnel, monitors and other equipments as well as a loss of perception of time. Mechanical ventilation and multiple painful procedures that often need to be carried out in these critically ill patients add to their overall anxiety. Sedation is therefore required not only to allay the stress and anxiety, but also to allow for mechanical ventilation and other invasive therapeutic and diagnostic procedures to be performed. The conventional intravenous sedative agents used in ICUs suffer from problems of over sedation, tachyphylaxis, drug accumulation, organ specific elimination and often lead to patient agitation on withdrawal. All this tend to prolong the ventilatory as well as ICU and hospital discharge time, which increase the risk for infection and add to the overall increase in morbidity, mortality and hospital costs. In 2005, the anaesthetic conserving device (AnaConDa(®)) was marketed for ICU sedation with volatile anaesthetic agents. A number of trials have shown the effectiveness of using volatile anaesthetic agents for ICU sedation with the AnaConDa device. Compared with intravenous sedatives, use of volatile anaesthetic agents have resulted in shorter wake up and extubation time, lesser duration of mechanical ventilation and faster discharge from hospitals. This review shall focus on the benefits, technical pre-requisites and status of sedation with volatile anaesthetic agents in ICUs with the AnaConDa(®) device.
Exposure to isoflurane gas prior to neurological injury, known as anesthetic preconditioning, has been shown to provide neuroprotective benefits in animal models of ischemic stroke. Given the common mediators of cellular injury in ischemic and hemorrhagic stroke, we hypothesize that isoflurane preconditioning will provide neurological protection in intracerebral hemorrhage (ICH).
24 h prior to intracerebral hemorrhage, C57BL/6J mice were preconditioned with a 4-h exposure to 1% isoflurane gas or room air. Intracerebral hemorrhage was performed using a double infusion of 30-μL autologous whole blood. Neurological function was evaluated at 24, 48 and 72 h using the 28-point test. Mice were sacrificed at 72 h, and brain edema was measured.
Mice preconditioned with isoflurane performed better than control mice on 28-point testing at 24 h, but not at 48 or 72 h. There was no significant difference in ipsilateral hemispheric edema between mice preconditioned with isoflurane and control mice.
These results demonstrate the early functional neuroprotective effects of anesthetic preconditioning in ICH and suggest that methods of preconditioning that afford protection in ischemia may also provide protection in ICH.
Anesthetic Agents protect the heart from ischemic injury during perioperative period. We evaluated the protective effects of 2 anesagents on myocardial ischemia -reperfusion injury in rabbit models.
58 anesthetized and mechaniventilated rabbits randomly received isoflurane (ISO) 2%, propofol (PRP), or were observed as the control group for 15 minutes. We applied vascular tourniquet around the left anterior descending artery (LAD). Myocardium was reperfused for 4 hours. Derivative of pressure over time (dP/dT(max)), left ventricular pressure (dLVP), isovolumetric relaxation time (Tau), and segment shortening (SS) were measured over the ischemic and non-ischemic regions of left ventricle (LV). Cardiac troponin I (cTnI), tissue concentrations of tumor necrosis factor á (TNFá), myeloperoxidase activity assay (MPO), and tissue malonyl dialdehyde (MDA) concentrations were measured as indices of cellular injury and inflammatory response.
dP/dT(max) values significantly decreased during ischemia. Following reperfusion, dP/dT(max), dLVP, and Tau remained depressed in the control animals. Both PRP and ISO restored the function of the myocardium globally.
Only ISO improved the recovery of the ischemic myocardium during reperfusion. The effects of PRP were global in nature and involved compensatory hypercontractile state in nonischemic regions of the myocardium. Implication. PRP and ISO protect the heart against an ischemic injury, but only ISO preserves the function of the myocardium at the ischemic region. The survival rate of the PRP-treated group versus the ISO-treated group supports the claim that PRP has smaller contribution to recovery from myocardial ischemia.
Renal ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury and often leads to multiorgan dysfunction and systemic inflammation. Volatile anesthetics have potent antiinflammatory effects. We aimed to determine whether the representative volatile anesthetic isoflurane protects against acute kidney injury-induced liver and intestinal injury and to determine the mechanisms involved in this protection.
Mice were anesthetized with pentobarbital and subjected to 30 min of left renal ischemia after right nephrectomy, followed by exposure to 4 h of equianesthetic doses of pentobarbital or isoflurane. Five hours after renal IRI, plasma creatinine and alanine aminotransferase concentrations were measured. Liver and intestine tissues were analyzed for proinflammatory messenger RNA (mRNA) concentrations, histologic features, sphingosine kinase-1 (SK1) immunoblotting, SK1 activity, and sphingosine-1-phosphate concentrations.
Renal IRI with pentobarbital led to severe renal, hepatic, and intestinal injury with focused periportal hepatocyte vacuolization; small-intestinal apoptosis; and proinflammatory mRNA up-regulation. Isoflurane protected against renal IRI and reduced hepatic and intestinal injury via induction of small-intestinal crypt SK1 mRNA, protein and enzyme activity, and increased sphingosine-1-phosphate. We confirmed the importance of SK1 because mice treated with a selective SK inhibitor or mice deficient in the SK1 enzyme were not protected against hepatic and intestinal dysfunction with isoflurane.
Isoflurane protects against multiorgan injury after renal IRI via induction of the SK1/sphingosine-1-phosphate pathway. Our findings may help to unravel the cellular signaling pathways of volatile anesthetic-mediated hepatic and intestinal protection and may lead to new therapeutic applications of volatile anesthetics during the perioperative period.
Isoflurane preconditioning has been shown to protect endothelial cells against lipopolysaccharide and cytokine induced injury. This study was designed to determine whether isoflurane preconditioning increased endothelial cell tolerance to ischaemia.
Bovine pulmonary arterial endothelial cells were exposed or not exposed to various concentrations of isoflurane for 1 h. After a 30-min isoflurane-free period, cells were subjected to oxygen-glucose deprivation (OGD) for 3 h and reoxygenation for 1 h. Lactate dehydrogenase release from cells was used to measure cell injury. In some experiments, various protein kinase C (PKC) inhibitors and ATP-sensitive potassium channel (K(ATP) channel) inhibitors were present from 30 min before isoflurane treatment to the end of isoflurane treatment.
Isoflurane preconditioning dose-dependently decreased the OGD induced lactate dehydrogenase release. This protection was inhibited by 2 µM chelerythrine, a general PKC inhibitor, or 10 µM Gö6976, an inhibitor for the conventional PKCs. This protection was also inhibited by 0.3 µM glybenclamide, a general K(ATP) channel inhibitor, and 500 µM 5-hydroxydecanoate, a mitochondrial K(ATP) channel blocker. In addition, pretreatment with 100 µM diazoxide, a K(ATP) channel activator, for 1 h also reduced OGD induced endothelial cell injury. This diazoxide induced protection was inhibited by chelerythrine.
The results suggest that isoflurane preconditioning induces endothelial protection against in-vitro simulated ischemia. This protection may be mediated at least in part by conventional PKCs and mitochondrial K(ATP) channels. The results also indicate that PKCs may be downstream of K(ATP) channels in causing endothelial protection.
Human embryonic stem cell (hESC)-derived cardiomyocytes potentially represent a powerful experimental model complementary to myocardium obtained from patients that is relatively inaccessible for research purposes. We tested whether anesthetic-induced preconditioning (APC) with isoflurane elicits competent protective mechanisms in hESC-derived cardiomyocytes against oxidative stress to be used as a model of human cardiomyocytes for studying preconditioning.
H1 hESC cell line was differentiated into cardiomyocytes using growth factors activin A and bone morphogenetic protein-4. Living ventricular hESC-derived cardiomyocytes were identified using a lentiviral vector expressing a reporter gene (enhanced green fluorescent protein) driven by a cardiac-specific human myosin light chain-2v promoter. Mitochondrial membrane potential, reactive oxygen species production, opening of mitochondrial permeability transition pore, and survival of hESC-derived cardiomyocytes were assessed using confocal microscopy. Oxygen consumption was measured in contracting cell clusters.
Differentiation yielded a high percentage (∼85%) of cardiomyocytes in beating clusters that were positive for cardiac-specific markers and exhibited action potentials resembling those of mature cardiomyocytes. Isoflurane depolarized mitochondria, attenuated oxygen consumption, and stimulated generation of reactive oxygen species. APC protected these cells from oxidative stress-induced death and delayed mitochondrial permeability transition pore opening.
APC elicits competent protective mechanisms against oxidative stress in hESC-derived cardiomyocytes, suggesting the feasibility to use these cells as a model of human cardiomyocytes for studying APC and potentially other treatments/diseases. Our differentiation protocol is very efficient and yields a high percentage of cardiomyocytes. These results also suggest a promising ability of APC to protect and improve engraftment of hESC-derived cardiomyocytes into the ischemic heart.
Assessing feasibility and physiological effects of sedation with sevoflurane, administered with the anesthetic conserving device (AnaConDa), in comparison with propofol and remifentanil.
Seventeen patients undergoing mechanical ventilation underwent sedation with sevoflurane delivered with AnaConDa (phase SevAn), preceded and followed by sedation with propofol and remifentanil (phases ProRe(1), ProRe(2)), with the same sedation targets.
With both strategies it was possible to achieve the sedation targets. Time required to sedate and awake patients was greater during SevAn than ProRe(1): respectively, 3.3 +/- 3.0 versus 8.9 +/- 6.1 and 7.47 +/- 5.05 versus 16.3 +/- 11.4 min. During SevAn the PaCO(2) and minute ventilation increased. Hemodynamics was stable between ProRe(1) and SevAn, except for an increase in heart rate in the SevAn phase. Environmental pollution from sevoflurane was within the safety limits.
Sevoflurane can be effectively and safely used for short-term sedation of ICU patients with stable hemodynamic conditions.
To compare isoflurane with midazolam for prolonged sedation in ventilated patients.
Randomised controlled study.
General intensive care unit in university teaching hospital.
Sixty patients aged 17-80 years who required mechanical ventilation for more than 24 h.
Sedation with either 0.1-0.6% isoflurane in an air-oxygen mixture (30 patients) or a continuous infusion of midazolam 0.02-0.20 mg/kg/h (30 patients). Sedation was assessed initially and hourly thereafter on a six point scale. The trial sedative was stopped when the patient was ready for weaning from ventilatory support.
Measurements were made of haemodynamic, respiratory and biochemical variables regularly during the period of sedation and for a week after stopping the sedative agent. There was no difference in any of the physiological or biochemical variables recorded between the two groups. Patients sedated with isoflurane recovered more rapidly and were weaned from mechanical ventilation sooner than those sedated with midazolam.
Isoflurane is a useful agent for prolonged sedation of ventilated patients and does not have any adverse effect on the cardiorespiratory system or on hepatic, renal or adrenal function.
Isoflurane is a fluorinated ether that is closely related to enflurane. It has a low blood gas coefficient such that alterations in the concentration administered rapidly result in changes in the depth of anesthesia or sedation. Although primarily used as an anesthetic, isoflurane has many of the desirable properties of an ideal sedative agent for use in an ICU. We report the prolonged use of isoflurane in three critically ill patients.
To compare isoflurane with midazolam for sedation of ventilated patients.
Randomised control study. Setting--Intensive care unit in university teaching hospital.
Sixty patients aged 18-76 who required mechanical ventilation.
Sedation with either 0.1-0.6% isoflurane in an air-oxygen mixture (30 patients) or a continuous intravenous infusion of midazolam 0.01-0.20 mg/kg/h (30 patients). Sedation was assessed initially and hourly thereafter on a six point scale. Incremental intravenous doses of morphine 0.05 mg/kg were given for analgesia as required. The trial sedative was stopped when the patient was judged ready for weaning from ventilatory support or at 24 hours (whichever was earlier).
Achievement of a predetermined level of sedation for as much of the time as possible.
Isoflurane produced satisfactory sedation for a greater proportion of time (86%) than midazolam (64%), and patients sedated with isoflurane recovered more rapidly from sedation.
Isoflurane is a promising alternative technique for sedation of ventilated patients in the intensive care unit.
A new way of saving anaesthetic vapours is described. The method is analogous to the heat-moisture exchanger principle: the vapour is trapped in a filter during expiration and is returned to the patient during the subsequent inspiration. Fresh vapour is supplied on the patient side of the filter. A small container with 60 ml of a hydrophobic zeolite (an inorganic material) was used as filter. In model lung tests, this reduced the isoflurane consumption by 51% at a tidal volume of 300 ml, by 57% at 600 ml and by 51% at 930 ml. Neither isoflurane nor halothane yielded any degradation products when brought in contact with the zeolite.
General anesthesia has been recommended to control convulsive status epilepticus that is refractory to conventional anticonvulsant therapy. Halothane has been the recommended agent, but without experimental justification. Isoflurane, which has no reported organ toxicity and produces electrographic suppression at clinically useful concentrations in normal humans, should be a better volatile anesthetic for this purpose. The efficacy and safety of isoflurane administered to control convulsive status epilepticus were assessed on 11 occasions in nine patients in seven North American hospitals. Isoflurane, administered for 1-55 h, stopped seizures in all patients and was able to be titrated to produce burst-suppression patterns on electroencephalograms. Blood pressure support with iv fluids and/or pressor infusions was required in all of the patients. Seizures resumed upon discontinuation of isoflurane on eight of 11 occasions. Six of the nine patients died. The three survivors sustained cognitive deficits. In one patient urine fluoride concentrations were elevated, although not to nephrotoxic levels. These cases suggest that isoflurane 1) is an effective, rapidly titratable anticonvulsant; 2) does not reverse underlying causes of the refractory seizures; and 3) usually necessitates hemodynamic support with fluids and/or pressors. Isoflurane may be administered for seizures, but only when iv agents in anesthetic doses are ineffective or produce unacceptable side effects.
We report a case of status asthmaticus that was unresponsive to the usual agents. The use of an inhalational anesthetic agent allowed us to ventilate the patient with lower inspiratory pressures; however, lasting improvement did not occur until she mobilized large quantities of secretions. To our knowledge, this is the first clinical report on the use of isoflurane anesthesia to treat severe asthma. Despite prolonged administration, there were no significant side-effects. This case demonstrates both the benefits and limitations of such therapy.
To separate reflex from direct actions of anesthetics on airways, the authors studied the effects of halothane and isoflurane (1.5 MAC) on Ascaris antigen-induced (a mixed reflex and direct stimulus) and methacholine-induced (a direct acting stimulus) airway constriction in Basenji-Greyhound dogs. Prior to aerosol challenge, pulmonary resistance [R(L)] and dynamic compliance [C(dyn)] were not different during control (thiopental), halothane, and isoflurane anesthesia. R(L) was 1.93 ± 0.15 (mean ± SE), 1.81 ± 0.23 and 2.1 ± 0.12 cm H2O.l-1.s during thiopental, halothane, and isoflurane, respectively. C(dyn) was 116 ± 8, 106 ± 16 and 110 ± 9 ml/cmH2O during thiopental, halothane, and isoflurane anesthesia, respectively. In control studies (thiopental), Ascaris antigen increased R(L) by 9.4 ± 2.44 fold and decreased C(dyn) to 0.29 ± .02 times the prechallenge value. Both halothane and isoflurane anesthesia significantly attenuated the increase in R(L) provoked by Ascaris antigen challenge and halothane significantly attenuated the decrease in C(dyn). During halothane and isoflurane anesthesia, Ascaris antigen increased R(L) by 3.8 ± 0.96 and 3.5 ± 0.57 fold, respectively, and decreased C(dyn) to 0.48 ± 0.09 and 0.38 ± .07 times the prechallenge value, respectively. In control studies (thiopental anesthesia), methacholine produced dose-related increases in R(L) and decreases in C(dyn). Both halothane and isoflurane attenuated the increase in R(L) and the decrease in C(dyn) provoked by methacholine with halothane being more effective than isoflurane with regards to C(dyn). The mechanism of action of halothane and isoflurane on airways is similar and complex, involving depression of airway reflexes as well as direct effects on airway smooth muscle.
We report the first clinical application of a new anaesthetic agent-saving device. The principles of a heat-moisture exchanger have been further developed to create a device that reduces inhalational agent consumption. Sixteen patients were randomly allocated to receive isoflurane through either a vaporiser or through the agent-saving device. A coaxial Mapleson D system (Bain) was used in both groups. A standard ventilatory setting was used, aiming for normocapnia. Mean (SD) isoflurane consumption was 24.5 (2.8) ml x MAC-hour(-1) with the vaporiser, compared with 15.2 (3.0) ml x MAC-hour(-1) with the new device (p < 0.05). This corresponded to a 40% saving in the consumption of isoflurane. The amount of isoflurane that was scavenged to the atmosphere was reduced by an average of 55%.
Isoflurane has been reported to cause dose-dependent constriction in isolated coronary microvessels. However, these results are inconsistent with data from in situ and in vivo heart preparations which show that isoflurane dilates the coronary vasculature. To clarify the direct effects of isoflurane on coronary tone, we measured the response of isolated porcine resistance arterioles (ID, 75 +/- 4.0 microm; range, 41-108 microm) to isoflurane in the presence and absence of adenosine triphosphate-sensitive and Ca2+-activated potassium channel blockers and also after endothelial removal.
Subepicardial arterioles were isolated, cannulated, and pressurized to 45 mmHg without flow in a 37 degrees C vessel chamber filled with MOPS buffer (pH = 7.4). After all vessels developed spontaneous (intrinsic) tone, dose-dependent (0.17-0.84 mm; approximately 0.5-2.5 minimum alveolar concentration) isoflurane-mediated effects on vessel ID were studied in the presence and absence of extraluminal glibenclamide (1 microm; an adenosine triphosphate-sensitive channel blocker) or iberiotoxin (100 nm; a Ca2+-activated potassium channel blocker) or before and after endothelial denudation using the nonionic detergent CHAPS (0.4%). Vessel ID was measured using an inverted microscope and videomicrometer, and vasomotor responses were analyzed by normalizing changes in arteriole ID to the dilation observed after exposure to 10-4 m sodium nitroprusside, which causes maximal dilation.
Isoflurane caused dose-dependent dilation of all coronary arterioles. This vasodilation was 6.0 +/- 0.7 microm at an isoflurane concentration of 0.16 mm (approximately 0.5 minimum alveolar concentration) and 25.3 +/- 2.1 microm at 0.75 mm (approximately 2.5 minimum alveolar concentration). These values represent 18.1 +/- 1.7% and 74.1 +/- 3.3%, respectively, of that observed with 10-4 sodium nitroprusside (34 +/- 3 microm). Glibenclamide, but not iberiotoxin, exposure affected arteriolar dilation in response to isoflurane. Glibenclamide caused a downward displacement of the isoflurane dose-response curve, reducing isoflurane-mediated dilation by an average of 36%. Denuded arterioles showed a marked (approximately 70%) reduction in their ability to dilate in response to isoflurane.
The authors conclude that isoflurane dilates coronary resistance arterioles in a dose-dependent manner, and that this dilation is partially mediated by adenosine triphosphate-sensitive channels and is highly dependent on the presence of a functioning endothelium.