Venovenous Extracorporeal Membrane Oxygenation in Intractable Pulmonary Insufficiency: Practical Issues and Future Directions.

Venovenous extracorporeal membrane oxygenation (vv-ECMO) is a highly invasive method for organ support that is gaining in popularity due to recent technical advances and its successful application in the recent H1N1 epidemic. Although running a vv-ECMO program is potentially feasible for many hospitals, there are many theoretical concepts and practical issues that merit attention and require expertise. In this review, we focus on indications for vv-ECMO, components of the circuit, and management of patients on vv-ECMO. Concepts regarding oxygenation and decarboxylation and how they can be influenced are discussed. Day-to-day management, weaning, and most frequent complications are covered in light of the recent literature.

Clinical course and complications following diagnostic bronchoalveolar lavage in critically ill mechanically ventilated patients.

BACKGROUND: Flexible, fibreoptic bronchoscopy (FFB) and bronchoalveolar lavage (BAL) have been used for diagnostic purposes in critically ill ventilated patients. The additional diagnostic value compared to tracheal aspirations in ventilator-associated pneumonia (VAP) has been questioned. Nevertheless, BAL can provide extra information for the differential diagnosis of respiratory disease and good antibiotic stewardship. These benefits should outweigh potential hazards caused by the invasiveness of this diagnostic technique. The focus of the present study was on the clinical course and complications of patients following BAL procedures up to 24 h. METHODS: Hundred sixty-four FFB guided BAL procedures for suspected pneumonia were analysed in an observational study. The clinical course of patients was monitored by respiratory and haemodynamic data before BAL, 1 and 24 h after BAL. Complications were defined and registered. Factors associated with complications were analysed by logistic regression. CLINICAL COURSE: a decrease in average pO2/FiO2 ratio 1 h after BAL from 29 kPa (218 mmHg) to 25 kPa (189 mmHg) (p < 0.05) was observed which fully recovered within 24 h. Respiratory complications: the incidence of procedure related hypo-oxygenation (SaO2 ≤ 88 %) and/or bronchospasm was 9 %; a decrease of >25 % PaO2/FiO2 ratio 1 h after BAL was found in 29 % of patients; no bleeding or pneumothorax were registered. Haemodynamic complications: there were no cases of hypertension and cardiac rhythm disturbances; haemodynamic instability within the first 24 h after BAL was recorded in 22 %; this was correlated with a cardiovascular diagnosis at admission (OR 2.9; 95 % CI 1.2 - 6.7) and the presence of cardiovascular co-morbidity (OR 3.5; 95 % CI 1.5 - 8.3). The incidence of bacteraemia was 7 %. There was no case of procedure related death. DISCUSSION: Frequently occurring haemodynamic and respiratory instability but no cases of cardiac rhythm disturbances, bleeding, pneumothorax or procedure related death were attributable to diagnostic FFB and BAL. The procedures should be conducted under careful supervision by experienced physicians. Only a randomized controlled trial that compares diagnostic FFB and BAL with a non-invasive strategy could ultimately establish the safety profile and clinical utility of these procedures in critically ill ventilated patients.

Electronic nose analysis of exhaled breath to diagnose ventilator-associated pneumonia.

BACKGROUND: Exhaled breath analysis is an emerging technology in respiratory disease and infection. Electronic nose devices (e-nose) are small and portable with a potential for point of care application. Ventilator-associated pneumonia (VAP) is a common nosocomial infection occurring in the intensive care unit (ICU). The current best diagnostic approach is based on clinical criteria combined with bronchoalveolar lavage (BAL) and subsequent bacterial culture analysis. BAL is invasive, laborious and time consuming. Exhaled breath analysis by e-nose is non-invasive, easy to perform and could reduce diagnostic time. Aim of this study was to explore whether an e-nose can be used as a non-invasive in vivo diagnostic tool for VAP. METHODS: Seventy-two patients met the clinical diagnostic criteria of VAP and underwent BAL. In thirty-three patients BAL analysis confirmed the diagnosis of VAP [BAL+(VAP+)], in thirty-nine patients the diagnosis was rejected [BAL-]. Before BAL was performed, exhaled breath was sampled from the expiratory limb of the ventilator into sterile Tedlar bags and subsequently analysed by an e-nose with metal oxide sensors (DiagNose, C-it, Zutphen, The Netherlands). From further fifty-three patients without clinical suspicion of VAP or signs of respiratory disease exhaled breath was collected to serve as a control group [control(VAP-]). The e-nose data from exhaled breath were analysed using logistic regression. RESULTS: The ROC curve comparing [BAL+(VAP+)] and [control(VAP-)] patients had an area under the curve (AUC) of 0.82 (95% CI 0.73-0.9). The sensitivity was 88% with a specificity of 66%. The comparison of [BAL+(VAP+)] and [BAL-] patients revealed an AUC of 0.69; 95% CI 0.57-0.81) with a sensitivity of 76% with a specificity of 56%. CONCLUSION: E-nose lacked sensitivity and specificity in the diagnosis of VAP in the present study for current clinical application. Further investigation into this field is warranted to explore the diagnostic possibilities of this promising new technique.

The changing landscape of intensive care medicine.

This manuscript is a very general and non-political review on major issues concerning the evolving structural and organizational aspects of intensive care medicine, which may influence the outcomes of patients. It merely raises a multitude of issues, which deserve discussion in the different contexts of countries or communities.

Empirical antibiotic therapy for pneumonia in intensive care units: a multicentre, retrospective analysis of potentially pathogenic microorganisms identified by endotracheal aspirates cultures.

The purpose of this investigation was to explore the presumed relationship between the days of hospitalisation and microorganisms identified by endotracheal aspirate cultures in relation to adequate empirical treatment strategies of pneumonia in the intensive care unit (ICU). All potentially pathogenic microorganisms identified by (surveillance) cultures of endotracheal aspirates obtained in the ICUs of two Dutch teaching hospitals in 2007 and 2012 were retrospectively collected and analysed. Antibiotic susceptibilities to 11 antibiotics were calculated for several time points (days or weeks) after hospital admission and expressed per patient-day. In total, 4184 potentially pathogenic microorganisms identified in 782 patients were analysed. Prevalence of the classic early-onset pneumonia-causing microorganisms decreased from 55 % on the first four days to 34 % on days 4-6 after hospital admission (p < 0.0001). Susceptibility to amoxicillin/clavulanic acid was below 70 % on all days. Except for days 0 and 12, susceptibility to ceftriaxone was below 80 %. The overall susceptibility to piperacillin/tazobactam was 1518/1973 (77 %) in 2007 vs. 727/1008 (67 %) in 2012 (p < 0.0001). After day 8 of hospital admission, susceptibility to piperacillin/tazobactam therapy was below 80 % in 2012. After one week of hospital admission, susceptibilities to antibiotics were lower in the hospital that included that antibiotic in the local empirical treatment protocols as compared to the hospitals in which that antibiotic was not or infrequently included: 90/434 (21 %) vs. 117/398 (29 %); p = 0.004 for amoxicillin/clavulanic acid and 203/433 (47 %) vs. 253/398 (64 %); p < 0.001 for ceftriaxone. No cut-off in the number of days after hospital admission could be identified to distinguish early-onset from late-onset pneumonia. Consequently, the choice of empirical antibiotics should probably not be based on the time of onset.

Retrograde autologous priming reduces transfusion requirements in coronary artery bypass surgery.

The hypothesis was tested whether retrograde autologous priming (RAP) of the cardiopulmonary bypass system, compared to a standard primed system (NON-RAP group), results in less haemodilution and less transfusion of packed red blood cells. Retrospectively, data was collected from the medical charts of one hundred patients undergoing elective coronary artery bypass grafting using cardiopulmonary bypass. Fifty patients where RAP was used have been compared to fifty patients using NON-RAP. The prime volume in the NON-RAP group was 1,627±108 mL versus 782±96 mL in the RAP group (p<0.001). The lowest haematocrit during perfusion was 22% in the NON-RAP group versus 26% when the RAP technique was used (p<0.001). In the NON-RAP group, 26% of the patients received packed red cells in contrast to 6% in the RAP group (p<0.012). A positive association was found between RAP and less transfusion of packed red blood cells (p<0.012). In conclusion, retrograde autologous priming, reducing the prime volume of the cardiopulmonary bypass system, causes less haemodilution and reduces intraoperative transfusion of packed red blood cells.

Predictors of cardiac responsiveness to fluid therapy after cardiac surgery.

OBJECTIVES: Central venous pressure (CVP) and pulmonary capillary wedge pressure (PCWP) are insensitive preload markers and sometimes misleading. The introduction of the pulse contour method for monitoring of continuous cardiac output enabled the real-time quantification of stroke volume variation (SVV). Studies evaluating the accuracy of this parameter as a measure of preload responsiveness are still limited and conflicting results have been published in cardiac surgical patients. The aim of this study was to reevaluate the predictive value of SVV regarding cardiac responsiveness to fluid therapy and to compare it with the standard preload variables in a clinical setting in the ICU after cardiac surgery. METHODS: The assessment of cardiac responsiveness to fluid therapy (HAES-steril 6% 10 mL * Body Mass Index) was performed in 92 ventilated coronary artery surgical patients after arrival in the ICU. After the fluid load, detailed hemodynamic measurements were performed. A 'responder' was defined as a patient with a gain in stroke volume index (SVI) of 5% or more from baseline value to the volume challenge. RESULTS: Post hoc analysis showed that there were 47 responders to the fluid challenge and 45 non-responders. Hemodynamic data before the fluid therapy show that stroke volume variation in the responders group was significantly higher than in the non-responders groups (9.7 +/- 4.3% versus 7.6 +/- 3.0%, P = 0.01). The receiver operating characteristic curves for the baseline values of CVP, PCWP and SVV were constructed for illustrative purposes. The area under the curve for baseline values of SVV was significantly higher than random guess (area = 0.65, p < 0.05), indicative for the value of SVV as a marker of cardiac responsiveness to fluid therapy. The static preload parameters CVP and PCWP had no predictive value. CONCLUSION: SVV as measured with the LiDCO system is a better functional marker of cardiac responsiveness to fluid therapy than the static parameters CVP and PCWP.

Pulmonary function and inflammatory markers in patients undergoing coronary revascularisation with or without cardiopulmonary bypass.

Lung injury after cardiac surgery is believed to result from cardiopulmonary bypass and its pro-inflammatory effects. To test this hypothesis, we compared the oxygenation ratios, extravascular lung water indices and systemic and pulmonary tumour necrosis factor alpha (TNF-alpha) and interleukin (IL)-8 at predetermined intervals in coronary artery surgery patients with or without cardiopulmonary bypass. No differences in oxygenation ratios or extravascular lung water indices were found. Serum values of TNF-alpha and IL-8 increased in both groups but were higher in the cardiopulmonary bypass group (end of surgery: mean (SD) TNF-alpha 3.68 (2.5) vs 2.20 (1.2) pg.ml(-1) (p = 0.043 (CI 0.05-2.9)) and mean (SD) IL-8 19.45 (10.8) vs 6.31 (5.3) pg.ml(-1) (p = 0.001 (CI 6.9-19.3)). In broncho-alveolar lavage fluid, TNF-alpha and IL-8 increased in both groups with no differences between the groups.

Remifentanil provides better protection against noxious stimuli during cardiac surgery than alfentanil.

BACKGROUND AND OBJECTIVE: We hypothesized that remifentanil-propofol cardiac anaesthesia, plus administration of pirinitramide (piritramide) upon cessation of the remifentanil infusion, would be associated with a shorter time to tracheal extubation than alfentanil-propofol anaesthesia, without the occurrence of major haemodynamic instability. METHODS: Haemodynamic stability and recovery characteristics of two remifentanil infusion regimens (0.5 microg kg(-1)min(-1); 0.25 microg kg(-1)min(-1)) were therefore compared with an alfentanil infusion regimen (1 microg kg(-1)min(-1)), in combination with target-controlled infusion of propofol, in a randomized blinded trial in 75 coronary artery surgery patients. RESULTS: Pirinitramide provided good postoperative analgesia without prolonging extubation times: median extubation time in minutes after stopping the opioid-sedative drugs was 300 in the higher-dose remifentanil group and 270 in the lower-dose remifentanil group and alfentanil group (P = 0.606). Significant time-by-treatment interactions were seen for systolic arterial pressure (P = 0.015), mean arterial pressure (P = 0.009) and diastolic arterial pressure (P = 0.006). No significant interaction (P = 0.489) and no constant treatment effect were seen for heart rate (P = 0.288). Time effects were highly significant (P < 0.0001) for all haemodynamic variables. Heart rate remained stable in all groups. In the higher-dose remifentanil group, blood pressure was significantly different and lower during surgery and in this group less bolus doses of the opioid-sedative drugs (P = 0.015) had to be given. CONCLUSION: The higher-dose remifentanil infusion provided superior suppression of haemodynamic responses to noxious stimuli with better haemodynamic stability.

Comparison of the effects of dexmedetomidine and esmolol on myocardial oxygen consumption in dogs.

BACKGROUND AND OBJECTIVE: The beta-adrenergic blocker esmolol and the alpha 2-adrenergic agonist dexmedetomidine have the potential to decrease perioperative myocardial ischaemia. The pathophysiological mechanisms involved in these anti-ischaemic properties have not been thoroughly studied. We compared the effects of esmolol and dexmedetomidine on two indices of overall myocardial oxygen demand and on directly measured myocardial oxygen consumption of the left anterior coronary artery territory. METHODS: Eleven mongrel dogs were instrumented to measure aortic and left ventricular pressure, aortic and left anterior coronary artery flow and myocardial wall thickening. Variables related to myocardial oxygen metabolism were also determined. Measurements were performed during four sequential experimental conditions in each dog (Control 1: esmolol; Control 2: dexmedetomidine). RESULTS: Esmolol and dexmedetomidine decreased haemodynamic indices of myocardial oxygen demand to a similar extent: esmolol decreased the rate-pressure product by 16+/-3% and the pressure-work index (PWI) by 16+/-3%, dexmedetomidine decreased the rate-pressure product by 26+/-3% and the PWI by 16+/-7%. However, these similar decreases resulted from different haemodynamic effects of the two study drugs. Dexmedetomidine had a more pronounced bradycardic effect than esmolol (P = 0.01) and increased systolic aortic pressure (SAP) by 15+/-4% while esmolol decreased SAP by 8+/-2% (P < 0.01). dP/dt(max) and regional myocardial area decrease were lower after esmolol than after dexmedetomidine. Neither drug had an effect on myocardial oxygen consumption. CONCLUSIONS: Esmolol and dexmedetomidine decreased two haemodynamic indices of overall myocardial oxygen demand to a similar extent but neither drug decreased directly measured myocardial oxygen consumption in the territory of the left anterior descending artery.

Risk stratification for adverse outcome in cardiac surgery.

Risk-adjusted outcome prediction is mainly important in two separate fields. The first is quality monitoring: measuring actual versus predicted mortality in an institution allows assessment of the clinical surgical and anaesthesia performance while adjusting for the risk profile of the patients. Without risk stratification, surgeons and hospitals treating high-risk patients will appear to have worse results than others. This may prejudice referral patterns, affect the allocation of resources and even discourage the treatment of high-risk patients. The second field is that of informed consent and clinical decision-making. Risk-adjusted predicted mortality should form an important part of patient and surgeon decisions on whether or not to proceed with surgery. Clearly, no 'perfect' model can be produced as some aspects of mortality will always be related to risk factors not included in the model (e.g. the quality of the distal coronary artery vessels in coronary artery surgery) or due to chance happenings not related to preoperative patient characteristics (such as surgical error). An individual patient will either survive or die after cardiac surgery. Clearly, no scoring system will predict the specific outcome for every patient. However, risk stratification will inform patients and clinicians of the likely risk of death for a group of patients with a similar risk profile undergoing the proposed operation. This information is useful and should form part of the basis on which the patient and surgeon decide whether to proceed.

Alleviation of the peripheral hemodynamic effects of dexmedetomidine by the calcium channel blocker isradipine.

BACKGROUND: Alpha 2-adrenergic agonists have peripheral vasoconstrictive effects and central sympatholytic and sedative effects. Whereas the latter are the basis of their use in anesthesia, the former could limit their clinical application. METHODS: To study whether a vasodilator could alleviate the systemic and coronary vasoconstrictor effects of dexmedetomidine without influencing the central sympatholytic effects, the calcium channel blocker isradipine was infused after a high dose of dexmedetomidine in anesthetized dogs. RESULTS: Dexmedetomidine 10 micrograms.kg-1 decreased plasma concentrations of norepinephrine and epinephrine by more than 90%, heart rate by 39%, cardiac output by 64%, dp/dtmax by 29% and increased mean arterial pressure by 55% and the left ventricular end-diastolic pressure (LVEDP) 4-fold as compared to baseline. In addition, coronary blood flow decreased by 52% and coronary venous oxygen saturation by 51%. Isradipine could completely antagonize all the coronary and systemic hemodynamic changes induced by dexmedetomidine, but only partially he increase in LVEDP. Isradipine caused no changes in plasma catecholamine levels. CONCLUSION: Isradipine could alleviate the peripheral hemodynamic actions of dexmedetomidine while having no effect on its central sympatholytic properties.

Beneficial effects of dexmedetomidine on ischaemic myocardium of anaesthetized dogs.

We have studied the effect of dexmedetomidine during coronary artery stenosis (CAS) in dogs. Three periods of 15 min of CAS were induced at 40-min intervals in two groups of dogs (dexmedetomidine compared with placebo). Dexmedetomidine was administered before the second and third periods of CAS in doses of 1 and 3 micrograms kg-1, respectively. Dexmedetomidine decreased plasma concentrations of noradrenaline by mean 71 (SEM 9)%, heart rate by 8 (4)%, cardiac output by 30 (6)% and increased mean arterial pressure by 23 (10)%. Dexmedetomidine reduced blood flow in non-ischaemic myocardium and in the ischaemic epicardial layer by 16 (8)%, but blood flow was preserved in the ischaemic mid-myocardial and subendocardial layers. Consequently, dexmedetomidine increased the ischaemic-non-ischaemic blood flow ratio. Dexmedetomidine did not change myocardial oxygen consumption but decreased myocardial oxygen demand from 4.91 (0.33) to 3.76 (0.25) mumol min-1 g-1, thereby reducing the oxygen deficiency of the ischaemic myocardium from 1.47 (0.37) to 0.29 (0.32) mumol min-1 g-1.

Coronary vascular effects of dexmedetomidine during reactive hyperemia in the anesthetized dog.

OBJECTIVE: The central sympatholytic effects of alpha2-adrenergic agonists are believed to be beneficial during myocardial ischemia, but the peripheral vasoconstrictive effects are controversial. The aim of this study was to investigate the coronary vascular effects of dexmedetomidine (DM) during reactive hyperemia. DESIGN: The study had a prospective, randomized, open-comparative design. SETTING: University animal laboratory. PARTICIPANTS: Nine mongrel dogs. INTERVENTIONS: Coronary artery occlusions lasting 2 minutes were induced five times at 40-minute intervals. DM, 0.1, 1, and 10 micrograms/kg was administered 15 minutes before the second, third, and fourth coronary occlusion, respectively. The alpha2-antagonist atipamezole was administered before the fifth coronary occlusion. MEASUREMENTS AND MAIN RESULTS: DM, 1 microgram/kg, significantly decreased heart rate (from 128 +/- 13 to 96 +/- 21 beats/min); 10 micrograms/kg of DM also significantly decreased cardiac output (from 3.4 +/- 1.1 to 1.4 +/- 0.4 L/min). DM decreased myocardial blood flow in all layers of normally perfused myocardium. In hyperemic myocardium, DM significantly decreased epicardial blood flow (from 3.30 +/- 1.43 to 1.44 +/- 0.49 mL/min/g after DM 10 micrograms/kg), whereas endocardial blood flow did not change, hereby significantly increasing the endo/epi blood flow ratio (from 0.99 +/- 0.54 to 2.28 +/- 0.78). CONCLUSIONS: In the postischemic hyperemic subendocardial layer, coronary blood flow was preserved after DM. DM reduced primary determinants of myocardial oxygen demand. These effects of DM may be beneficial in conditions of temporary coronary artery occlusion and subsequent reperfusion.

The effects of alpha 2-adrenergic stimulation with mivazerol on myocardial blood flow and function during coronary artery stenosis in anesthetized dogs.

The central sympatholytic effect of alpha 2 agonists may be beneficial during myocardial ischemia, but could be opposed by their peripheral vasoconstrictive effect. We studied the effects of mivazerol during periods of moderate coronary artery stenosis in anesthetized dogs. Mivazerol decreased heart rate (from 125 +/- 6 to 106 +/- 6 bpm) and cardiac output (from 4.4 +/- 0.6 to 1.8 +/- 0.2L/min) under normal conditions, while mean arterial pressure did not change. Mivazerol reduced blood flow in nonischemic myocardium and in the ischemic epicardial layer, but blood flow was preserved in the ischemic midmyocardial and subendocardial layer. Mivazerol had no effect on myocardial oxygen extraction during the stenoses, and regional myocardial oxygen consumption was unchanged. However, mivazerol decreased myocardial oxygen demand from 4.51 +/- 0.51 to 3.17 +/- 0.24 mumol.min-1.g-1, thereby reducing oxygen deficiency of ischemic myocardium to values significantly lower than in the placebo group (from 1.07 +/- 0.32 to 0.47 +/- 0.41 mumol.min-1.g-1). Mivazerol had no effect on myocardial lactate production during the stenoses. We conclude that mivazerol reduced myocardial oxygen demand while blood flow was preserved in the inner layers of ischemic myocardium.

Continuous infusions of alfentanil and propofol for coronary artery surgery.

OBJECTIVE: To study the anesthetic efficacy of two different background infusion rates for alfentanil in a total intravenous anesthesia (TIVA) technique using propofol. Therefore, the effects of these infusions on hemodynamic stability and on the suppression of hemodynamic and somatic responses to noxious stimuli were compared. DESIGN: Prospective and randomized. SETTING: The study was performed in a university hospital setting. Two patient groups were compared. INTERVENTIONS: Anesthesia was induced in group 1 (n = 16) with alfentanil 50 micrograms/kg and in group 2 (n = 14) with alfentanil 75 micrograms/kg, infused in 4 min, as well as with an infusion of propofol at a rate of 10 mg/kg/h in both groups. After 4 min, the alfentanil infusion was reduced to 1 microgram/kg/min in group 1 and to 2 micrograms/kg/min in group 2. The propofol infusion was reduced following sternal spread to 3 mg/kg/h. Responses indicating inadequate anesthesia were treated with additional alfentanil bolus doses. MEASUREMENTS AND MAIN RESULTS: Induction of anesthesia in group 1 was associated with significant decreases in systolic and diastolic (-13%) blood pressures, cardiac index (-16%) and left ventricular stroke work index (-31%). Hemodynamic changes were similar in group 2, except for the greater fall in systemic vascular resistance during maintenance of anesthesia. There was no difference in the incidence of breakthrough hypertension between the two groups (in 44% and 43% of the patients, respectively) and in the number of alfentanil bolus supplements. There were also no differences in the incidence of ischemia, myocardial infarction or duration of postoperative ventilation. CONCLUSIONS: Because both infusions provided equally stable anesthesia, the lower infusion regimen for alfentanil is the more appropriate technique. Using this technique, the administration of additional alfentanil boluses just before stressful surgical episodes will further improve hemodynamic stability.

Infusion of propofol versus midazolam for sedation in the intensive care unit following coronary artery surgery.

The use and the hemodynamic effects of propofol and midazolam were studied during titrated continuous infusions to deep sedation (sedation level 5: asleep, sluggish response to light glabellar tap or loud auditory stimulus) following coronary artery surgery. The drugs were compared in 30 ventilated patients in an open randomized study. The duration of infusion was approximately 570 minutes in both groups. After a loading dose of propofol (1 mg/kg) or midazolam (0.07 mg/kg), the infusion rates were 2.71 +/- 1.13 mg/kg/h and 0.092 +/- 0.028 mg/kg/h, respectively. An analgesic infusion of sufentanil was also given in both groups. In the midazolam group, to maintain the predetermined level of sedation, more frequent additional bolus doses (4.7 +/- 1.8; P < 0.001) and infusion rate adjustments (5.3 +/- 1.6; P < 0.001) were required than for similar sedation in the propofol group (2.3 +/- 1.0 bolus doses and 3.3 +/- 1.2 adjustments). The time from stopping sedation to patient responsiveness was 11 +/- 8 minutes in the propofol group and 72 +/- 70 minutes in the midazolam group (P < 0.001), and the time from stopping sedation to extubation was 250 +/- 135 minutes and 391 +/- 128 minutes (P < 0.014), respectively. Following the loading dose of propofol, there was a fall in blood pressure (BP) (mean from 80 +/- 11 mmHg to 67.5 +/- 10 mmHg; P < 0.05). After approximately 15 minutes, BP started to rise but remained below pretreatment level throughout sedation.(ABSTRACT TRUNCATED AT 250 WORDS)