Sodium-glucose co-transporter type-2 inhibitors: pharmacology and peri-operative considerations.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors are an emerging class of oral hypoglycaemic agents with therapeutic benefits beyond better glycaemic control. A major concern of the sodium-glucose co-transporter 2 inhibitors is their propensity to cause euglycaemic ketoacidosis in the peri-operative period and the potential for this critical diagnosis to be delayed or missed entirely. This review attempts to collate the case reports of sodium-glucose co-transporter 2 inhibitor ketoacidosis associated with surgery to highlight and put a perspective on this peri-operative issue. Preventive strategies and the management of the ketoacidosis are discussed.

The effects of haemodilution with hydroxyethyl starch 130/0.4 solution on coagulation as assessed by thromboelastography and platelet receptor function studies in vitro.

This study evaluated the effects of haemodilution with either 6% hydroxyethyl starch (HES) 130/0.4 (Voluven(®)) or 0.9% normal saline (NS) on blood coagulation in vitro. Haemodilution with 6% HES 130/0.4 impaired coagulation, as indicated by the changes in thromboelastographic parameters k-time, α-angle and maximum amplitude. Light transmission aggregometry and multiple electrode aggregometry demonstrated that impaired platelet receptor function occurred only at high levels of haemodilution (40%) with both fluids, but there was no significant difference between the two fluids (P=0.05). The thromboelastographic functional fibrinogen assay showed that the fibrinogen component of clot strength was significantly impaired with haemodilution with HES 130/0.4 compared with haemodilution with NS (whole blood [14.4 ± 4.6 mm] versus 40% HES dilution [3.7 ± 1.9], [P=0.001]; versus 40% NS dilution [10.4 ± 4.6], [P=0.129]). These findings suggest that there is little difference between HES or NS in relation to coagulation or platelet function during minor or moderate haemodilution, but at high levels of haemodilution with HES, fibrinogen activity is more impaired compared with NS.

The effects of haemodilution with albumin on coagulation in vitro as assessed by rotational thromboelastometry.

We investigated the in vitro viscoelastic changes of progressive haemodilution with 4% albumin compared with normal saline (NS) using rotational thromboelastometry (ROTEM(®), Pentapharm Co., Munich, Germany). Whole blood samples obtained from 20 healthy volunteers were diluted in vitro with 4% albumin or NS by 10%, 20% and 40%. Fibrinogen concentration and ROTEM(®) (EXTEM [screening test for the extrinsic haemostasis system], FIBTEM [EXTEM-based assay for the fibrin part of the clot]) variables including coagulation time, clot formation time (CFT), α-angle, maximum clot firmness and lysis index were measured in the undiluted sample and at each degree of haemodilution. There was no significant difference in fibrinogen concentration at equivalent haemodilutions with normal saline and 4% albumin solutions. Forty percent haemodilution with albumin significantly prolonged coagulation time (EXTEM P=0.007, FIBTEM P=0.0001) and significantly decreased lysis index (FIBTEM P=0.009) compared with NS. A significant decrease in maximum clot firmness from undiluted measurements (P=0.05) was observed at lower haemodilutions with albumin (20% with EXTEM, 10% with FIBTEM) compared with NS (40% with EXTEM and FIBTEM). The adverse effects of large degrees of haemodilution with 4% albumin solution are in excess of what can be explained by haemodilution alone. This study suggests that large degrees of haemodilution with albumin impair fibrinogen activity to a greater extent than equivalent degrees of haemodilution with NS.

Interventional neuroradiological procedures-a review for anaesthetists.

Interventional neuroradiology is a rapidly expanding field, and the complexity and duration of these procedures makes anaesthetic support essential to their success. Such has been the development in this area, that the American Heart Association has published a scientific statement on the indications for these procedures. A detailed understanding of patient pathology, the technical aspects of the interventions and their associated risks, and the remote location in which they are performed are important for providing expert anaesthetic care. The aim of this article is to provide a description and contemporary analysis of the common interventional neuroradiology procedures relevant to the anaesthetist. This article will cover the management of intracranial aneurysms, cerebral vasospasm following intracranial haemorrhage, intracranial and spinal arteriovenous malformations, idiopathic intracranial hypertension, carotid artery stenting, intra-arterial thrombolysis for stroke and endovascular treatment of intracranial atherosclerosis. Protection from ionising radiation and acute kidney injury are also discussed.

Ankylosing spondylitis: recent developments and anaesthetic implications.

Ankylosing spondylitis can present significant challenges to the anaesthetist as a consequence of the potential difficult airway, cardiovascular and respiratory complications, and the medications used to reduce pain and control the disease. There is also an increased risk of neurological complications in the peri-operative period. Awake fibreoptic intubation is the safest option in those patients with a potentially difficult airway as it allows continuous neurological monitoring while achieving a definitive airway. Neurophysiological monitoring (somatosensory and motor evoked potentials) should be considered in patients undergoing surgery for cervical spine deformity. The medical management of the disease has improved with the use of anti-tumour necrosis factor-alpha agents. There is potential for increased wound infection in patients taking these drugs. This article reviews the anaesthetic issues in patients with ankylosing spondylitis. The challenge to the anaesthetist is in the understanding of these issues so that appropriate management can be planned and undertaken.

Chlorhexidine--pharmacology and clinical applications.

Chlorhexidine is a widely used skin antisepsis preparation and is an ingredient in toothpaste and mouthwash. It is an especially effective antiseptic when combined with alcohol. Its antimicrobial effects persist because it is binds strongly to proteins in the skin and mucosa, making it an effective antiseptic ingredient for handwashing, skin preparation for surgery and the placement of intravascular access. Catheters impregnated with chlorhexidine and antimicrobial agents can reduce the incidence of catheter-related bloodstream infections. Contact dermatitis related to chlorhexidine is not common in health care workers. The incidence of contact dermatitis to chlorhexidine in atopic patients is approximately 2.5 to 5.4%. Acute hypersensitivity reactions to chlorhexidine are often not recognised and therefore may be underreported. This review discusses the pharmacology, microbiology, clinical applications and adverse effects of chlorhexidine.

Intravascular iodinated contrast media and the anaesthetist.

The use of intravascular iodinated contrast media (ICM) in radiological investigations is common. Increasingly, anaesthetists and intensivists are involved in the care of patients undergoing these investigations. Whilst the use of ICM is generally safe there are important adverse effects that need to be recognised and measures instigated to prevent or treat these effects. In patients at risk of developing adverse reactions it is important to consider alternative modes of imaging so that ICM can be avoided. Strategies for the prevention of ICM nephropathy should be considered in all patients receiving ICM. Currently intravascular volume expansion with 0.9% saline has the strongest evidence base. The use of isotonic sodium bicarbonate combined with N-acetylcysteine appears promising in providing further benefits. Although the use of N-acetylcysteine alone has not been shown to significantly reduce the incidence of ICM nephropathy it is cheap, has few adverse effects and it would seem reasonable to continue its use in conjunction with intravascular volume expansion. The routine use of corticosteroid and antihistamine premedication is not always effective in preventing general adverse reactions.

Botulinum toxin: pharmacology and clinical developments: a literature review.

Botulinum toxin is used as first line therapy for some muscular disorders, and is efficacious in treating hypersecretory and some pain syndromes. When used appropriately it has a good safety profile. It has been evaluated in treating a number of conditions that as yet do not have obvious effective or beneficial treatment. With the greater acceptance and use of botulinum toxin therapy for cosmetic purposes, botulinum toxin use will increase. An understanding of the pharmacology, and potential adverse effects is essential for the physician when managing patients having or who would benefit from botulinum toxin therapy.

Propofol infusion syndrome.

The clinical features of propofol infusion syndrome (PRIS) are acute refractory bradycardia leading to asystole, in the presence of one or more of the following: metabolic acidosis (base deficit > 10 mmol.l(-1)), rhabdomyolysis, hyperlipidaemia, and enlarged or fatty liver. There is an association between PRIS and propofol infusions at doses higher than 4 mg.kg(-1).h(-1) for greater than 48 h duration. Sixty-one patients with PRIS have been recorded in the literature, with deaths in 20 paediatric and 18 adult patients. Seven of these patients (four paediatric and three adult patients) developed PRIS during anaesthesia. It is proposed that the syndrome may be caused by either a direct mitochondrial respiratory chain inhibition or impaired mitochondrial fatty acid metabolism mediated by propofol. An early sign of cardiac instability associated with the syndrome is the development of right bundle branch block with convex-curved ('coved type') ST elevation in the right praecordial leads (V1 to V3) of the electrocardiogram. Predisposing factors include young age, severe critical illness of central nervous system or respiratory origin, exogenous catecholamine or glucocorticoid administration, inadequate carbohydrate intake and subclinical mitochondrial disease. Treatment options are limited. Haemodialysis or haemoperfusion with cardiorespiratory support has been the most successful treatment.

Transfusion-related acute lung injury: a literature review.

Transfusion-related acute lung injury (TRALI) is a serious and potentially fatal complication of transfusion of blood and blood components. TRALI is under-diagnosed and under-reported because of a lack of awareness. A number of models have been proposed to explain the pathogenesis of TRALI: an antibody mediated model; a two-event biologically active mediator model; and a combined model. TRALI can occur with any type of blood product and can occur with as little as one unit. Its presentation is similar to other forms of acute lung injury and management is predominantly supportive. The main strategy in combating TRALI is prevention both through manipulation of the donor pool and through clinical strategies directed at reducing transfusion of blood products including, but not limited to, evidence-based lower transfusion thresholds. This article presents a review of TRALI and addresses the definition, pathology, pathogenesis, clinical manifestations, treatment and prevention of the syndrome.

Obesity: basic science and medical aspects relevant to anaesthetists.

Obesity is becoming a major public health problem throughout the world. It is now the second leading cause of death in the United States and is associated with significant, potentially life-threatening co-morbidities. Significant advances in the understanding of the physiology of body weight regulation and the pathogenesis of obesity have been achieved. A better understanding of the physiology of appetite control has enabled advances in the medical and surgical treatment of obesity. Visceral or abdominal obesity is associated with an increased risk of cardiovascular disease and type 2 diabetes. Various drugs are used in the treatment of mild obesity but they are associated with adverse effects. Surgery has become an essential part of the treatment of morbid obesity, notwithstanding the potential adverse events that accompany it. An appreciation of these problems is essential to the anaesthetist and intensivist involved in the management of this group of patients.

An unexpected cause of an acute hypersensitivity reaction during recovery from anaesthesia.

Acute hypersensitivity reactions to chlorhexidine in the operating room are probably more likely to occur during the early phases of anaesthesia because chlorhexidine is often used for cleaning the surgical field or during placement of indwelling catheters. We report a case of an acute hypersensitivity reaction that occurred in the post anaesthetic care unit. Subsequent skin testing suggested sensitivity to chlorhexidine, which had been applied over the vaginal mucosa at the end of surgery. Relevant issues in the investigation of acute hypersensitivity reactions in the post anaesthetic period are discussed.

Anabolic steroid abuse: physiological and anaesthetic considerations.

This review summarises the physiological and pharmacological effects of the anabolic steroids used to enhance performance in sports. The anabolic steroids promote muscle growth and protein synthesis. Side-effects of anabolic steroids include cardiomyopathy, atherosclerosis, hypercoagulopathy, hepatic dysfunction, and psychiatric and behavioural disturbances. It is therefore appropriate that the anaesthetist be familiar with the abuse of anabolic steroids, their potential adverse effects, and the peri-operative risk associated with the use of these drugs.

Direct thrombin inhibitors: pharmacology and clinical relevance.

Although heparin has been a cornerstone of treatment for the prevention of thrombosis, it is limited by its adverse effects and unpredictable bioavailability. Direct thrombin inhibitors are a novel class of drugs that have been developed as an effective alternative mode of anticoagulation in patients who suffer from heparin-induced thrombocytopaenia, and for the management of thromboembolic disorders and acute coronary syndromes. The main disadvantages of the direct thrombin inhibitors are the lack of an antidote or readily available clinical monitoring. The mechanism of action, the properties of direct thrombin inhibitors and their potential to replace currently available anticoagulants are reviewed.

Isolated limb infusion with fotemustine after dacarbazine chemosensitisation for inoperable loco-regional melanoma recurrence.

BACKGROUND: Isolated limb infusion (ILI) is a simple yet effective alternative to conventional isolated limb perfusion for the treatment of advanced melanoma of the extremities. PATIENTS AND METHODS: The study group comprised 13 patients with very advanced limb disease who had failed to achieve a satisfactory response to one or more ILIs with melphalan, and in whom amputation was the only other realistic treatment option. The aim of this study was to evaluate the efficacy and toxicity of ILI with fotemustine after systemic chemosensitisation with dacarbazine (DTIC). RESULTS: Complete remission was achieved in four patients and partial remission in eight patients, with a median response duration of 3 months. Limb salvage was achieved in five of 12 assessable patients (42%). Limb toxicity peaked 9 days after ILI; two patients experienced Wieberdink grade IV (severe) toxicity and four patients had grade V toxicity (requiring early amputation). CONCLUSIONS: ILI with fotemustine after DTIC chemosensitisation can be successful when gross limb disease has not been controlled by one or more ILIs with melphalan. However, it cannot be recommended as a routine method of treatment for advanced melanoma of the extremities because of the high incidence of severe limb toxicity.

Vasopressin and terlipressin: pharmacology and its clinical relevance.

Vasopressin and its analogue, terlipressin, are potent vasopressors that may be useful therapeutic agents in the treatment of cardiac arrest, septic and catecholamine-resistant shock and oesophageal variceal haemorrhage. The aim of this article is to review the physiology and pharmacology of vasopressin and summarise its efficacy and safety in clinical trials and its subsequent therapeutic use. Recent studies indicate that the use of vasopressin during cardiopulmonary resuscitation may improve the survival of patients with asystolic cardiac arrest. Vasopressin deficiency can contribute to refractory shock states associated with sepsis, cardiogenic shock and cardiac arrest. Low doses of vasopressin and terlipressin can restore vasomotor tone in conditions that are resistant to catecholamines, with preservation of renal blood flow and urine output. They are also useful in reducing bleeding and mortality associated with oesophageal variceal haemorrhage. The long-term outcome of the use of these drugs is not known.

Mast cell tryptase: a review of its physiology and clinical significance.

Mast cells, which are granulocytes found in peripheral tissue, play a central role in inflammatory and immediate allergic reactions. beta-Tryptase is a neutral serine protease and is the most abundant mediator stored in mast cell granules. The release of beta-tryptase from the secretory granules is a characteristic feature of mast cell degranulation. While its biological function has not been fully clarified, mast cell beta-tryptase has an important role in inflammation and serves as a marker of mast cell activation. beta-Tryptase activates the protease activated receptor type 2. It is involved in airway homeostasis, vascular relaxation and contraction, gastrointestinal smooth muscle activity and intestinal transport, and coagulation. Serum mast cell beta-tryptase concentration is increased in anaphylaxis and in other allergic conditions. It is increased in systemic mastocytosis and other haematological conditions. Serum beta-tryptase measurements can be used to distinguish mast cell-dependent reactions from other systemic disturbances such as cardiogenic shock, which can present with similar clinical manifestations. Increased beta-tryptase levels are highly suggestive of an immunologically mediated reaction but may also occur following direct mast cell activation. Patients with increased mast cell beta-tryptase levels must be investigated for an allergic cause. However, patients without increased mast cell tryptase levels should be investigated if the clinical picture suggests severe anaphylaxis.

Tissue factor and tissue factor pathway inhibitor.

The classical 'cascade/waterfall' hypothesis formulated to explain in vitro coagulation organised the amplification processes into the intrinsic and extrinsic pathways. Recent molecular biology and clinical data indicate that tissue factor/factor-VII interaction is the primary cellular initiator of coagulation in vivo. The process of blood coagulation is divided into an initiation phase followed by a propagation phase. The discovery of tissue factor pathway inhibitor further supports the revised theory of coagulation. Tissue factor is also a signalling receptor. Recent evidence has shown that blood-borne tissue factor has an important procoagulant function in sepsis, atherosclerosis and cancer, and other functions beyond haemostasis such as immune function and metastases.