A new, minimally invasive technique for measuring cardiac index: clinical comparison of continuous cardiac dynamic monitoring and pulmonary artery catheter methods.

To assess the utility of a relatively simple bedside method of estimating cardiac index during major surgery or in the intensive care unit, we conducted a prospective study in patients undergoing elective cardiac bypass surgery where a pulmonary artery catheter was inserted as part of routine monitoring. The cardiac index was estimated using standard techniques and compared with estimates from continuous cardiac dynamic monitoring using HEARTSMART software. Two hundred and seventy sets of measurements were suitable for comparison. The mean bias (95% limits of agreement), for the pre-bypass cardiac index was -0.09 (-1.26 to 1.08) l x min(-1) x m(-2), and post-bypass was 0.12 l x min(-1) x m(-2) (-1.32 to 1.56). These results suggest that continuous cardiac dynamic monitoring using HEARTSMART is sufficiently accurate for assessment of haemodynamic variables in critically ill patients, facilitating goal-directed therapies.

Remifentanil patient-controlled analgesia following cardiac surgery.

BACKGROUND: Remifentanil is increasingly used as a component of cardiac anaesthesia. Following cardiac surgery remifentanil is often substituted for alternative opioids on the intensive care unit. We were interested to evaluate postoperative continuation of remifentanil in the form of remifentanil patient control analgesia (RPCA) for those patients who received intraoperative remifentanil. The objectives of this study were to assess the safety, efficacy and feasibility of the RPCA. METHODS: Ten patients who received an intravenous infusion of remifentanil perioperatively for coronary artery bypass graft surgery (CABG) had their remifentanil infusion converted to RPCA following extubation on the intensive care unit. Remifentanil patient control analgesia delivered an initial background infusion consistent with the infusion rate at extubation and with a bolus facility of 50 microg administered over 5 min followed by a 5-min lockout. Data collection included sedation and pain scores, respiratory rate, arterial blood gases, number of successful/unsuccessful attempts and the background infusion rate for each subject over a period of 12 h following extubation. RESULTS: The data from nine male and one female patient were analyzed by using SPSS11 for Windows. During the study period the patients achieved adequate pain control and made more RPCA attempts at lower background infusion rates. No episodes of apnoea, SpO(2) less than 95% or a rise in PaCO(2) greater than 6.5 kPa were observed. CONCLUSION: Remifentanil patient control analgesia with a background infusion was effective and safe for postoperative pain relief in this group of spontaneously breathing ICU patients following cardiac surgery.

Giving long-persistent starch as volume replacement can cause pruritus after cardiac surgery.

We reviewed the prevalence and severity of pruritus in 85 patients after cardiac surgery. EloHAES, a long-lasting hydroxyethylated starch, was given to 59 of these patients. None of the patients who did not receive EloHAES developed pruritus, compared with 22% of those who did (P = 0.007). The timing of onset, duration and severity of the pruritus are similar to those found previously for other hydroxyethylated starches, and the cause of this pruritus is likely to be similar. Hydroxyethyl starch can cause long-term pruritus.

Randomized trial of diaspirin cross-linked hemoglobin solution as an alternative to blood transfusion after cardiac surgery. The DCLHb Cardiac Surgery Trial Collaborative Group.

BACKGROUND: Risks associated with transfusion of allogeneic blood have prompted development of methods to avoid or reduce blood transfusions. New oxygen-carrying compounds such as diaspirin cross-linked hemoglobin (DCLHb) could enable more patients to avoid allogeneic blood transfusion. METHODS: The efficacy, safety, hemodynamic effects, and plasma persistence of DCLHb were investigated in a randomized, active-control, single-blind, multicenter study in post-cardiac bypass surgery patients. Of 1,956 screened patients, 209 were determined to require a blood transfusion and met the inclusion criteria during the 24-h post-cardiac bypass period. These patients were randomized to receive up to three 250-ml infusions of DCLHb (n = 104) or three units of packed erythrocytes (pRBCs; n = 105). Further transfusions of pRBCs or whole blood were permitted, if indicated. Primary efficacy end points were the avoidance of blood transfusion through hospital discharge or 7 days postsurgery, whichever came first, and a reduction in the number of units of pRBCs transfused during this same time period. Various laboratory, physiologic, and hemodynamic parameters were monitored to define the safety and pharmacologic effect of DCLHb in this patient population. RESULTS: During the period from the end of cardiopulmonary bypass surgery through postoperative day 7 or hospital discharge, 20 of 104 (19%) DCLHb recipients did not receive a transfusion of pRBCs compared with 100% of control patients (P < 0.05). The overall number of pRBCs administered during the 7-day postoperative period was not significantly different. Mortality was similar between the DCLHb (6 of 104 patients) and the control (8 of 105 patients) groups. Hypertension, jaundice/hyperbilirubinemia, increased serum glutamic oxalo-acetic transaminase, abnormal urine, and hematuria were reported more frequently in the DCLHb group, and there was one case of renal failure in each group. The hemodynamic effects of DCLHb included a consistent and slightly greater increase in systemic and pulmonary vascular resistance with associated increases in systemic and pulmonary arterial pressures compared with pRBC. Cardiac output values decreased more in the DCLHb group patients after the first administration than the control group patients. At 24 h postinfusion, the plasma hemoglobin level was less than one half the maximal level for any amount of DCLHb infused. CONCLUSIONS: Administration of DCLHb allowed a significant number (19%) of cardiac surgery patients to avoid exposure to erythrocytes postoperatively.

Separation of the voriconazole stereoisomers by capillary electrophoresis and liquid chromatography.

A chiral capillary electrophoresis (CE) method has been developed for the direct separation of the four stereoisomers of a new broad spectrum antifungal agent, voriconazole. Cyclodextrin (CD) modified micellar electrokinetic chromatography employing, alpha-CD, beta-CD, gamma-CD, hydroxypropyl-beta-CD and hydroxyethyl-beta-CD was not sufficiently selective for the four neutral stereoisomers. Three anionic sulphobutyl-ether-beta-CD (SBE-beta-CD) electrolyte additives, each having a defined degree of substitution (DS) (6.5, 4.5 and 1.0) were subsequently examined. The complete CE separation of all four stereoisomers was obtained when using the medium substituted additive DS = 4.5. In liquid chromatography (LC), two approaches were examined for the direct chiral separation of the stereoisomers of voriconazole: (a) use of the neutral and anionic CD mobile phase additives and (b) a vancomycin chiral stationary phase. The CD additives were shown to be extremely selective for two stereoisomers of voriconazole (active drug and its enantiomer) but unable to discriminate between the opposite two stereoisomers. The converse was observed, however, when the vancomycin chiral stationary phase was employed.

Use of 1H-NMR spectroscopy to determine the enantioselective mechanism of neutral and anionic cyclodextrins in capillary electrophoresis.

One-dimensional (ID) and two-dimensional (2D) 1H nuclear magnetic resonance (NMR) techniques have been used to investigate the chiral recognition process in capillary electrophoresis (CE) for seven different cyclodextrins (CDs) with the calcium channel blocker amlodipine as a model compound. These include five neutral CDs (alpha-CD, beta-CD, gamma-CD, hydroxypropyl-beta-CD and hydroxyethyl-beta-CD) and two anionic CDs (sulphobutyl-ether-beta-CD and carboxymethyl-beta-CD) where mixtures of amlodipine with each of the seven CDs were examined by 1D NMR in deuterated phosphate buffer at pD 3.4. The resonance shift of signals with added CD, relative to the CD-free position (shift displacement, delta delta) and shift non-equivalence (delta delta *) of enantiomeric signals shifted relative to each other after addition of CD were examined for non-overlapped protons of amlodipine. The possible correlations of NMR shift non-equivalence data with chiral separation in CE for amlodipine have been critically assessed. Qualitative differences in the 1D NMR shifts and enhanced enantioselectivity in CE were observed for amlodipine with sulphobutyl-ether-beta-CD. Further experiments on the through-space interactions using 2D rotating frame nuclear Overhauser effect spectroscopy (ROESY) indicated that there was no association between internal glucopyranose hydrogen atoms and the aromatic hydrogens of amlodipine. This gives evidence for the aromatic ring not being included in this CD. Moreover, data from spin-lattice relaxation times (T1) measured for amlodipine in the free state and after addition of the anionic sulphobutyl-ether-beta-CD indicate that the aromatic moiety of amlodipine is not included into the sulphobutyl-ether-beta-CD cavity. There is evidence that it interacts with the sulphobutyl side chains, and may adopt a preferred orientation outside the sulphobutyl-ether-beta-CD toroid itself.

Chiral recognition in liquid chromatography utilising chargeable cyclodextrins for resolution of doxazosin enantiomers.

The chromatographic resolution of rac-doxazosin using reversed-phase high performance liquid chromatography (HPLC) with the chargeable chiral mobile phase additive, carboxymethyl-beta-cyclodextrin (CM-beta-CD), is described. The effects of different modifiers (acetonitrile, methanol and tetrahydrofuran), pH, temperature, and cyclodextrin concentration were investigated to a) assess the key chromatographic parameters for subsequent chemometric optimisation, and b) explore the enantioselective mechanism. Assuming a 1:1 complex between each doxazosin enantiomer and CM-beta-CD, studies of the relationship between the capacity factors (k') and functions of CM-beta-CD concentration indicate that the mechanisms for retention and chiral selectivity are comparable with those proposed earlier by Sybilska et al. Stability constants (KG) calculated for rac-doxazosin complexed with CM-beta-CD (647 +/- 55 and 594 +/- 45 M-1 for each enantiomer respectively) are significantly larger than those calculated for the barbiturates complexed with beta-CD (ca. 101-108 M-1). Investigations on pH indicate an ionic or ino-pair interaction between the anionic CM-beta-CD and the cationic doxazosin enantiomers. A central composite design was used to optimise the key chromatographic parameters: pH, methanol (v/v) and CM-beta-CD concentration. The Kaiser peak separation index, Pi, was used for the response function. The predicted response for this chiral separation has been compared with that observed experimentally and samples of the four-dimensional response surface have been assessed for their value in showing robustness.

Acid-base management during cardiopulmonary bypass. Current trends in the United Kingdom.

Controversy exists over which method of acid-base management should be used during hypothermic cardiopulmonary bypass: the alpha-stat method or the pH-stat method. We surveyed 40 centres in the United Kingdom to assess current practice; whether practice has changed recently; and if so, why. Ten years ago, 31 centres (77.5%) used pH-stat and seven (17.5%) used alpha-stat. Currently nine centres (22.5%) are using pH-stat, 25 (62.5%) are using alpha-stat and four (10%) are using both. One centre (2.5%) has always used a modified pH-stat technique, and one continues to use alpha-stat in children and pH-stat in adults. Twenty-one of the 22 centres which have changed their practice did so because of increasing reports incriminating pH-stat in postoperative morbidity, particularly cerebral dysfunction. Our results show a marked trend towards using alpha-stat methods rather than the more traditional pH-stat approach.

Method development in liquid chromatography with a charged cyclodextrin additive for chiral resolution of rac-amlodipine utilising a central composite design.

A negatively charged derivative of beta-cyclodextrin, sulphobutyl ether-beta-cyclodextrin (SBE-beta-CD), was examined as a chiral mobile phase additive in reversed-phase high-performance liquid chromatography for the enantiomeric resolution of the calcium channel blocker rac-amlodipine. Theoretical and practical aspects are discussed for setting up a central composite design applicable to any analytical method. These include the correct location of factor points for maintaining orthogonality within the design and the augmentation of centrepoint experiments to allow a larger factor space by increasing the distance of axial star points. Optimised separation was achieved using a reverse-phase column with eluent comprising: acetonitrile (ACN)-potassium dihydrogen phosphate (pH 3.93) containing 2.66 mM SBE-beta-CD (26.5:73.5% v/v) at a flow rate of 1.0 ml/min. This yielded a Kaiser peak separation index, Pi = 0.96, at tR2 = 52 min with satisfactory reproducibility, relative standard deviation values: tR1, 0.39%; tR2, 0.47% (n = 5). These experimental results were in excellent agreement with those predicted by the SAS software package for a chromatographic response function model. Multiple regression analysis in four dimensions, with three response models based on Rs, Pi, and a function of Pi, produced response surfaces which revealed zones of optimum robustness and illustrated the interactions involved between the key chromatographic factors. Putative proposals for a mechanism involving the interaction of each of the positively charged enantiomers with the negatively charged cyclodextrin are also discussed. These examine the possibility of ion-pairing and inclusion phenomena to account for the excellent resolution observed.

Impurities in drug substances and drug products: new approaches to quantification and qualification.

Regulatory requirements for the identification, qualification and control of impurities in drug substances and their formulated products are now being increasingly explicitly defined, particularly through the International Conference on Harmonisation. The implications of the recent guidelines are reviewed, both from their regulatory impact and the impact upon analytical technology. Impurities also have important safety consequences, and suggestions for possible routes to the qualification of impurities which do not involve the need to undertake additional studies are made.

Effects of changes in mean arterial pressure on SjO2 during cerebral aneurysm surgery.

Twenty-six patients requiring clipping of cerebral aneurysms were anaesthetized with propofol, alfentanil and atracurium infusions and their lungs ventilated mechanically to hypocapnia (3.4-4.5 kPa). SjO2 was measured continuously with an Oximetrix fibreoptic oximetry catheter. Normovolaemia was maintained by observing the response of mean arterial pressure (MAP) and central venous pressure (CVP) to fluid administration. The response of SjO2 to increased MAP was noted and the lactate oxygen index (LOI) calculated at regular intervals. SjO2 measurements indicated a critical MAP of between 80 and 110 mm Hg in nine patients, and one patient had a persistently low SjO2 value despite an MAP of 110 mm Hg. An increase in MAP was associated with an increase in SjO2 in 19 patients (P < 0.001). When the effects of changes in PaCO2 were eliminated, this change was still significant (P = 0.004) (n = 9). Patients with an LOI > 0.08 at any time during the procedure had a worse initial outcome (within the first day) (P < 0.02) than patients who had a normal LOI throughout. Long-term outcome was similar to those with a normal LOI. Increasing MAP did not have a consistent effect on LOI. Jugular bulb cannulation to assess hypoperfusion in conjunction with lactate measurements and calculation of LOI provide useful information on which to base the intra- and postoperative management of patients with subarachnoid haemorrhage.

The SMART needle. A new Doppler ultrasound-guided vascular access needle.

Central venous access is an essential part of patient management in many clinical settings. Traditionally this has been achieved by a blind, external landmark guided technique which may not correlate exactly with the location of the vessel. We have prospectively evaluated the SMART needle, a new Doppler ultrasound guided vascular access device, in 40 patients, to evaluate whether it can improve on the standard technique. The SMART needle was easy to use and reliably distinguished between arterial and venous signals. No advantage was demonstrated in 'easy' internal jugular vein cannulations. Although ease of cannulation in difficult cases was subjectively improved, the differences in time to cannulation and number of passes between the groups failed to reach statistical significance and the complication rates were similar. However, the use of the SMART needle on two occasions enabled avoidance of carotid artery puncture by correctly distinguishing the artery from the vein, so that it may have a rôle in patients in whom difficult internal jugular venous cannulation is anticipated.

Surgical emphysema and upper airway obstruction complicating recovery from anaesthesia.

We describe a case of surgical emphysema and life-threatening airway obstruction resulting from a small pharyngeal perforation. The perforation apparently resulted from the use of a Yankauer-type sucker after uneventful anaesthesia for stapedectomy.

Influence of cardiac output on the correlation between mixed venous and central venous oxygen saturation.

The influence of cardiac output on the correlation between central venous oxygen saturation and mixed venous oxygen saturation was assessed in 51 patients who had both a pulmonary artery catheter and separate central venous catheter in situ. Seventy-six paired samples were taken from the catheters and oxygen saturation measured immediately in a Ciba Corning 2500 Co-oximeter. Cardiac output was measured using a standard thermodilution technique. The data were separated into groups with low cardiac index (< 2.5 litre min-1 m-2; n = 20), medium cardiac index (2.5-4.0 litre min-1 m-2; n = 36) and high cardiac index (> 4.0 litre min-1 m-2; n = 20). The correlation coefficients of the three groups were: low cardiac index 0.95, medium cardiac index 0.88 and high cardiac index 0.95 (P < .001 for all three groups). All measurements were made before any x-ray and necessary repositioning of the central venous catheter. These results suggest that central venous oxygen saturation is a useful estimate of mixed venous oxygen saturation and that the influence of cardiac output on that estimate is minimal.

Advanced trauma life support. A time for reappraisal.

The experience of Advanced Trauma Life Support training received by three anaesthetists is discussed with particular reference to the teaching of airway management, the grade of staff who should attend the present courses and the relevance to the British hospital system. We conclude that these courses are useful but limited by their inflexibility and failure to recognise the difference in skill mix in the British setting.

Chemometrics in pharmaceutical analysis.

Pharmaceutical analysis is undergoing a slow revolution as chemometric principles become increasingly incorporated. This paper reviews some of the more recent advances, with particular focus on spectrophotometry, chromatography and expert systems.

Brain stem death and organ donation.

Organs for donation are in short supply in the United Kingdom, resulting in allegations that relatives of potential donors are not being asked for consent. Legislation on "required request" has been proposed to overcome this. The incidence, causes, complications, and patterns of organ donation in brain stem dead patients in one referral centre were studied over 12 months. Data were collected on all patients fulfilling criteria for brain stem death or considered suitable for donating organs after circulatory arrest. Forty two patients fulfilled the criteria for brain stem death, and in 10 further patients circulatory arrest occurred before formal testing was finished. The major causes of brain stem death were head injury (28) and intracranial haemorrhage (17). Consent to organ donation was obtained for 24 potential donors, and organs were donated by 23 of them. Twenty nine patients did not donate organs. The commonest reasons for failure to donate were medical unsuitability (13) and the coroner not releasing the body (eight). Consent was not sought in three cases, and the relatives refused consent in the remaining five. This study suggests that required request will not considerably increase the supply of donor organs.