P. C. A. Kam

Apoptosis: mechanisms and clinical implications

The balance between cell survival and death is under tight genetic control. A multiplicity of extracellular signals and intracellular mediators is involved in maintaining this balance. When the cell is exposed to physical, biochemical or biological injury, or deprived of necessary substances, it activates a series of stress‐response genes. With minimal insults, the cell may recover. With greater insults, single cell death, or apoptosis, results; the cell dies and is recycled to its neighbours. If the insult overwhelms a large number of cells then necrosis ensues, with an accompanying inflammatory response. Dysregulation of the controlling mechanisms of this system results in disease. Deficient apoptosis is associated with cancer, auto‐immunity and viral infections. Excessive apoptosis is associated with ischaemic heart disease, stroke, neurodegenerative disease, sepsis and multiple organ dysfunction syndrome. There are myriad therapeutic options unfolding as understanding is gained of apoptosis and its control.

Gabapentin: pharmacology and its use in pain management

Summary Although its exact mode of action is not known, gabapentin appears to have a unique effect on voltage‐dependent calcium ion channels at the postsynaptic dorsal horns and may, therefore, interrupt the series of events that possibly leads to the experience of a neuropathic pain sensation. Gabapentin is especially effective at relieving allodynia and hyperalgesia in animal models. It has been shown to be efficacious in numerous small clinical studies and case reports in a wide variety of pain syndromes. Gabapentin has been clearly demonstrated to be effective for the treatment of neuropathic pain in diabetic neuropathy and postherpetic neuralgia. This evidence, combined with its favourable side‐effect profile in various patient groups (including the elderly) and lack of drug interactions, makes it an attractive agent. Therefore, gabapentin should be considered an important drug in the management of neuropathic pain syndromes.

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.

ISOLATED LIMB INFUSION WITH CYTOTOXIC AGENTS : A SIMPLE ALTERNATIVE TO ISOLATED LIMB PERFUSION

Isolated limb perfusion (ILP) with cytotoxic agents is an effective but complex procedure. Isolated limb infusion (ILI) has been developed as a simpler alternative. Catheters are inserted percutaneously into the axial artery and vein of the affected limb and a pneumatic tourniquet is inflated proximally. Cytotoxic agents are then infused through the arterial catheter and circulated with a syringe for 15 to 20 minutes. Progressive hypoxia occurs, but normothermia is maintained. To date, 175 ILIs have been performed: 164 for melanoma and 11 for other tumours. Results obtained are similar to those obtained by conventional ILP. Morbidity is low and treatment of frail and elderly patients who would not tolerate ILP is possible. An elective double ILI protocol can be used to obtain the additional benefits of fractionated chemotherapy. The possibility of increasing ILI response rates by using other drugs and drug combinations and by multiple fractionated dosing is being investigated.

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. β‐Tryptase is a neutral serine protease and is the most abundant mediator stored in mast cell granules. The release of β‐tryptase from the secretory granules is a characteristic feature of mast cell degranulation. While its biological function has not been fully clarified, mast cell β‐tryptase has an important role in inflammation and serves as a marker of mast cell activation. β‐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 β‐tryptase concentration is increased in anaphylaxis and in other allergic conditions. It is increased in systemic mastocytosis and other haematological conditions. Serum β‐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 β‐tryptase levels are highly suggestive of an immunologically mediated reaction but may also occur following direct mast cell activation. Patients with increased mast cell β‐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.

Prognostic factors after isolated limb infusion with cytotoxic agents for melanoma.

BackgroundIsolated limb perfusion (ILP) with cytotoxic agents is a remarkably effective but complex technique used to treat locally recurrent and metastatic melanoma confined to a limb. Isolated limb infusion (ILI), essentially a low-flow ILP performed without oxygenation via percutaneous catheters, has been developed as a simpler alternative.MethodsThe outcome in 135 patients treated by ILI was reviewed.ResultsThe overall response rate in the treated limb was 85% (complete response [CR] rate 41%, partial response rate 44%). Median response duration response was 16 months (24 months for patients with CR). Median patient survival was 34 months. In those with a CR, the median survival was 42 months. CR rate and survival time decreased with increasing disease stage. Patients aged >70 years had a better overall response than younger patients. On multivariate analysis, factors associated with an improved outcome were a lower stage of disease, a final limb temperature >37.8°C, and a tourniquet time >40 minutes.ConclusionsThe frequency and duration of responses after ILI were comparable to those achieved by conventional ILP. The ILI technique is particularly useful for older patients who might not be considered suitable for conventional ILP.

The thienopyridine derivatives (platelet adenosine diphosphate receptor antagonists), pharmacology and clinical developments

Summary The thienopyridines, ticlopidine and clopidogrel, are antiplatelet drugs. They are prodrugs and are metabolised in the liver to active metabolites that are non‐competitive antagonists of the platelet adenosine diphosphate receptor, P2Y12. Inhibition of platelet aggregation by these drugs is delayed until 24–48 h after administration, with maximal inhibition achieved after 3–5 days. Recovery of platelet function after drug withdrawal is slow (7–14 days). Ticlopidine and clopidogrel are effective in preventing atherothrombotic events in cardiovascular, cerebrovascular and peripheral vascular disease. Gastrointestinal side effects and skin rashes are common. However, neutropenia and thrombotic thrombocytopenic purpura are significant and sometimes fatal adverse effects of ticlopidine. Clopidogrel appears to offer several advantages over ticlopidine: a more rapid onset of action and a lower incidence of neutropenia and thrombotic thrombocytopenic purpura.A combination of clopidogrel and aspirin has become standard for antithrombotic therapy in cardiovascular disease. The anaesthetic considerations of patients taking the thienopyridine compounds are discussed.

Gamma-hydroxybutyric acid: an emerging recreational drug

Gamma‐hydroxybutyric acid (GHB) is no longer used as an anaesthetic induction agent because of the high incidence of myoclonic seizures and vomiting. However, it is used occasionally in Europe for the treatment of narcolepsy, alcohol dependence and opiate dependence. Since the early 1990s, GHB has become a drug of abuse in youths for its euphoric, sedative and anabolic effects. Common adverse effects include a rapid onset of drowsiness, nausea, vomiting, myoclonic seizures and coma of short duration. Clinicians should be alert for these adverse effects and consider the possibility of GHB abuse in young adults with unusual clinical presentations in the emergency department.

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.

Noise pollution in the anaesthetic and intensive care environment

Noise in the operating theatre, recovery room and intensive care unit is above internationally recommended levels. The psychological and physiological effects of noise are reviewed. Equipment and conversation among the staff are major sources of noise in these areas. Equipment design, modification of nursing care procedures, and increased awareness of noise created by the staff may be effective in reducing noise pollution in these areas.