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.

Assessment of platelet inhibition secondary to clopidogrel and aspirin therapy in preoperative acute surgical patients measured by Thrombelastography Platelet Mapping.

BACKGROUND: Increasing numbers of patients prescribed clopidogrel and aspirin are presenting for non-elective surgery. No consensus on the timing of surgery exists after withdrawal of antiplatelet and tests of platelet function are not routinely available. The Thrombelastography Platelet Mapping (TEG-PM) assay is designed to assess platelet inhibition secondary to antiplatelet therapy. We assessed its ability to detect platelet inhibition in preoperative acute surgical patients. METHODS: We conducted a prospective observational study in three groups of preoperative patients: those taking clopidogrel or aspirin up to admission, and a control group. TEG-PM was performed on the day of admission and alternate days until surgery. RESULTS: Mean (SD) platelet thromboxane A(2) receptor inhibition in the control group was 17.5% (23.8) (n=20), 52.6% (32.3) (n=18) in the aspirin group, and 31.9% (27.6) (n=21) in the clopidogrel group (P<0.01). Mean (SD) platelet adenosine diphosphate (ADP) receptor inhibition in the control group was 47.8% (18.9) (n=20), 52.6% (19.7) (n=18) in the aspirin group, and 71.5% (18.4) (n=21) in the clopidogrel group (P<0.01). Among the clopidogrel group awaiting surgery, mean platelet ADP channel inhibition decreased on day 3 to 67.1% (24.7) (n=11), 48.8% (24.4) (n=4) on day 5, and 36.1% (15.9) (n=2) on day 7 (P=0.57). CONCLUSIONS: TEG-PM can identify statistically significant platelet inhibition after antiplatelet therapy; however, the overlap in platelet receptor inhibition between the three groups is likely to limit the clinical usefulness of this test.

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.

Alveolar recruitment strategy improves arterial oxygenation after cardiopulmonary bypass.

Atelectasis occurs during general anaesthesia. This is partly responsible for the impairment of gas exchange that occurs peri-operatively. During cardiopulmonary bypass, this atelectasis is exacerbated by the physical collapse of the lungs. As a result, poor arterial oxygenation is often seen postoperatively. We tested the effect of an 'alveolar recruitment strategy' on arterial oxygenation in a prospective randomised study of 78 patients undergoing cardiopulmonary bypass. Patients were divided equally into three groups of 26. Group 'no PEEP' received a standard post bypass manual lung inflation, and no positive end-expiratory pressure was applied until arrival at intensive care unit. Group '5 PEEP' received a standard post bypass manual inflation, and then 5 cmH2O of positive end-expiratory pressure was applied and maintained until extubation on intensive care. The third group, 'recruitment group', received a pressure-controlled stepwise increase in positive end-expiratory pressure up to 15 cmH2O and tidal volumes of up to 18 ml x kg(-1) until a peak inspiratory pressure of 40 cmH2O was reached. This was maintained for 10 cycles; the positive end-expiratory pressure of 5 cmH2O was maintained until extubation on intensive care. There was a significantly better oxygenation in the recruitment group at 30 min and 1 h post bypass when compared with the no PEEP and 5 PEEP groups. There was no significant difference in any of the groups beyond 1 h. Application of 5 cmH2O positive end-expiratory pressure alone had no significant effect on oxygenation. No complications due to the alveolar recruitment manoeuvre occurred. We conclude that the application of an alveolar recruitment strategy improves arterial oxygenation after cardiopulmonary bypass surgery.

Postoperative radiotherapy following mastectomy for high-risk breast cancer. A randomised trial.

Grade III, node-positive breast cancer carries a high risk of loco-regional relapse after simple mastectomy. A randomised trial was conducted to assess whether this would be significantly reduced by postoperative radiotherapy. Between 1985 and 1991, 76 patients who had undergone a simple mastectomy and axillary sampling, and whose tumours had been found to be grade III and node-positive, were randomised to receive postoperative radiotherapy to the chest wall and axilla or no further loco-regional treatment. Radiotherapy was delivered with 8 MV X-rays to the axilla and supraclavicular fossa and with 8 MeV electrons to the chest wall, to a dose of 45 Gy in 15 fractions over 3 weeks. All patients have been followed-up until death, or for a minimum of 10 years. All loco-regional recurrences occurred within the first 4 years after mastectomy. There were 26 such events in the 40 patients randomised to the 'watch' policy (65%), as opposed to 9 out of 36 (25%) who received radiotherapy (P<0.01). Ten-year survival was 39% in the radiotherapy arm as opposed to 25% in the no radiotherapy arm. Recruitment to the trial was closed in 1991, when a preliminary safety analysis revealed the size of the effect of radiotherapy, and from then on all node-positive patients with grade III tumours have routinely been given this treatment. Further follow-up has confirmed this finding, as borne out by these 10-year results, which shows that radiotherapy has a significant impact on reducing loco-regional recurrence in patients at high risk after mastectomy. There is an apparent survival benefit although, because of the small numbers in this trial, this has not reached statistical significance.

The EORTC clinical research coordinators group. European Organisation for Research and Treatment of Cancer.

The Clinical Research Coordinators Group (CRCG) is an umbrella organisation, compiled from four existing groups, namely the Oncology Nurses Group, the Data Management Group, the Radiation Technologists Group and the Early Clinical Studies Group Research Nurses. From the existing steering committees, a new board was formed and consists of two members per group. The CRCG will function as an independent group within the EORTC. The CRCG will create conditions and standards for implementing and conducting clinical protocols according to Good Clinical Practice.

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.

The haemodynamic effects of propofol in combination with ephedrine in elderly patients (ASA groups 3 and 4).

The marked vasodilator and negative inotropic effects of propofol are disadvantages in frail elderly patients. We investigated the safety and efficacy of adding different doses of ephedrine to propofol in order to obtund the hypotensive response. The haemodynamic effects of adding 15, 20 or 25 mg of ephedrine to 200 mg of propofol were compared to control in 40 ASA 3/4 patients over 60 years presenting for genito-urinary surgery. The addition of ephedrine to propofol appears to be an effective method of obtunding the hypotensive response to propofol at all doses used in this study. However, marked tachycardia associated with the use of ephedrine in combination with propofol occurred in the majority of patients, occasionally reaching high levels in individual patients. Due to the risk of this tachycardia inducing myocardial ischemia, we would not recommend the use in elderly patients of any of the ephedrine/propofol/mixtures studied.

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.

Does hypothermia prevent cerebral ischaemia during cardiopulmonary bypass?

It is believed that moderate hypothermia (25-32 degrees C) during cardiopulmonary bypass provides cerebral protection by reducing the cerebral metabolic rate (CMRO2). Nevertheless episodes of ischaemia do occur and thus it has been suggested that cerebral oxygenation should be monitored by jugular venous oximetry. However, this technique is cumbersome and invasive. Near infrared spectroscopy (NIRS) provides a non-invasive assessment of cerebral oxygenation and this was used together with continuousjugular venous oximetry in 21 patients undergoing hypothermic cardiopulmonary bypass. During the hypothermic period, jugular venous oximetry indicated reduced oxygen extraction consistent with a reduction in CMRO2 (increase from 61 +/- 2.5% to 74 +/- 2.5%). In contrast, near infrared spectroscopy demonstrated increased oxygen extraction (HbO2 - 11.5 +/- 1 microM, HHb + 3.2 +/- 0.3 microM) and a fall in the cerebral concentration of oxidized cytochrome oxidase ( - 1.7 +/- 0.3 microM) indicating ischaemia. These results suggest that cerebral ischaemia occurs during hypothermic cardiopulmonary bypass with a spurious rise in jugular venous oxygen saturation, which represents arterio-venous shunting. Thus if hypothermia does facilitate cerebral protection it does not appear to be a direct result of a reduction in CMRO2 and oxygen requirement.

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.

A comparison of late cosmetic results following two different radiotherapy techniques for treating basal cell carcinoma.

Fractionated superficial X-ray therapy and gold grain brachytherapy Elastoplast mould (EPM) methods of treating basal cell carcinoma (BCC) on facial skin were compared for long term cosmesis. Thirty patients were traced who had been treated successfully for a BCC on the face more than ten years previously. Late skin and subcutaneous changes were graded. Fifteen had been treated with 116 kV X-rays (32.5 Gy in five fractions on 5 consecutive days, and the remaining 15 with radioactive gold EPMs, delivering a dose of 6000-6500 R with an application lasting 7 days). The late cosmetic result scores of the patients treated by X-rays gave a mean score of 2.13; only three of these patients had a score of less than 2. The mean score for the patients treated with EPMs was 1.47; none had a score greater than 2. The difference is statistically significant (P < 0.01, Wilcoxon rank sum test). The EPM gave much more acceptable late cosmetic results.

The haemodynamic effects of propofol in combination with ephedrine.

Forty ASA1 patients presenting for minor gynaecological surgery were randomly allocated into four study groups to compare the haemodynamic effects of adding different doses of ephedrine to an induction dose of propofol. Heart rate, oxygen saturation and non-invasive arterial blood pressure were monitored before and for 5 min after induction. In those patients who received propofol alone, there was a significant decrease in both systolic (p < 0.001) and diastolic (p = 0.003) blood pressure. The addition of ephedrine 15 mg or 20 mg to 1% propofol 20 ml was very effective in maintaining blood pressure at pre-induction values. There was a statistically significant increase from baseline in systolic (p = 0.004) and diastolic (p = 0.031) pressures, but this only occurred at 1 min postinduction. The addition of ephedrine 10 mg was insufficient to prevent hypotension. There was no significant effect on either heart rate or oxygen saturation in any group. We conclude that ephedrine may be safely employed to reduce the degree of hypotension during induction with propofol in this patient group.

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.