Anaesthetic agents for thoracic surgery: what s best?

Transcription

1 REVIEW C URRENT OPINION Anaesthetic agents for thoracic surgery: what s best? David J.R. Duthie Purpose of review Pneumonectomy is still associated with a 5% 30-day mortality in a large series involving a variety of anaesthetic agents and techniques. Recent findings As well as the immediate anaesthetic complications of pain, nausea and vomiting and respiratory dysfunction, differences between anaesthetic agents have emerged in systemic inflammation, postoperative cognitive dysfunction, immune suppression and cell signalling after surgery. Summary No one anaesthetic agent has emerged as best. There is a trade-off between initial success and long-term problems or vice versa. Keywords adverse effects, anaesthetic agent, outcome, thoracic anaesthesia INTRODUCTION Beyond the universal requirements to maintain oxygenation, a stable circulation, temperature, glycaemic control and give prophylactic antibiotics to prevent wound infection, thoracic anaesthesia presents particular challenges for airway management, one-lung ventilation in the presence of parenchymal lung disease and the potential for massive haemorrhage. The thoracotomy wound generates severe pain, difficult to control after surgery, and the patient may be experiencing the immediate pulmonary consequences of anaesthesia and surgery with less lung tissue than before surgery. To perform surgery without patients feeling pain, volatile anaesthetic agents and nitrous oxide held sway for about 100 years until intravenous anaesthetics were introduced in the 1930s, just at the time open lung resections were being performed. The choice of agents now lies principally between the newer volatile anaesthetic agents and intravenous anaesthesia with propofol, with or without regional analgesia and opioids. Much of the work comparing these agents has been done in the laboratory and in other surgical specialities and has to be extrapolated to make choices in thoracic anaesthesia. Although the apparent efficacy and safety of anaesthesia has improved, secondary effects affecting inflammation, immunity and cell biology are causing unexpected outcomes that are now being recognized. NAUSEA AND VOMITING Maintenance of anaesthesia with propofol is followed by less postoperative nausea and vomiting than volatile anaesthetic agents. This difference exists regardless of the induction agent, volatile agent used with or without nitrous oxide, age of patient and dose of opioid [1]. Propofol has clinically important direct antiemetic properties [2] and has a direct inhibitory effect on 5-HT 3A receptors [3] consistent with its antiemetic properties [4]. NITROUS OXIDE Nitrous oxide use worsens nausea and vomiting after surgery [5,6], and because of this, and its inactivation of vitamin B 12, inhibition of methionine synthase with accumulation of homocysteine [7] and myelopathy [8], its use has declined. Nitrous Leeds General Infirmary, Leeds, UK Correspondence to David J.R. Duthie, MD, FRCA, FFICM, Leeds General Infirmary, Great George Street, Leeds LS1 3EX, UK. duthie@doctors.org.uk Curr Opin Anesthesiol 2013, 26:53 57 DOI: /ACO.0b013e32835bcff ß 2013 Wolters Kluwer Health Lippincott Williams Wilkins

2 Thoracic anesthesia KEY POINTS The key component of reversible loss of consciousness that characterizes clinical anaesthesia conceals unexpected long-term consequences. These consequences include systemic inflammation, postoperative cognitive dysfunction, immune suppression and alterations in cell signalling. Different anaesthetic agents affect the endothelial glycocalyx, apoptosis, cytotoxic lymphocytes, gene expression and transcription differently. No one anaesthetic agent is indicated. There is a compromise between initial success and long-term damage or vice versa. oxide is avoided often in thoracic anaesthesia because it diffuses into and enlarges airspaces [9]. It has been given no place in anaesthesia for surgery of emphysema [10]. However, despite its known side-effects, hospital stay and mortality have not been demonstrated to be worse in noncardiac surgery with nitrous oxide, and there have been reports of fewer respiratory complications with its use and a reduced morbidity and in-hospital mortality in patients who received nitrous oxide compared with those who did not [11,12 ]. AWARENESS Different studies of over 4000 patients have found either double the incidence of awareness with propofol [13] or no difference between propofol and volatile agents [14]. The effect response curves for a given infusion rate of propofol are much wider than the effect response curve for a set inhaled concentration of a volatile anaesthetic agent. Distribution, metabolism and excretion of propofol introduce more variability than the physical processes of ventilation, uptake and exhalation of volatile agents. At the upper end of these curves, there are dose-related side-effects such as hypotension and at the lower end is awareness. A minimum alveolar concentration of 0.5 of the volatile agent and 2.5 mg/kg/h of propofol are guides to avoid awareness [15]. The depth of anaesthesia monitors that are available currently are inadequate to predict awareness reliably [16,17]. The National Audit Project in the UK, (NAP5), will examine unintentional awareness under anaesthesia [18 ]. HYPOXIC PULMONARY VASOCONSTRICTION Experimentally, the pulmonary artery smooth muscle cell contracts in response to cellular hypoxia [19 ]. Volatile agents abolish this protective mechanism, whereas it is preserved using propofol in the laboratory. Attractive as it would be to preserve hypoxic pulmonary vasoconstriction during onelung anaesthesia, these results have not been reproduced in clinical practice [20]. Arterial oxygen tensions show an early and sustained fall during onelung anaesthesia that is no different whether propofol or volatile agents are used to maintain anaesthesia [21]. INFLAMMATION Regardless of the effects of the surgery, the act of occluding a bronchus is followed by an inflammatory response in the lung on re-expansion. The magnitude of the response is proportionate to the duration of lung collapse, and the inflammatory changes can be detected systemically [22 ]. Volatile agents, but not propofol, can reduce the expression of inflammatory mediators such as tumour necrosis factor, interleukin-8 and interleukin-1b into bronchoalveolar lavage fluid [23,24]. When these finding were related to the clinical course of thoracotomy patients, there were significantly more inflammatory and infective complications in the patients given propofol than those anaesthetised with sevoflurane [24]. There were no more deaths, but there were significantly more surgical interventions, prolonged hospital stay and antibiotic requirements in the propofol group. One explanation for this could be damage to the glycocalyx layer that lines the endothelium. This is a covering of transmembrane and membrane-bound molecules of heparan sulphate and syndecan-1 that combine with plasma proteins and dissolved glycosaminoglycans to retain part of the intravascular plasma volume stationary against the endothelium. With a frond-like appearance of a sea anemone against the endothelial wall, this combination of molecules and plasma presents a barrier to permeability across the endothelium. Loss of this barrier leads to an increase in capillary permeability and oedema, with subsequent inflammation and infection [25,26 ]. Volatile anaesthetic agents but not propofol protect the endothelial glycocalyx and preserve its integrity after episodes of ischaemia reperfusion [24,27 ]. COGNITIVE DYSFUNCTION AND ALZHEIMER S DISEASE Postoperative cognitive dysfunction after anaesthesia and surgery impairs memory, concentration and learning. There is usually an improvement over 54 Volume 26 Number 1 February 2013

3 Anaesthetic agents for thoracic surgery Duthie time, but cognitive dysfunction may be permanent [28,29]. Permanent cognitive dysfunction raises the possibility that anaesthetic agents promote dementia. Brains of patients with Alzheimer s disease accumulate b-amyloid plaques and tau tangles, with a loss of neurones, synapses, brain size and function [30]. Volatile agents have been associated with cognitive dysfunction after anaesthesia and surgery [31]. Experimental in-vivo and in-vitro studies in human H4 neuroglioma cells and in mice demonstrate that sevoflurane induces apoptosis and caspase activation in brain cells. It enhances b-site amyloid precursor protein-cleaving enzyme and Ab concentrations. These increased Ab concentrations induce further rounds of apoptosis and cell death [32]. This is not a class effect. Isoflurane but not desflurane opens mitochondrial permeable transition pores (mptp), increases reactive oxygen species and activates caspase 3. Relating these experimental findings to outcome studies in humans has yet to demonstrate a causal relationship. Older patients are more likely to be found to have dementia after anaesthesia and surgery, but anaesthesia has yet to demonstrate a new onset of dementia, progression of clinical features or a difference in onset of dementia between different anaesthetic techniques [33,34]. IMMUNE SUPPRESSION A large part of thoracic surgical practice is resection of lung cancer. Many cancer deaths are due to metastases and not the primary lung tumour, and resection of the primary tumour is potentially curative [35 ]. However, surgery itself can promote metastasis. Tumour cells can be shed during resection and there can be suppression of factors that limit new vessel growth, and suppression of antimetastatic immunity [36]. The systemic effects of anaesthetics can also have a bearing on cancer immunity [37]. A systemic effect affected by an anaesthetic technique has been demonstrated from patients having localized surgery. Serum taken from women having breast cancer surgery under either propofol and paravertebral analgesia or sevoflurane and opioids was then incubated with the MDA-MB-231 breast carcinoma cell line. With propofol and paravertebral analgesia, but not sevoflurane, there was inhibition of cell proliferation. Cell migration was unaffected [37]. Throughout life, there is a constant immunosurveillance. Cytotoxic lymphocytes that are a subset of the cell-mediated immunity system, natural killer cells, are prominent in this role. Promotion or inhibition of these natural killer cells may influence disease progression and survival [36]. Fischer rats anaesthetised for 1 h with one of ketamine, thiopentone, halothane or propofol demonstrated a reduction in natural killer cell activity, increased MADB106 lung tumour retention and lung metastases for all anaesthetic agents except propofol [38]. Sevoflurane has had less effect on T cell populations than desflurane during abdominal surgery [39]. Neuraxial blockade has not been demonstrated to have a consistent effect on natural killer cell function [40 ], and in abdominal surgery for colon cancer, using epidural analgesia was not associated with improved cancer-free survival [41 ]. Intravenous anaesthesia with propofol may have a protective role. DIRECT NONIMMUNE EFFECTS Volatile anaesthetic agents have been shown to modulate gene expression in breast and brain tumour cell cultures in a specific and time-dependent manner, allowing cells to proliferate more rapidly [42]. Gene expression has been used to predict outcome and direct treatment; so, alterations can influence the progression of the disease itself and choices made to manage it. Expression of factors influencing angiogenesis can be affected by the choice of anaesthetic agent. Vascular endothelial growth factor C (VEGF-C) was increased in patients given volatile agents instead of paravertebral block and propofol [43] promoting tumour angiogenesis. In contrast, transforming growth factor b (TGF-b) concentrations fell in patients given volatile agents [43]. Both factors are recognized to increase angiogenesis in tumours and promote metastasis. Damage to the basement membrane is necessary to allow epithelial tumours to invade locally. The family of matrix metalloproteinases (MMP) are agents that promote damage to the basement membrane as tumours grow. In patients undergoing breast surgery under anaesthesia using volatile agents with morphine and not paravertebral block and propofol, increased concentrations of MMP-3 and MMP-9 but not MMP-1 were measured. REGIONAL ANALGESIA Paravertebral block to treat pain after thoracotomy has analgesic and functional benefits postoperatively, and can avoid some of the adverse effects of thoracic epidural analgesia [44,45], but benefits on disease progression are more difficult to demonstrate [46]. Improved 5-year survival after colon cancer has been found in 22.9% of patients given epidural ß 2013 Wolters Kluwer Health Lippincott Williams Wilkins 55

4 Thoracic anesthesia analgesia, but cancer recurrence in patients was not affected [47 ]. Regional analgesia has not been ascribed an innate effect but may exert an effect by reducing the amount of volatile anaesthetic and opioid use and reducing the stress of surgery. The contribution of morphine to tumour recurrence and metastasis is inconclusive [48]. Animal experiments have suggested a reduction in cancer growth using regional analgesia [49], but cancer recurrence has not been affected [50]. In humans, most studies are retrospective [51]. CELL SIGNALLING Anaesthetic agents are known to induce pharmacological protection to cell hypoxia in a corresponding way in which hypoxic preconditioning can protect cells from damage during a subsequent episode of hypoxia [35 ]. Hypoxia-inducible factors are involved in both processes [52,53]. They accumulate in the cytoplasm, translocate into the nucleus where they bind to signalling genes and promote the transcription of these genes to generate mrna. This mrna is then involved in the generation of factors that are essential for protection in health such as surfactant [54 ], but when co-opted by cancer cells, can promote angiogenesis, proliferation and metastasis of tumour cells [35 ]. Upregulation of hypoxia-inducible factors is associated with spread and metastasis of cancer cells. Anaesthetic agents that have the same effect on hypoxia-inducible factor would be expected [55] to offer protection from ischaemic cell injury [56], but worsen outcome in a malignant disease [57]. CONCLUSION Which to choose? There is no best anaesthetic agent for thoracic surgery. Regional analgesia provides effective pain relief and limits the need for opioids, but thoracic epidural analgesia is associated with complications. Volatile anaesthetic agents are associated with less awareness and reduce the inflammation and infective consequences of surgery that cause early morbidity and mortality. Intravenous propofol is less able to preserve the glycocalyx and limit inflammatory injury, but is not associated with the long-term cognitive dysfunction and Alzheimer s disease and tumour progression and metastases associated with volatile agents. But similar to nitrous oxide, by avoiding the known, characterized side-effects of some anaesthetic agents, the alternatives may expose patients to worse outcomes. Acknowledgements None. Conflicts of interest There are no conflicts of interest. REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 101). 1. 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