Diabetes mellitus and hypertension are common chronic diseases that frequently occur simultaneously. The induction of streptozotocin (STZ) diabetes mellitus in spontaneously hypertensive rats (SHR) offers the opportunity to investigate the influence of both entities in a reproducible manner. We investigated the effects of various vasoconstrictors on isolated small arteries from the mesenteric vascular bed of normotensive rats (Wistar-Kyoto rats, WKY) and SHR with chronic (8 weeks), STZ-induced diabetes mellitus. No consistent changes in hemodynamic parameters of the (STZ-) normotensive and (STZ-) hypertensive rats were noted. The K(+)-normalization procedure yields the individual optimal lumen diameter, which was the same for the arteries of the four groups of rats. The passive wall tension resulting from this normalization procedure was higher only in preparations from the control hypertensive group as compared with those from the control normotensive rats. Morphological investigations showed that small arteries from control SHR had an increased tunica media thickness as compared with those of control WKY; the STZ-WKY had an increased tunica media thickness as compared with preparations from control WKY. The vasoconstriction caused by alpha 1-adrenoceptor stimulation [norepinephrine (NE), methoxamine] and serotonin is unchanged in chronic experimental diabetes. The diabetic state reduced the sensitivity [-log EC50(M)] for the concentration-response curves (CRC) of calcium chloride. The CRC of potassium chloride indicated the same sensitivities, but maximal active wall tensions of vessels from STZ-SHR were reduced as compared with those from STZ-WKY. The well-known enhancement of the effects of various contractile stimuli caused by hypertension could not be demonstrated for the isolated small arteries used in the present study, although a nonsignificant tendency was observed. However, the STZ-diabetic state did not cause important additional pharmacodynamic changes, despite the morphological alterations in those vessels.
We have studied the effects of both hypertension and streptozotocin-induced diabetes mellitus on α1-adrenoceptor mediated vasoconstriction, endothelium-dependent and endothelium-independent vasodilation. The experiments were performed in perfused mesenteric vascular bed preparations taken from age-matched SHR, WKY, diabetic SHR and diabetic WKY. For the α1-adrenoceptor agonist methoxamine, the mesenteric preparations from SHR and diabetic SHR yielded significantly (p < 0.05) stronger maximal responses than preparations taken from WKY and diabetic WKY, respectively. The diabetic state significantly (p < 0.05) decreased the responsiveness to methoxamine in arteries from SHR and WKY. Hypertension does not significantly change the concentration response-curves for (acetyl-β) methacholine, histamine, adenosine diphosphate and sodium-nitroprusside. However, the sensitivity to endothelium-dependent vasodilation decreased in preparations from diabetic animals (< 0.05). It is concluded that mesenteric resistance arteries from SHR and diabetic SHR are more reactive to α1-adrenoceptor stimulation, whereas diabetes reduces the responsiveness to methoxamine in WKY and SHR. Hypertension does not affect the endothelium-dependent relaxation in mesenteric arteries. However, diabetes decreases the sensitivity to endothelium-dependent relaxation without altering the sensitivity to sodium-nitroprusside. These findings are indicative of a diabetes-induced endothelial dysfunction in mesenteric resistance arteries. In preparations from diabetic hypertensive rats the reduced response to methoxamine and the endothelial dysfunction seem to run parallel.
Abstract: Device‐induced thrombogenesis was studied in an in vitro model using human blood circulated through an artificial ventricle. A new constant pressure filtration technique was used to detect circulating microemboli, the activated partial thromboplastin time (APTT) test was used to monitor the blood for the presence of anticoagulant activity of heparin, and hemolysis was quantified by measuring the plasma free hemoglobin level. Circulation of blood through a 20‐ml stroke volume pneumatically driven ventricle for 6‐9 h resulted in a significant reduction of APTT, indicating the loss of the anticoagulant effect of heparin. Microemboli concentration was minimal until the APTT decreased below 125 s, at which time the microemboli concentration increased rapidly. This was presumed to be due to the formation of thrombi following a decrease in heparin activity. A significant increase in hemolysis was also noted when blood was pumped. None of these changes was noted in the nonpumped control blood. Spontaneous loss of heparin activity in blood circulated by a pneumatically driven pump may have clinical implications and may help understanding of the problems associated with device‐induced thrombogenesis.
Historically, metformin was withheld before surgery for fear of metformin‐associated lactic acidosis. Currently, however, this risk is deemed to be low and guidelines have moved towards the continuation of metformin. We hypothesized that continuing metformin peri‐operatively would lower postoperative serum glucose level without an effect on plasma lactate levels. We performed a single‐blind multicentre randomized controlled trial in people with type 2 diabetes mellitus scheduled for non‐cardiac surgery and continued (MF+ group) or withheld (MF ‐ group) metformin before surgery. The main outcome measures were the differences in peri‐operative plasma glucose and lactate levels. We randomized 70 patients (37 MF+ group and 33 MF ‐ group) with type 2 diabetes mellitus. Postoperative glucose levels were similar in the MF+ and the MF ‐ groups (8.2 ± 1.8 vs 8.3 ± 2.3 mmol/L P = .95) Although preoperative lactate levels were slightly higher in the MF+ group compared with the MF ‐ group (1.5 vs 1.2 mmol/L; P = .02), the postoperative lactate levels were not significantly different (1.2 vs 1.0 mmol/L; P = .18). In conclusion, continuation of metformin during elective non‐cardiac surgery does not improve glucose control or raise lactate levels to a clinically relevant degree.
The constant-pressure filtration (CPF) method has been developed to assess blood microemboli (BME) in terms of their ability to occlude microvascular flow. Previous reports suggest that the method is sensitive to the effects of platelet stimulation and to blood-pumping conditions. BME production and heparin activity were studied in bovine and human blood pumped by a Pellethane ventricle with Pellethane molded valves connected via smooth quick-connects to a Pellethane horseshoe-shaped reservoir. In each experiment, blood was collected into heparin by cardiac puncture from a stunned animal or by venepuncture from a human donor. The blood from each donor was filled into three ventricle-reservoir systems (50 cc ventricle and 1,500 cc reservoir for the bovine blood, and 20 cc ventricle and 150 cc reservoir for the human blood). One of the systems received aspirin (ASA; 25 mg/dl) shortly after the onset of pumping, whereas the other two served as pumping and non-pumping controls. The blood was pumped in a full-fill/full-eject mode for up to 10 h. BME concentration was measured by the CPF method in which the blood was filtered through 20-microns pore filters at 20 mm Hg for 10 s, and the flowrate curves were evaluated from occlusion model. Heparin activity was measured by the activated partial thromboplastin time (APTT) test. In the early period after the onset of pumping, the BME concentration increased, whereas the APTT decreased from an initial value of greater than 250 s, with the relative rate of change for both the BME and the APTT being the following: pumping control greater than pumping ASA blood greater than quiescent control.(ABSTRACT TRUNCATED AT 250 WORDS)
Hüsken BCP, van der Wal AC, Teeling P, Mathy M-J, Mertens MJF, Pijl AJ, Pfaffendorf M, van Zwieten PA. Heterogeneity in morphological characteristics of coronary arteries and aortae in various models of hypertension.Objective: Hypertension is associated with important structural and functional changes in vascular smooth muscle. The question arises whether different vascular beds and different models of hypertension react similarly or in a heterogeneous manner to the hypertensive state. Methods: We quantitatively investigated the morphology of the coronary arteries and thoracic aortae taken from 4, 30 and 52-week-old spontaneously hypersensitive rats (SHR) and Wistar Kyoto rats (WKY), respectively, and from hypertensive rats with aortic stenosis (ASR). Results: In coronary arteries taken from the SHR the media area was slightly increased compared with those obtained from the age-matched WKY. Increasing age caused a significant increase in media area of the SHR vessels, but not in WKY tissues. No differences were found in the media area values of the coronary arteries obtained from the ASR compared with those obtained from SHAM (operated control rats) rats. The media area of the aortae taken from SHR was increased when compared with those from the age-matched WKY rats. In addition, the media area of the aortae from the surgically induced aortic stenosis rats (ASR) when compared with tissues from SHAM rats was significantly increased. Conclusions: Different animal models of hypertension appear to develop largely heterogeneous profiles of vascular hypertrophy, with different morphometric characteristics.
Editor, Spinal muscular atrophy (SMA) type III (Wohlfart–Kugelberg–Welander syndrome) is a progressive neuromuscular disorder that leads to degeneration of the anterior horn cells of the spinal cord.1 It is an autosomal recessive disease associated with deletions or mutations in the survivor motor neurone genes located on chr5q.2 Clinical manifestations are primarily muscle weakness of the extremities, initially presenting with an abnormal gait. With progression of the symptoms, the patient will ultimately become wheelchair-dependent. Progression of the disease may also involve the intercostal and accessory muscles of respiration resulting in respiratory failure. Respiratory complications are common and a cause for concern in the management of patients.3 Patients with the syndrome develop symptoms after 18 months of age and may have a normal life expectancy. The prognosis depends on the extent and timing of respiratory complications. A 62-year-old woman with SMA type III presented for laparoscopic cholecystectomy because of progressive biliary colic pain. She was wheelchair-bound as a result of severe limitations of the upper and lower extremities. She was only able to direct her electric wheelchair by moving one finger. She did not report difficulties with swallowing or breathing. Spirometry showed near-normal pulmonary function [maximum vital capacity 1.97 l (93% of predicted); forced vital capacity 1.79 (83% of predicted); forced expiratory volume in 1 s 1.49 l (83% of predicted)]. She did, however, show limitations in inspiratory and expiratory strength with maximal negative inspiratory pressure −70 cmH2O and maximal positive expiratory pressure +33 cmH2O. Blood pressure, electrocardiogram and chest radiograph showed no abnormalities. Capillary blood gas values were within normal limits. Prior to surgery, prophylactic physiotherapy was commenced using air-stacking techniques. Anaesthesia was induced using remifentanil and propofol target-controlled infusions. The depth of anaesthesia was evaluated using Bispectral index monitoring throughout the operation.4 The patient's trachea was intubated by direct laryngoscopy (Cormack–Lehane grade 1) without the use of muscular relaxants. Mechanical ventilation was commenced with an oxygen/air mixture (FiO2 0.45) through a circle system. The intra-abdominal carbon dioxide insufflation pressure was maintained at 12 mmHg during the laparoscopy. Airway pressure remained constant below 20 mmHg even after carbon dioxide insufflation and controlled ventilation was possible throughout the operation without the administration of any muscle relaxation. The surgeon reported optimal surgical conditions according to a five-point surgical rating scale.5 There was no cardiovascular or respiratory instability during the uneventful 55 min surgical procedure. After the procedure, the patient's trachea remained intubated and she was transferred to our ICU. She was ventilated with pressure support ventilation for a short period in the ICU. She quickly regained consciousness and tracheal extubation occurred within 30 min, with a normal breathing pattern and with no signs of respiratory fatigue. Postoperative analgesia was provided by paracetamol and diclofenac. No adverse effects, nausea, vomiting or pain, were reported and the patient was discharged in good condition on the next postoperative day. Experience with general anaesthesia in patients with SMA type III is limited. We were unable to find any previously published reports of general anaesthesia for laparoscopic operations in the English literature and studies specifically addressing the use of inhalational anaesthetic agents in these patients are lacking. Several reports, however, have been published that have demonstrated that propofol can be safely used in patients with SMA.6,7 A 25-year-old patient with SMA type III underwent urgent corneal grafting under general anaesthesia using a laryngeal mask and propofol-based intravenous anaesthetic without complications.6 Although propofol seems well tolerated for short interventions, prolonged anaesthesia with propofol in combination with lipolysis, perioperative fasting and decreased β-oxidation was hypothesised to have contributed to liver failure in a child with SMA type II.8 In this case, however, there were multiple contributory factors in addition to the prolonged duration and type of anaesthesia. As the use of muscle relaxants for tracheal intubation may cause problems in patients with SMA, we choose to use an approach without neuromuscular blockade. In this respect the major concern is the prolonged impairment of the bulbar and respiratory neuromuscular function, which can compromise the limited pulmonary reserve leading to acute respiratory failure. Depolarising muscle relaxants are not recommended because of the possible risk of inducing rhabdomyolysis and hyperkalemia.9 Sensitivity to nondepolarising muscle blockers, however, appears to vary. Cases have been described of prolonged residual muscle weakness despite the reversal of neuromuscular blockage.10 Additionally, train-of-four monitoring is not always reliable in patients with SMA.11 Although surgical conditions may be optimised by the use of neuromuscular blockade during laparascopic surgery,5 the patient in our report had such profound pre-existing muscle weakness that avoiding neuromuscular blocking drugs did not adversely effect the operative conditions. Furthermore, the effect of profound muscle relaxation in patients with SMA is unknown, because in the study of Martini et al.5 patients with neuromuscular disease were excluded. In addition to hypersensitivity to nondepolarising muscle relaxants it may also be possible that patients with SMA could be less sensitive to these agents. As a result of chronic denervation the composition of the endplate acetylcholine receptors can change from an adult into a foetal structure. These foetal-type receptors are more resistant to neuromuscular nondepolarising blocking agents.9 Instead of intubating the tracheal without neuromuscular blocking drugs, the reversal of neuromuscular blockade with sugammadex is a promising approach. Experience with sugammadex in SMA, however, is currently limited to a single case report that showed reversal of neuromuscular blockade without side-effects.12 Further studies using sugammadex in patients with SMA should be performed to confirm its safety and efficacy. Owing to concerns regarding possible respiratory complications as a result of general anaesthesia, our patient's biliary condition had been successfully managed pharmacologically for more than 20 years. Finally, however, her symptoms from gallstones had worsened and made surgical intervention inevitable. On the basis of the present case, we conclude that general anaesthesia for laparoscopic surgery can be safely performed in patients with SMA type III using short-acting anaesthetic agents without the use of muscle relaxants. Prior to surgery we suggest undertaking respiratory function tests and if possible, to start air-stacking techniques to try and minimise the risk of postoperative respiratory complications. Acknowledgements relating to this article Assistance with the letter: none. Financial support and sponsorship: none. Conflicts of interest: none.
Summary We compared two newer dihydropyridine-calcium antagonists (lacidipine and nisoldipine) with the classic prototype of this group, nifedipine, in the rat working heart preparation. The hearts were paced at a frequency of 5 Hz and perfused with Tyrode's solution of 37°C. The following five parameters were determined: left ventricular pressure (LVP), maximal rate of pressure increase ( + dP/dtmax), aortic output (AO), coronary blood flow (CBF), and cardiac output (CO). First, dose-response curves were constructed; from these data the EC50 concentration for the three calcium antagonists was calculated. Subsequently, washout from the cardiac tissue for these three compounds was determined. The effects of lacidipine did not diminish during <90-min washout, whereas the effects of nifedipine disappeared completely in 10 min. The effects of nisoldipine, however, disappeared partly in 10 min. In separate experiments, the antiischemic activity of the three calcium antagonists was analyzed, using low-flow ischemia. The calcium antagonists were used in a concentration that produced a 60% reduction in contractile force (EC60). Nifedipine and nisoldipine caused significant improvement in functional recovery. The antiischemic properties of lacidipine could not be shown because of its slow kinetic properties with accumulation in the membrane phase and slow kinetics with the channel. Nisoldipine and lacidipine appear to be more potent calcium antagonists as compared with nifedipine, whereas lacidipine displays a clearly different kinetic pattern in comparison to nifedipine and nisoldipine. In particular, the extremely slow onset and very long duration of action of lacidipine are of interest.
