Glucagon-like peptide-1 receptor agonists: a narrative review of clinical pharmacology and implications for peri-operative practice.

BACKGROUND: Glucagon-like peptide-1 receptor agonists are used increasingly in the management of patients living with type 2 diabetes mellitus and obesity. In patients using glucagon-like peptide-1 receptor agonists, a key concern in the peri-operative period is the increased risk of pulmonary aspiration due to delayed gastric emptying. This review provides an overview of the pharmacodynamic and pharmacokinetic properties of glucagon-like peptide-1 receptor agonists and the risk of delayed gastric emptying and aspiration. METHODS: We conducted searches of MEDLINE and EMBASE databases of articles published before January 2024 using the keywords and medical subject headings: incretins; glucagon-like peptide-1; GLP-1; glucagon-like peptide-1 receptor agonists; GLP-1 RA; peri-operative period; perioperative; peri-operative; stomach emptying; gastric emptying; pulmonary aspiration; aspiration; food regurgitation; and regurgitation. The evidence was analysed, synthesised and reported narratively. RESULTS: A total of 1213 articles were located after duplicates were removed. Two authors screened the titles and abstracts to identify those studies which assessed specifically the risk of delayed gastric emptying and pulmonary aspiration or regurgitation in the peri-operative period. We searched manually the reference lists of relevant studies to identify any additional case reports. Ten studies were identified. Available evidence was limited to case reports, case series and observational work. CONCLUSIONS: There is insufficient evidence to put forward definitive guidance regarding the ideal cessation period for glucagon-like peptide-1 receptor agonists before elective surgery. Precautionary practice is required until more evidence becomes available. We suggest an individualised, evidence-based approach. In patients living with type 2 diabetes mellitus, there is concern that prolonged cessation before surgery will have a detrimental effect on peri-operative glycaemic control and discussion with an endocrinologist is advised. For patients taking glucagon-like peptide-1 receptor agonists for weight management, these drugs should be withheld for at least three half-lives before an elective surgical procedure.

Association between intraoperative oliguria and postoperative acute kidney injury in non-cardiac surgical patients: a systematic review and meta-analysis.

PURPOSE: This systematic review and meta-analysis aimed to evaluate the association between intraoperative oliguria and the risk of postoperative acute kidney injury (AKI) in patients undergoing non-cardiac surgery. METHODS: The MEDLINE and EMBASE databases were searched up to August 2022 for studies in adult patients undergoing non-cardiac surgery, where the association between intraoperative urine output and the risk of postoperative AKI was assessed. Both randomised and non-randomised studies were eligible for inclusion. Study selection and risk of bias assessment were independently performed by two investigators. The risk of bias was evaluated using the Newcastle-Ottawa scale. We performed meta-analysis of the reported multivariate adjusted odds ratios for the association between intraoperative oliguria (defined as urine output < 0.5 mL/kg/hr) and the risk of postoperative AKI using the inverse-variance method with random effects models. We conducted sensitivity analyses using varying definitions of oliguria as well as by pooling unadjusted odds ratios to establish the robustness of the primary meta-analysis. We also conducted subgroup analyses according to surgery type and definition of AKI to explore potential sources of clinical or methodological heterogeneity. RESULTS: Eleven studies (total 49,252 patients from 11 observational studies including a post hoc analysis of a randomised controlled trial) met the selection criteria. Seven of these studies contributed data from a total 17,148 patients to the primary meta-analysis. Intraoperative oliguria was associated with a significantly elevated risk of postoperative AKI (pooled adjusted odds ratio [OR] 1.74; 95% confidence interval [CI] 1.36-2.23, p < 0.0001, 8 studies). Sensitivity analyses supported the robustness of the primary meta-analysis. There was no evidence of any significant subgroup differences according to surgery type or definition of AKI. CONCLUSIONS: This study demonstrated a significant association between intraoperative oliguria and the risk of postoperative AKI, regardless of the definitions of oliguria or AKI used. Further prospective and multi-centre studies using standardised definitions of intraoperative oliguria are required to define the thresholds of oliguria and establish strategies to minimise the risk of AKI.

Treatment of in-transit Merkel cell carcinoma by isolated limb infusion with cytotoxic drugs.

Merkel cell carcinoma of the skin is a rare but aggressive malignancy, which predominantly affects older adults with fair skin. Isolated limb infusion (ILI) using melphalan and actinomycin D was first developed as a minimally invasive treatment option to treat unresectable metastatic melanoma confined to the limb. We report on a 62-year-old male with in-transit metastases (ITMs) treated with ILI to highlight the ongoing role this treatment has when all other therapies have been exhausted. At presentation, the patient had widespread ITMs in the right leg. Positron emission tomography scan demonstrated recurrent disease in the thigh and pelvis, and it was decided to treat the patient with ILI. The patient progressed well in the immediate post-operative period. The patient was able to mobilize from Day 6 post-ILI and was discharged on Day 10. There was an immediate clinical response seen in the lesions, with necrosis developing in the larger lesions.

Burnout in anaesthesiology residents: A systematic review of its prevalence and stressors.

BACKGROUND: Burnout is an occupational hazard precipitated by chronic exposure to excessive work-related stress. It can have negative impacts on the health and safety of patients and clinicians. Anaesthesiologists are at a high risk of burnout; anaesthetic residents especially may experience higher levels of stress as a result of training requirements and postgraduate examinations. However, the scale of burnout among anaesthesiology residents is not well evaluated. OBJECTIVES: To determine the prevalence of burnout and identify risk factors contributing to it among anaesthesiology residents worldwide and evaluate preventive strategies at institutional and departmental levels. DESIGN: A systematic review without meta-analysis. DATA SOURCES: We searched PubMed, Embase, Scopus and PsycInfo for English language articles published up to 24 May 2021. ELIGIBILITY CRITERIA: The inclusion criteria for qualitative analysis were a reported burnout prevalence in anaesthesiology residents and the use of an assessment tool. Exclusion criteria were reviews/meta-analyses/correspondence, non-English articles, articles without anaesthesiology residents and lacking information on burnout prevalence and metrics for assessment. RESULTS: Twelve studies met the inclusion criteria; seven studies utilised the 22-item Maslach Burnout Inventory Human Services Survey (MBI-HSS) and five utilised the abbreviated Maslach Burnout Inventory (aMBI). The reported burnout prevalence among anaesthesiology residents varied between 2.7 and 67.0% (median = 24.7%). Differences in burnout criteria contributed significantly to methodological heterogeneity. Factors predisposing to burnout included long working hours, poor workplace relationships, professional examinations and adverse clinical events. Protected rest time and restricted work hours were identified as effective strategies to prevent burnout. Other preventive strategies include mindfulness and resilience courses, as well as departmental initiatives such as exercise. CONCLUSION: Burnout is common amongst anaesthesiology residents. Standardised tools and diagnostic criteria are needed to distinguish methodological heterogeneity from true heterogeneity in study populations. Interventions have been proposed to improve management strategies to minimise burnout anaesthesiology residents. PROSPERO REFERENCE: CRD42019140472.

The role of prehabilitation in frail surgical patients: A systematic review.

INTRODUCTION: Increasing emphasis is being placed on the detection of frailty in the pre-operative setting given its association with surgical morbidity and mortality. Prehabilitation seeks to increase the physiological reserve of frail patients, attenuating the risk of irreversible functional decline following surgery. AIM/HYPOTHESIS: This systematic review appraises the evidence available for prehabilitation in frail surgical patients. We proposed that exercise prehabilitation would especially benefit frail patients, with improvements in pre-operative functional capacity, and reductions in complications and length of hospital stay. METHODS: A literature search was conducted in MEDLINE, PubMed and CINAHL databases. Studies were included if they consisted of a prehabilitation intervention in frail patients undergoing surgery and specified a frailty model/index. Eight studies were included for analysis, 2 of which are ongoing studies. RESULTS: In 3 studies, prehabilitation consisted of an exercise intervention alone. There was a high feasibility of prehabilitation and a trend to improved pre-operative function, however, no evidence of improved post-operative functional recovery was there. In 2 studies, prehabilitation consisted of both exercise and nutritional interventions. Reductions in mortality and duration of hospital stay were reported, but the quality of evidence was judged to be very low. There was a lack of evidence of improved outcomes following pre-operative inspiratory muscle training in frail patients. DISCUSSION: This systematic review focuses on prehabilitation in frail surgical patients and reports that evidence supporting any outcome is limited, despite high feasibility and acceptability. There is a need for large randomised controlled trials to better establish the effects of prehabilitation in frail patients.

Isolated limb infusion with melphalan and actinomycin D for melanoma: a systematic review.

Isolated limb infusion (ILI) was developed as a simplified and minimally invasive alternative to isolated limb perfusion (ILP) to treat unresectable limb melanoma. A number of centers around the world have reported their results using this procedure. In this study a systematic review of reported ILI experiences was undertaken. A literature search was conducted according to the guidelines for systematic reviews in order to select eligible papers reporting limb toxicity and response rates following ILI using melphalan and actinomycin D to treat limb melanoma. A total of 576 patients from seven publications were included. Regional toxicity following ILI was low: no visible effect of the treatment or slight erythema or edema was observed in 79% of the patients, while considerable erythema and/or edema with blistering was experienced by 19%. In 2% there was a threatened or actual compartment syndrome. No procedure-related amputation was reported. Complete response occurred in 33% of the patients and partial response in 40%, an overall response rate of 73%. Stable disease and progressive disease were achieved in 14% and 13% of the patients, respectively. This first systematic review of ILI procedures using melphalan and actinomycin D indicates that regional toxicity was generally low, with satisfactory response rates. When comparing ILI and ILP, it must be borne in mind that ILI is often performed in significantly older patients and in patients with higher stages of disease, which decreases the likelihood of a favorable response.

Isolated limb infusion: technical aspects.

OBJECTIVE: To describe the technique of isolated limb infusion (ILI) for regional high dose chemotherapy in patients with advanced malignancies confined to a limb, as currently practiced at Melanoma Institute Australia (MIA). BACKGROUND: ILI is progressively being used around the world but to date the reported response rates are generally lower than those reported by MIA. DISCUSSION: This description of the ILI protocol at MIA provides details that may allow other surgeons to improve results.

Preoperative cardiac evaluation and management of patients undergoing elective non-cardiac surgery.

Perioperative cardiac complications are a common cause of death and major morbidity in patients undergoing non-cardiac surgery. Preoperative evaluation and medical optimisation can improve outcomes, although the evidence base is limited. Evidence of effectiveness is strongest for prophylactic use of ß-blockers in high-risk patients and aspirin in patients with coronary artery disease. Particular challenges arise among patients with heart failure or valvular heart disease or those receiving antithrombotic therapy for coronary artery stents or atrial fibrillation. Close liaison between general practitioners, surgeons, anaesthetists and cardiologists is needed for optimising preoperative management and subsequent clinical outcomes in high-risk patients.

Is melphalan dose adjustment according to ideal body weight useful in isolated limb infusion for melanoma?

BACKGROUND: Isolated limb infusion (ILI), introduced in 1992, is a technique used to deliver regional chemotherapy to treat advanced melanoma confined to a limb. Adjusting melphalan dose according to ideal body weight (IBW) has been proposed as a method of decreasing limb toxicity without compromising outcome. The current study analyzed this proposed dose adjustment. METHODS: We reviewed 99 consecutive patients with lower extremity melanomas treated by ILI at our institution between May 1998 and February 2009. Toxicity and outcomes were tested for correlation with differences between administered dose and calculated adjusted dose, both in mg and mg/L, and with differences between actual limb volume and calculated adjusted limb volume. RESULTS: The median actual body weight was 71 kg, whereas the calculated median IBW was 57 kg (p < .001). Median administered melphalan dose was 7.7 mg/L. The median calculated adjusted dose was 6.5 mg/L (range 3.2-9.3 mg/L, p < .001). None of the three aforementioned parameters correlated with either Wieberdink toxicity grade or outcome. BMI did not correlate with toxicity either. Interestingly, a higher total melphalan dose did not only correlate with higher toxicity, but also with a lower response rate. CONCLUSIONS: Adjusting the melphalan dose for IBW does not appear to reduce toxicity following ILI for melanoma. The effect on outcome remains uncertain. More research is needed to optimize melphalan concentrations in individual patients during ILI to limit toxicity without compromising the response.

Does increased experience with isolated limb infusion for advanced limb melanoma influence outcome? A comparison of two treatment periods at a single institution.

BACKGROUND: Isolated limb infusion (ILI) with cytotoxic drugs has been used since 1992 to treat advanced melanoma confined to a limb. Over this time the technique has undergone progressive modification. In this study we evaluated our experience with ILI by analyzing outcome and toxicity from an "early" and a "late" treatment period. METHODS: We compared the results from our institution for 94 patients treated by ILI in the early period (1992-1999) with the results for 91 patients treated in the late period (2000-2007). All patients had advanced limb melanoma and received a combination of melphalan and actinomycin D. RESULTS: The patient characteristics of the early and late groups were similar, but there was greater tumor load in the late group, who had a significantly greater number of lesions (median 4 vs. 5; p = 0.02) and deeper tumor infiltration (p = 0.03). Drug circulation times were longer in the late group: 22 vs. 31 min (p < 0.0001). In the late group, higher initial and final limb temperatures were achieved. Overall response rates were 85% in both groups. The late treatment group showed a trend towards less toxicity (p = 0.06). CONCLUSIONS: Response rates and survival following ILI for advanced melanoma in our late treatment period were similar to those of our early treatment period, despite the significantly greater tumor load of the patients treated in the late period. This could be attributed to increased experience and protocol modifications, which allowed longer drug exposure times and higher limb temperatures to be achieved without increased toxicity.

Isolated limb infusion with melphalan and actinomycin D in melanoma patients: factors predictive of acute regional toxicity.

IMPORTANCE OF THE FIELD: Isolated limb infusion (ILI) is a simple, minimally invasive technique of delivering high concentrations of cytotoxic drugs to a diseased limb for achieving disease control in that limb. Recent studies have suggested that mild hyperthermic (38 degrees C) ILI might be the best initial treatment for extensively recurrent limb melanoma given its simplicity, low morbidity and a complete response rate of 30 - 40%. AREAS COVERED IN THIS REVIEW: Since 1994 when ILI was first described by Thompson et al., the procedure has been adopted by several centres around the world; research and improvements in the technique have resulted in reduction in limb toxicity without reducing its clinical efficacy. The pharmacokinetics of melphalan and the clinical efficacy and adverse effects of ILI from various centres are summarised. Minor but possibly important differences in the ILI techniques used in different institutions may be important in improving its efficacy and reducing the toxic effects. WHAT THE READER WILL GAIN: An understanding of the efficacy and toxicity associated with ILI with cytotoxic drugs in melanoma patients and of methods to optimise regional therapy for malignant disease in a limb. TAKE HOME MESSAGE: ILI with mild hyperthermia (38 degrees C) is well tolerated with tumour remission rates in melanoma patients similar to those achieved by isolated limb perfusion. Mild (grade I - II) and moderate/severe (grade > or = III) limb toxicities occur in 58 - 68% and 32 - 41% of patients, respectively, but long-term morbidity is rare. A high peak and high final melphalan concentration in the infusate, the AUC of melphalan concentration in the infusate and an increased postoperative serum creatine phosphokinase concentration are factors predictive of acute regional toxicity. Drug dose adjusted for ideal body weight and gender may reduce acute toxicity following ILI. It has been suggested that the use of papaverine prior to the infusion of melphalan might increase its efficacy, but it may also increase toxicity. Large prospective studies are needed to more accurately define the perioperative factors that influence acute regional toxicity after ILI and to establish strategies to optimise clinical outcome.

Safety and efficacy of isolated limb infusion with cytotoxic drugs in elderly patients with advanced locoregional melanoma.

INTRODUCTION: The treatment of elderly patients with advanced metastatic melanoma confined to a limb remains controversial. Isolated limb infusion (ILI) is an effective minimally invasive alternative to isolated limb perfusion (ILP) and is therefore a potentially valuable therapeutic option for this group. METHODS: From our prospective database 185 patients with advanced metastatic melanoma of the limb treated with a single ILI between 1992 and 2007 were identified. In all patients a cytotoxic combination of melphalan and actinomycin-D was used. RESULTS: Eighty-six patients (46%) were >or=75 years of age (range: 75-93). The patient characteristics in both groups were comparable except that the older group comprised more women (71% vs. 54%; P = 0.02) and had a lower body mass index (median: 24.4 vs. 26.4; P = 0.008). Complete response rates were 34% for those >or=75 years and 41% in the younger group (P = 0.28). There was no difference in limb recurrence free interval after a complete response (median: 24 months for both groups; P = 0.51) or in survival (median: 36 months for <75, 39 months for >or=75; P = 0.36) between both groups. Older patients experienced less limb toxicity after the procedure (Wieberdink grade III/IV toxicity in 36%) compared with younger patients (51%; P = 0.009) while systemic toxicity, complications, and long-term morbidity were similar. CONCLUSIONS: Elderly patients with advanced metastatic melanoma of the limb experience the same or lower toxicity after ILI compared with younger patients while response rates, limb recurrence free interval, survival, and morbidity are similar. ILI is an attractive alternative to the more laborious ILP, especially for older patients.

Major amputation for irresectable extremity melanoma after failure of isolated limb infusion.

INTRODUCTION: Isolated limb infusion (ILI) is an effective, minimally invasive treatment option that delivers high-dose regional chemotherapy to treat metastatic melanoma confined to a limb. In some patients, however, locoregional disease does not respond to the treatment or extensive recurrence occurs so that an amputation may become inevitable. In this study we analyzed indications for and results of amputation in these cases. METHODS: 14 patients were identified in whom amputation of the affected limb had to be carried out after failure of ILI. RESULTS: Following ILI, three patients had a complete response, seven had a partial response, two had stable disease and two patients had progressive disease. The median duration of response after ILI was 7 months (range 2-30). The median interval between ILI and amputation was 10 months. Amputation was performed in six of 20 patients who had been treated with an upper limb ILI, compared to eight amputations that were performed in 215 patients who had been treated with a lower limb ILI (P = .001). The indications for amputation were severe pain due to progression of tumor (n = 3), uncontrollable and troublesome tumor progression (n = 6) and bleeding from ulcerated lesions (n = 5). Five patients developed stump recurrence after amputation; these were treated by excision or radiation. Six of the eight patients who had a lower limb amputation became ambulant with the aid of prosthesis. Median survival after amputation was 13 months: three patients survived more than 5 years. CONCLUSIONS: Amputation following upper extremity ILI is more common compared to lower extremity ILI. Amputation may provide effective long-term palliation in selected patients when there is extensive inoperable progressive or recurrent disease after ILI.

Efficacy of repeat isolated limb infusion with melphalan and actinomycin D for recurrent melanoma.

BACKGROUND: : Isolated limb infusion (ILI) is an effective and minimally invasive treatment option for delivering regional chemotherapy in patients with metastatic melanoma confined to a limb. Recurrent or progressive disease after an ILI, however, presents a challenge for further treatment. The value of repeat ILI in this situation has not been well documented. METHODS: : Forty-eight patients were identified who had been treated with a repeat ILI. In all patients, a cytotoxic combination of melphalan and actinomycin D was used. RESULTS: : The median time between the 2 procedures was 11 months. The complete response (CR) rate after repeat ILI was 23%, compared with 31% after the initial ILI (P = .36). The overall response was 83%, compared with 75% after the first procedure (P = .32). The median duration of response was 11 months (10 months for patients with CR; P = .80), and median survival was 38 months. In those patients achieving a CR, the median survival was 68 months (P = .003). Toxicity after repeat ILI was increased, with 20 patients experiencing Wieberdink grade III limb toxicity (considerable erythema and edema with blistering) and 5 patients experiencing grade IV toxicity (threatened or actual compartment syndrome), whereas after the initial ILI these toxicity grades occurred in 14 patients and 1 patient, respectively (P = .03). No patient experienced grade V toxicity (requiring amputation). CONCLUSIONS: : Repeat ILI is an attractive treatment option to achieve limb salvage in patients with inoperable recurrent or progressive melanoma after a previous ILI. It can be associated with significant short-term regional toxicity, but is well tolerated by most patients, with satisfactory response rates. Cancer 2009. (c) 2009 American Cancer Society.

Isolated limb infusion as palliative treatment for advanced limb disease in patients with AJCC stage IV melanoma.

INTRODUCTION: In the treatment of patients with advanced limb melanoma a major treatment dilemma can arise when distant metastases are present also. Isolated limb infusion (ILI) has proved to be a useful limb-saving treatment and could potentially be of palliative value in patients with American Joint Committee on Cancer (AJCC) stage IV melanoma. METHODS: We identified 37 patients with advanced symptomatic limb disease as well as documented distant metastases at the time of their ILI. In all patients a drug combination of melphalan and actinomycin D was used. RESULTS: Fifty one percent had visceral distant metastases and 49% had cutaneous distant metastases only. The overall response rate in the treated limb was 76% [complete response (CR) rate 22%, partial response (PR) rate 54%]. Median response duration was 11 months (28 months for patients with CR; p = 0.08). Median survival after CR was 22 months, 17 months after PR, and only 4 months for those with stable or progressive disease (p = 0.002). Patients with visceral distant metastases had a significantly decreased survival compared with those with cutaneous distant metastases only (8 and 21 months, respectively; p = 0.03). Limb salvage was achieved in 86% of the patients. The procedure was well tolerated, with only one patient developing Wieberdink grade IV toxicity (threatened/actual compartment syndrome) and none requiring amputation as a result of the procedure (grade V toxicity). CONCLUSIONS: Minimally invasive ILI can effectively be used as palliative treatment to provide local tumor control and limb salvage in stage IV melanoma patients with advanced, symptomatic limb disease.

Factors predictive of acute regional toxicity after isolated limb infusion with melphalan and actinomycin D in melanoma patients.

INTRODUCTION: Isolated limb infusion (ILI) with cytotoxic drugs is a low-flow isolated limb perfusion (ILP) performed via percutaneous catheters without oxygenation to treat metastatic melanoma confined to a limb. Response rates and duration of response following ILI are similar to those after ILP. Previously we have shown that more significant limb toxicity is not associated with a higher response rate or improved patient outcome. In this study we sought to determine factors predicting toxicity following ILI. METHODS: From our prospective database 185 patients with advanced metastatic melanoma of the limb treated with a single ILI between 1992 and 2007 were identified. In all patients a cytotoxic combination of melphalan and actinomycin D was used. Drug circulation time was 20-30 min under mild hyperthermic conditions (38-39 degrees C). Limb toxicity was assessed using the Wieberdink scale. RESULTS: The average patient age was 74 years (range 29-93 years) and 62% were female. Most patients (134/185) had MD Anderson stage III disease (satellites and in-transit metastases). Toxicity grade I (no reaction) occurred in 3 patients, grade II (slight erythema and edema) in 105 patients, grade III (considerable erythema and edema +/- blistering) in 72 patients, and grade IV (threatened or actual compartment syndrome) in 5 patients. No patient developed grade V toxicity (requiring amputation). On univariate analysis high peak and high final melphalan concentrations were found to be predictive factors for grade III/IV limb toxicity as well as the area under the curve of the melphalan concentration. Surprisingly, a greater rise in the CO(2) level during the procedure was associated with lower toxicity in the univariate analysis. Increased serum creatine phosphokinase (CK) postoperatively was related to higher toxicity score. In the multivariate analysis high final melphalan concentration and shorter tourniquet time were independent predictive risk factors for developing grade III/IV limb toxicity. CONCLUSIONS: ILI is a safe alternative to the more invasive and laborious ILP technique to treat melanoma confined to a limb. Regional acute toxicity following ILI is mild to moderate in most patients. Based on the predictive factors found in this series, altering melphalan dose and tourniquet time may allow further reductions in post-ILI toxicity without compromising effectiveness.

Pharmacokinetics of regional therapy: isolated limb infusion and other low flow techniques for extremity melanoma.

Isolated limb infusion (ILI) provides a simple, minimally invasive, and yet effective method of delivering high doses of cytotoxic drugs into tumor tissue with minimal systemic side effects because there is no significant drug leakage into the systemic circulation. The ILI technique is a technically less complex procedure than conventional ILP that can be used in patients who have advanced or persistently recurrent disease in an extremity. It is an attractive palliative option because it preserves limb function and maintains quality of life. Repeat ILI is safe and effective. Because the risk for systemic leakage is extremely low, ILI provides an excellent model in which to test new drugs and drug combinations.

Outcomes following isolated limb infusion for melanoma. A 14-year experience.

BACKGROUND: Isolated limb infusion (ILI) is a minimally invasive technique for delivering regional chemotherapy in patients with advanced and metastatic melanoma confined to a limb. It is essentially a low-flow isolated limb perfusion (ILP) performed via percutaneous catheters without oxygenation. METHODS: From our prospective database 185 patients with advanced metastatic melanoma of the limb treated with a single ILI between 1993 and 2007 were identified. In all patients a cytotoxic drug combination of melphalan and actinomycin-D was used. Drug circulation time was 20-30 min under mild hyperthermic conditions (38-39 degrees C). RESULTS: The majority of patients (62%) were female. Their average age was 74 years (range 29-93 years). Most patients had MD Anderson stage III disease (134/185). The overall response rate was 84% [complete response (CR) rate 38%, partial response rate 46%]. Median response duration was 13 months (22 months for patients with CR; P = 0.01). Median follow-up was 20 months and median survival was 38 months. In those patients with a CR, the median survival was 53 months (P = 0.005). CR rate and survival time decreased with increasing stage of disease. On multivariate analysis significant factors for a favorable outcome were achievement of CR, stage of disease, thickness of primary melanoma, the CO(2 )level in the isolated circuit, and a Wieberdink limb toxicity score of III (considerable erythema and edema). CONCLUSION: The response rates and duration of response after ILI are comparable to those achieved by conventional ILP. ILI is a minimally invasive alternative to the much more complex and morbid conventional ILP technique for patients with advanced metastatic melanoma confined to a limb.

Anaesthetic management of a patient with thrombocytopenia.

PURPOSE OF REVIEW: New insights into the role of platelets in haemostasis have enabled a better understanding of the pathophysiology of conditions associated with thrombocytopenia. The development of new drugs and the advances in blood transfusion technology have improved the clinical management of patients with thrombocytopenia. The aim of this article is to provide a concise review of major advances in the perioperative management of patients with thrombocytopenia. RECENT FINDINGS: Thrombocytopenia is a symptom, and the underlying cause must be evaluated. Immunotherapy, corticosteroids, immunosuppressive drugs and thrombopoietic growth factors can increase the number of platelets in thrombocytopenic patients. Further, a better understanding of the pathophysiology of heparin-induced thrombocytopenia type II and the development of direct thrombin inhibitors have improved the management of these patients, especially in the perioperative period. SUMMARY: The lack of clinical methods for predicting which type of patients with thrombocytopenia are at risk of bleeding and the effectiveness of various platelet preparations call for research initiatives to provide better guidelines for transfusion practice. Controlled clinical trials are required to evaluate strategies for the prophylactic use of platelets and thrombopoietic factors in idiopathic thrombocytopenic purpura and the use of direct thrombin inhibitors in patients with heparin-induced thrombocytopenia.