Optimizing pH-responsive polymeric micelles for drug delivery in a cancer photodynamic therapy model.

Different pH-sensitive, randomly- and terminally-alkylated N-isopropylacrylamide (NIPAM) copolymers were synthesized and used to prepare pH-responsive polymeric micelles (PM). These copolymers were modified from previously-studied copolymers by incorporating an additional hydrophilic monomer, N-vinyl-2-pyrrolidone (VP) to decrease uptake by the mononuclear phagocyte system (MPS) and improve localization in tumors. VP lowered the phase transition pH of the copolymers but did not affect the onset of micellization. The in vitro cytotoxicity of the copolymers was evaluated on EMT-6 mouse mammary tumor cells in comparison to Cremophor EL (CRM). The anticancer photosensitizer aluminum chloride phthalocyanine (AlClPc) was loaded into the PM with a standard dialysis procedure. Biodistribution and in vivo photodynamic activity were then evaluated in Balb/c mice bearing intradermal EMT-6 tumors. All NIPAM copolymers demonstrated substantially lower cell cytotoxicity than the control surfactant CRM. In vivo, similar AlClPc tumor uptake was observed for the PM and CRM formulations. However, the PM appeared to exhibit greater activity in vivo than CRM formulation at an AlClPc subtherapeutic dose. Therefore, NIPAM-based copolymers containing VP units represent promising alternatives for the formulation of poorly water-soluble phthalocyanines.

Pulmonary metabolism of endothelin 1 during on-pump and beating heart coronary artery bypass operations.

BACKGROUND: Coronary artery bypass operations are associated with increased circulating levels of the powerful vasoconstrictor endothelin 1. The pulmonary circulation is an important site for both production and clearance of endothelin 1. Lung endothelial injury resulting from cardiopulmonary bypass could modify pulmonary endothelin 1 metabolism through an increase in production, a reduction in removal, or a combination of both. METHODS: Pulmonary endothelin 1 kinetics were quantified by using the indicator-dilution technique in patients undergoing coronary artery bypass grafting with (n = 11) or without cardiopulmonary bypass (ie, beating heart; n = 10). Mixed venous endothelin 1 levels were also measured in samples from the pulmonary artery, and systemic levels were obtained from the radial artery. RESULTS: Pulmonary artery endothelin 1 levels were similar before and after cardiopulmonary bypass, with means of 1.59 +/- 0.37 pg/mL and 1.33 +/- 0.15 pg/mL (P =.45), respectively. Systemic endothelin 1 levels, however, increased after bypass from 1.64 +/- 0.22 pg/mL to 2.07 +/- 0.16 pg/mL (P =.01). In the beating heart group, endothelin 1 levels before and after the operation were similar in the pulmonary artery (1.25 +/- 0.27 pg/mL and 1.45 +/- 0.31 pg/mL, respectively; P =.38), as well as in the radial artery (1.70 +/- 0.26 pg/mL and 1.73 +/- 0.35 pg/mL, respectively; P =.92). The capacity to clear endothelin 1 from the pulmonary circulation, as computed from the permeability-surface area product for endothelin 1, was not affected by cardiopulmonary bypass before and after the operation (25.19 +/- 2.67 mL/s and 23.12 +/- 4.39 mL/s, respectively; P =.49). It was similar and also unaffected in the beating heart group. CONCLUSION: Coronary artery bypass grafting with cardiopulmonary bypass is associated with an increase in systemic endothelin 1 levels. The mechanism involved is not related to a decreased pulmonary clearance of endothelin 1 from the systemic circulation but rather to an increased endothelin 1 release by the lungs.

In-vitro and in-vivo evaluation of pH-responsive polymeric micelles in a photodynamic cancer therapy model.

pH-sensitive polymeric micelles of randomly and terminally alkylated N-isopropylacrylamide copolymers were prepared and characterized. Aluminium chloride phthalocyanine (AlClPc), a second generation sensitizer for the photodynamic therapy of cancer, was incorporated in the micelles by dialysis. Their photodynamic activities were evaluated in-vitro against EMT-6 mouse mammary tumour cells and in-vivo against EMT-6 tumours implanted intradermally on each hind thigh of Balb/c mice. pH-sensitive polymeric micelles were found to exhibit greater cytotoxicity in-vitro than control Cremophor EL formulations. In the presence of chloroquine, a weak base that raises the internal pH of acidic organelles, in-vitro experiments demonstrated the importance of endosomalllysosomal acidity for the pH-sensitive polymeric micelles to be fully effective. Biodistribution was assessed by fluorescence of tissue extracts after intravenous injection of 2 micromol kg(-1) AlClPc. The results revealed accumulation of AlClPc polymeric micelles in the liver, spleen and lungs, with a lower tumour uptake than AlClPc Cremophor EL formulations. However, polymeric micelles exhibited similar activity in-vivo to the control Cremophor EL formulations, demonstrating the higher potency of AlClPc polymeric micelles when localized in tumour tissue. It was concluded that polymeric micelles represent a good alternative to Cremophor EL preparations for the vectorization of hydrophobic drugs.

Preparation and characterization of pH-responsive polymeric micelles for the delivery of photosensitizing anticancer drugs.

pH-responsive polymeric micelles (PM) consisting of random copolymers of N-isopropylacrylamide (NIPA), methacrylic acid (MAA), and octadecyl acrylate (ODA) were prepared and characterized. The critical aggregation concentration, as determined by a fluorescence probe technique, was approximately 10 mg/L in water and phosphate-buffered saline. Phase transition pH was estimated at 5.7. The decrease in pH was accompanied by the destruction of hydrophobic clusters. Micelle size was dependent on temperature and the nature of the aqueous medium. The micelles were successfully loaded with a substantial amount of a photoactive anticancer drug, namely, aluminum chloride phthalocyanine (AlClPc). pH-responsive PM loaded with AlClPc were found to exhibit higher cytotoxicity against EMT-6 mouse mammary cells in vitro than control Cremophor EL formulation. These results show the potential of poly(NIPA-co-MAA-co-ODA) for in vivo administration of water-insoluble, photosensitizing anticancer drugs.

Comparison of the hemodynamic effects of sevoflurane anesthesia induction and maintenance vs TIVA in CABG surgery.

PURPOSE: To compare the hemodynamic effects of sevoflurane when used for induction and maintenance of anesthesia with a total intravenous technique in patients with known coronary artery disease (CAD). METHODS: Thirty patients undergoing elective coronary artery bypass graft (CABG) were randomly allocated to receive either sevoflurane (S group, n = 15) at a minimal concentration of 4% in oxygen for induction and at 0.5-2 MAC end-tidal concentration for maintenance, or a total intravenous technique (T group, n = 15) consisting of midazolam for induction and propofol for maintenance. In both groups, anesthesia was supplemented with sufentanil and muscle relaxation with cis-atracurium. Hemodynamic measurements included systemic and pulmonary pressures, heart rate, mixed venous oxygen saturation and cardiac output at the following times: pre-induction, 7 and 25 min post-induction, chest closure, one hour after surgery and pre and post tracheal extubation. RESULTS: More patients in the S group (8/15) presented bradycardia in the induction period (T:2/15) (P = 0.05). During maintenance of anesthesia, treatment of hypertension was more frequent in the T group (12/15) than in the S group (6/15) (P = 0.025). All other parameters were comparable. CONCLUSION: Induction of anesthesia in patients with CAD, VCRII with sevoflurane supplemented by sufentanil provided hemodynamic responses comparable with those of TIVA although bradycardia was observed more often with sevoflurane. Intraoperative control of systemic blood pressure was achieved with fewer interventions with a sevoflurane/sufentanil maintenance than with a propofol/sufentanil technique in CABG surgery.

Propofol or midazolam for sedation and early extubation following cardiac surgery.

PURPOSE: The purpose of this randomized, double-blind study was to evaluate the efficacy of midazolam and propofol for postoperative sedation and early extubation following cardiac surgery. METHODS: ASA physical status II-III patients scheduled to undergo elective first-time cardiac surgery with an ejection fraction > 45% were eligible. All patients received a standardized sufentanil/isoflurane anaesthesia. During cardiopulmonary bypass 100 micrograms.kg-1.min-1 propofol was substituted for isoflurane. Upon arrival in the Intensive Care Unit (ICU), patients were randomized to either 10 micrograms.kg-1.min-1 propofol (n = 21) or 0.25 microgram.kg-1.min-1 midazolam (n = 20). Infusion rates were adjusted to maintain sedation within a predetermined range (Ramsay 2-4). The infusion was terminated after four hours. Patients were weaned from mechanical ventilation and their tracheas extubated when Haemodynamic stability, haemostasis, normothermia and mental orientation were confirmed. Haemodynamic measurements, arterial blood gas tensions and pulmonary function tests were recorded at specified times. RESULTS: There were no differences between the two groups for the time spent at each level of sedation, number of infusion rate adjustments, amount of analgesic and vasoactive drugs, times to awakening and extubation. The costs of propofol were higher than those of midazolam. There were no differences in haemodynamic values, arterial blood gas tensions and pulmonary function. CONCLUSION: We conclude that midazolam and propofol are safe and effective sedative agents permitting early extubation in this selected cardiac patient population but propofol costs were higher.

Hemodynamic and pharmacodynamic comparison of doxacurium and high-dose vecuronium during coronary artery bypass surgery: a cost-benefit study.

Doxacurium (DOX), a new nondepolarizing neuromuscular blocking drug (NMBD), was compared in a randomized, double-blind fashion to high-dose vecuronium (VEC) in 60 coronary artery bypass grafting (CABG) patients. A third group of 15 patients older than 70 years of age (DOX-70) was added to compare the effects of DOX to VEC in the older population. Endpoints of the study were hemodynamic stability, ease of ventilation and intubation, anesthesiologist's satisfaction, drug interventions to correct hemodynamic instability, and total cost of the drug. Anesthesia was induced with fentanyl (30 micrograms/kg) along with the NMBD (DOX 80 micrograms/kg, VEC 400 micrograms/kg) over a 2-minute period. Following induction, heart rate (HR) and mean arterial pressure (MAP) were decreased (P < 0.01) in all groups. Tracheal intubation caused the HR to return to baseline in the DOX-70 group. There was no difference in central venous pressure, pulmonary artery occlusive pressure, cardiac index, systemic vascular resistance, and drug intervention for DOX and VEC. None of the patients had evidence of myocardial ischemia. There was a statistically significant but clinically irrelevant decrease in central venous pressure and systemic vascular resistance in the DOX-70 group. The durations of the induction and maintenance doses of DOX were similar in the younger and older patients. Although the intubating dose of VEC had a faster onset of action, this had no effect on the ease of ventilation, conditions for tracheal intubation, and overall anesthesiologist satisfaction. The total cost for each NMBD was not different.(ABSTRACT TRUNCATED AT 250 WORDS)

Successful non-surgical extraction of a knotted pulmonary artery catheter trapped in the right ventricle.

A patient is presented in whom a pulmonary artery catheter (PAC) formed a knot which was fixed in the region of the tricuspid valve chordea. The PAC was successfully and nonsurgically freed from its attachment and removed. A guide wire was introduced by the distal port of the PAC and under fluoroscopy the PAC was manipulated free and then extracted easily.

[Anesthetic induction with Althesin or diazepam in patients undergoing an aortocoronary bypass]. / Induction anesthésique avec Alfatésine ou diazépam chez des patients opérés pour pontage aorto-coronarien.

The haemodynamic effects of induction of anaesthesia with diazepam (group D) and Althesin (group A) were studied in 25 coronary patients under betablockers with good myocardial function. Haemodynamic variables monitored were vascular pressures, cardiac output and systolic time intervals. The effects of both drugs were observed when used alone (time I) and in combination with fentanyl, pancuronium and nitrous oxide (time II). The results seemed to show that Althesin (12.51% fall in SI and 10.79% increase in PEP/LVET) depressed myocardial function more than diazepam (no significant difference), but the introduction of fentanyl, pancuronium and nitrous oxide removed the differences between the drugs as to their effect on myocardial performance. These drugs added a depressant effect to diazepam (13.83% fall in SI and 15.77% increase in PEP/LVET) without increasing Althesin's negative inotropic effect. However, in group A at time II, the pulmonary arterial pressure, the wedge pressure and the pulmonary vascular resistance were significantly reduced, while they remained stable in the diazepam group.

Pathophysiology of rupture of the pulmonary artery by pulmonary artery balloon-tipped catheters.

High pressures have been reported in pulmonary artery catheter balloons. This study was undertaken to determine the in vitro rupturing pressures of human peripheral pulmonary arteries and to evaluate whether such pressures could be generated under clinical conditions. The in vitro model then was confirmed in vivo in the dog and the evolution of a rupture of a peripheral pulmonary artery studied. In vitro, pulmonary arteries of subjects under age 60 yr are remarkably resistant and tolerate intra-balloon pressures of 2700 mm Hg in the one mid-pulmonary artery studied and up to 4219 +/- 720 mm Hg (mean +/- SD) in the distal pulmonary artery. Subjects over the age of 60 yr have significantly lower rupturing pressures (1965 +/- 540 mm Hg in the mid-pulmonary artery, and 2498 +/- 600 mm Hg in the distal pulmonary artery), (P less than 0.05). Thus overdistension by the balloon may explain most ruptures. Preexisting pulmonary hypertension did not affect in vitro rupturing pressures. Clinicians generated intraballoon mean pressures of 795 +/- 130 mm Hg, with 20% of them generating higher and potentially dangerous pressures (1000 mm Hg or more). The in vitro model was confirmed by in vivo studies in dogs with pressures that cause pulmonary artery rupture. Furthermore, in normal dogs, rupture of a peripheral pulmonary artery was without complications. This suggests that rupture of the peripheral pulmonary artery may occur clinically more frequently than reported. The user of flotation pulmonary arterial catheters should be aware of the dangers associated with this diagnostic tool. In particular, liquids must never be used to inflate pulmonary arterial catheter balloons.

A simple classification of the risk in cardiac surgery.

A new risk classification for patients undergoing cardiac surgery has been used for the last two years by the anaesthesiologists of the Montreal Heart Institute. The following factors known to be associated with a greater operative morbidity and mortality were selected: (1) poor left ventricular function, (2) congestive heart failure, (3) unstable angina or recent (less than 6 weeks) myocardial infarction, (4) age over 65 years, (5) severe obesity (Body Mass Index greater than 30), (6) reoperation, (7) emergency surgery, (8) other significant or uncontrolled systemic disturbances. Patients with none of the above factors were classified as normal risks; those presenting with one of those selected factors were classified as increased risks, and those with more than one factor were said to carry a high risk. In a prospective study of 500 consecutive open-heart surgery patients classified according to this method, we found that the operated population at normal risk (50 per cent of cases) had a mortality of 0.4 per cent, the patient group with increased risk (32 per cent of cases) had a mortality of 3.1 per cent, and the high risk group (18 per cent of cases) had a 12.2 per cent mortality. Furthermore, 50 deaths following open-heart surgery were assessed retrospectively using the classification; 58 per cent of these patients were classified as high risk, 34 per cent had an increased risk, and only eight per cent were found to be in the normal risk group. Thus, this new risk classification has proven to be a reliable and useful tool for preoperative assessment of patients undergoing open-heart surgery and for teaching purposes.

Hypertension following coronary artery bypass graft.

Hypertension following coronary surgery is generally reported at an alarmingly high incidence (30 to 75 per cent). A vigilance program carried out in 1977 at the Montreal Heart Institute disclosed a low incidence of 3.5 per cent in 200 consecutive unselected cases. A similar program in 1980 based on 160 cases showed an incidence of 23.7 per cent. This highly significant difference is found to be related to the differences in anaesthetic management which have occurred since 1977 when anaesthesia was primarily morphine 1.0 to 1.5 mg . kg-1 supplemented as needed with low dose halogenated agents and vasodilation therapy. In 1980, only one of the authors (J.T.) still uses this technique. The incidence of hypertension in 40 of his patients was 2.5 per cent. The others use low dose fentanyl (7.5 to 10 micrograms . kg-1) supplemented as needed with halogenated agents and vasodilating therapy; the incidence of hypertension in 160 cases was 23.7 per cent. Would these results be the same with an anaesthetic technique comparing both drugs at equipotent doses? A prospective clinical study is addressing this question.

[The pre-operative visit in cardiovascular surgery]. / La visite pre-operatoire en chirurgie cardio-vasculaire.

This text is intended for new residents in the development of anaesthesia of the Montreal Heart Institute. It presents a classification of the risk of cardiovascular surgery used in that institution and discusses current problems encountered with this type of patient (pulmonary and coagulation problems, diabetes renal failure). The attitudes of anaesthetists of this institution towards patients' medication and premedication are also discussed. The risk is classified as usual, increased or high, depending on the presence (or absence) of several factors known to increase the risk: ventricular dysfunction, heart failure, unstable angina or recent infarction, significant involvement of other systems (unstable diabetes, renal insufficiency, significant pulmonary dysfunction), age, emergency surgery and non-cardiac surgery in the presence of important cardiac pathology. With surgical procedures carrying a high mortality, for example dissecting thoracic aneurysm, the usual risk is high and is classified as such. A table of the usual risk of current surgical procedures is proposed.