Markus W. Hollmann

Minimally invasive versus open oesophagectomy for patients with oesophageal cancer: a multicentre, open-label, randomised controlled trial

BACKGROUND Surgical resection is regarded as the only curative option for resectable oesophageal cancer, but pulmonary complications occurring in more than half of patients after open oesophagectomy are a great concern. We assessed whether minimally invasive oesophagectomy reduces morbidity compared with open oesophagectomy. METHODS We did a multicentre, open-label, randomised controlled trial at five study centres in three countries between June 1, 2009, and March 31, 2011. Patients aged 18-75 years with resectable cancer of the oesophagus or gastro-oesophageal junction were randomly assigned via a computer-generated randomisation sequence to receive either open transthoracic or minimally invasive transthoracic oesophagectomy. Randomisation was stratified by centre. Patients, and investigators undertaking interventions, assessing outcomes, and analysing data, were not masked to group assignment. The primary outcome was pulmonary infection within the first 2 weeks after surgery and during the whole stay in hospital. Analysis was by intention to treat. This trial is registered with the Netherlands Trial Register, NTR TC 2452. FINDINGS We randomly assigned 56 patients to the open oesophagectomy group and 59 to the minimally invasive oesophagectomy group. 16 (29%) patients in the open oesophagectomy group had pulmonary infection in the first 2 weeks compared with five (9%) in the minimally invasive group (relative risk [RR] 0·30, 95% CI 0·12-0·76; p=0·005). 19 (34%) patients in the open oesophagectomy group had pulmonary infection in-hospital compared with seven (12%) in the minimally invasive group (0·35, 0·16-0·78; p=0·005). For in-hospital mortality, one patient in the open oesophagectomy group died from anastomotic leakage and two in the minimally invasive group from aspiration and mediastinitis after anastomotic leakage. INTERPRETATION These findings provide evidence for the short-term benefits of minimally invasive oesophagectomy for patients with resectable oesophageal cancer. FUNDING Digestive Surgery Foundation of the Unit of Digestive Surgery of the VU University Medical Centre.

Laparoscopy in combination with fast track multimodal management is the best perioperative strategy in patients undergoing colonic surgery: a randomized clinical trial (LAFA-study).

Objective:To investigate which perioperative treatment, ie, laparoscopic or open surgery combined with fast track (FT) or standard care, is the optimal approach for patients undergoing segmental resection for colon cancer. Summary Background Data:Important developments in elective colorectal surgery are the introduction of laparoscopy and implementation of FT care, both focusing on faster recovery. Methods:In a 9-center trial, patients eligible for segmental colectomy were randomized to laparoscopic or open colectomy, and to FT or standard care, resulting in 4 treatment groups. Primary outcome was total postoperative hospital stay (THS). Secondary outcomes were postoperative hospital stay (PHS), morbidity, reoperation rate, readmission rate, in-hospital mortality, quality of life at 2 and 4 weeks, patient satisfaction and in-hospital costs. Four hundred patients were required to find a minimum difference of 1 day in hospital stay. Results:Median THS in the laparoscopic/FT group was 5 (interquar-tile range: 4–8) days; open/FT 7 (5–11) days; laparoscopic/standard 6 (4.5–9.5) days, and open/standard 7 (6–13) days (P < 0.001). Median PHS in the laparoscopic/FT group was 5 (4–7) days; open/FT 6 (4.5–10) days; laparoscopic/standard 6 (4–8.5) days and open/standard 7 (6–10.5) days (P < 0.001). Secondary outcomes did not differ significantly among the groups. Regression analysis showed that laparoscopy was the only independent predictive factor to reduce hospital stay and morbidity. Conclusions:Optimal perioperative treatment for patients requiring segmental colectomy for colon cancer is laparoscopic resection embedded in a FT program. If open surgery is applied, it is preferentially done in FT care. This study was registered under NTR222 (www.trialregister.nl).

Local anesthetics and the inflammatory response: a new therapeutic indication?

Local Anesthetics and the Inflammatory Response: A New Therapeutic Indication? Markus Hollmann;Marcel Durieux; Anesthesiology

Mechanical Ventilation with Lower Tidal Volumes and Positive End-expiratory Pressure Prevents Pulmonary Inflammation in Patients without Preexisting Lung Injury

Background:Mechanical ventilation with high tidal volumes aggravates lung injury in patients with acute lung injury or acute respiratory distress syndrome. The authors sought to determine the effects of short-term mechanical ventilation on local inflammatory responses in patients without preexisting lung injury. Methods:Patients scheduled to undergo an elective surgical procedure (lasting ≥5 h) were randomly assigned to mechanical ventilation with either higher tidal volumes of 12 ml/kg ideal body weight and no positive end-expiratory pressure (PEEP) or lower tidal volumes of 6 ml/kg and 10 cm H2O PEEP. After induction of anesthesia and 5 h thereafter, bronchoalveolar lavage fluid and/or blood was investigated for polymorphonuclear cell influx, changes in levels of inflammatory markers, and nucleosomes. Results:Mechanical ventilation with lower tidal volumes and PEEP (n = 21) attenuated the increase of pulmonary levels of interleukin (IL)-8, myeloperoxidase, and elastase as seen with higher tidal volumes and no PEEP (n = 19). Only for myeloperoxidase, a difference was found between the two ventilation strategies after 5 h of mechanical ventilation (P < 0.01). Levels of tumor necrosis factor α, IL-1α, IL-1β, IL-6, macrophage inflammatory protein 1α, and macrophage inflammatory protein 1β in the bronchoalveolar lavage fluid were not affected by mechanical ventilation. Plasma levels of IL-6 and IL-8 increased with mechanical ventilation, but there were no differences between the two ventilation groups. Conclusion:The use of lower tidal volumes and PEEP may limit pulmonary inflammation in mechanically ventilated patients without preexisting lung injury. The specific contribution of both lower tidal volumes and PEEP on the protective effects of the lung should be further investigated.

Pregabalin in patients with central neuropathic pain: A randomized, double-blind, placebo-controlled trial of a flexible-dose regimen

&NA; The effective treatment of patients suffering from central neuropathic pain remains a clinical challenge, despite a standard pharmacological approach in combination with anticonvulsants and antidepressants. A randomized, double‐blinded, placebo‐controlled trial evaluated the effects of pregabalin on pain relief, tolerability, health status, and quality of life in patients with central neuropathic pain caused by brain or spinal cord injuries. At baseline and 4 weeks after the start of treatment subjects were evaluated with standard measures of efficacy: pain intensity measured by visual analog scale, health status (Pain Disability Index and EQ‐5D) and quality of life (SF‐36). Forty patients received escalating doses of either pregabalin (150, 300, and 600 mg/day) or matching placebo capsules. In both groups, patients started with 1 capsule per day (either 150 mg of pregabalin or placebo). If pain relief was insufficient, patients were titrated to a higher dose. There was a statistically significant decrease in mean pain score at endpoint for pregabalin treatment, compared with placebo (P = 0.016). Follow‐up observation showed no significant difference in Pain Disability Index scores between the two groups. The pregabalin group, however, showed a statistically significant improvement for the EQ‐5D. Pregabalin treatment led to a significant improvement in the bodily pain domain of the SF36. In the other domains, more favorable scores were reported without reaching statistical significance. Pregabalin, in a flexible‐dose regime, produced clinically significant reductions in pain, as well as improvements in health status in patients suffering from severe central neuropathic pain.

Noninvasive continuous arterial blood pressure monitoring with Nexfin

Background: If invasive measurement of arterial blood pressure is not warranted, finger cuff technology can provide continuous and noninvasive monitoring. Finger and radial artery pressures differ; Nexfin® (BMEYE, Amsterdam, The Netherlands) measures finger arterial pressure and uses physiologic reconstruction methodologies to obtain values comparable to invasive pressures. Methods: Intra-arterial pressure (IAP) and noninvasive Nexfin arterial pressure (NAP) were measured in cardiothoracic surgery patients, because invasive pressures are available. NAP-IAP differences were analyzed during 30 min. Tracking was quantified by within-subject precision (SD of individual NAP-IAP differences) and correlation coefficients. The ranges of pressure change were quantified by within-subject variability (SD of individual averages of NAP and IAP). Accuracy and precision were expressed as group average ± SD of the differences and considered acceptable when smaller than 5 ± 8 mmHg, the Association for the Advancement of Medical Instrumentation criteria. Results: NAP and IAP were obtained in 50 (34–83 yr, 40 men) patients. For systolic, diastolic, mean arterial, and pulse pressure, median (25–75 percentiles) correlation coefficients were 0.96 (0.91–0.98), 0.93 (0.87–0.96), 0.96 (0.90–0.97), and 0.94 (0.85–0.98), respectively. Within-subject precisions were 4 ± 2, 3 ± 1, 3 ± 2, and 3 ± 2 mmHg, and within-subject variations 13 ± 6, 6 ± 3, 9 ± 4, and 7 ± 4 mmHg, indicating precision over a wide range of pressures. Group average ± SD of the NAP-IAP differences were −1 ± 7, 3 ± 6, 2 ± 6, and −3 ± 4 mmHg, meeting criteria. Differences were not related to mean arterial pressure or heart rate. Conclusion: Arterial blood pressure can be measured noninvasively and continuously using physiologic pressure reconstruction. Changes in pressure can be followed and values are comparable to invasive monitoring.

Perioperative strategy in colonic surgery; LAparoscopy and/or FAst track multimodal management versus standard care (LAFA trial)

BackgroundRecent developments in large bowel surgery are the introduction of laparoscopic surgery and the implementation of multimodal fast track recovery programs. Both focus on a faster recovery and shorter hospital stay.The randomized controlled multicenter LAFA-trial (LAparoscopy and/or FAst track multimodal management versus standard care) was conceived to determine whether laparoscopic surgery, fast track perioperative care or a combination of both is to be preferred over open surgery with standard care in patients having segmental colectomy for malignant disease.Methods/designThe LAFA-trial is a double blinded, multicenter trial with a 2 × 2 balanced factorial design. Patients eligible for segmental colectomy for malignant colorectal disease i.e. right and left colectomy and anterior resection will be randomized to either open or laparoscopic colectomy, and to either standard care or the fast track program. This factorial design produces four treatment groups; open colectomy with standard care (a), open colectomy with fast track program (b), laparoscopic colectomy with standard care (c), and laparoscopic surgery with fast track program (d). Primary outcome parameter is postoperative hospital length of stay including readmission within 30 days. Secondary outcome parameters are quality of life two and four weeks after surgery, overall hospital costs, morbidity, patient satisfaction and readmission rate.Based on a mean postoperative hospital stay of 9 +/- 2.5 days a group size of 400 patients (100 each arm) can reliably detect a minimum difference of 1 day between the four arms (alfa = 0.95, beta = 0.8). With 100 patients in each arm a difference of 10% in subscales of the Short Form 36 (SF-36) questionnaire and social functioning can be detected.DiscussionThe LAFA-trial is a randomized controlled multicenter trial that will provide evidence on the merits of fast track perioperative care and laparoscopic colorectal surgery in patients having segmental colectomy for malignant disease.

Modulation of NMDA receptor function by ketamine and magnesium: Part I.

N- methyl-d-aspartate (NMDA) receptors are important components of pain processing. Ketamine and Mg2+ block NMDA receptors and might therefore be useful analgesics, and combinations of Mg2+ and ketamine provide more effective analgesia. We investigated their interactions at NMDA receptors. Xenopus oocytes, expressing NR1/NR2A or NR1/NR2B glutamate receptors, were studied. The effects of Mg2+, racemic ketamine and its isomers, and the combination of Mg2+ and S(+)-ketamine on NMDA signaling were determined. Mg2+ and ketamine alone inhibited NMDA receptors noncompetitively (half-maximal inhibitory effect concentration: Mg2+ 4.2 ± 1.2 × 10−4 M at NR1/NR2A and 6.3 ± 2.4 × 10−4 M at NR1/NR2B; racemic ketamine 13.6 ± 8.5 × 10−6 M at NR1/NR2A and 17.6 ± 7.2 × 10−6 M at NR1/NR2B; S(+)-ketamine 4.1 ± 2.5 × 10−6 at NR1/NR2A and 3.0 ± 0.3 at NR1/NR2B; R(−)-ketamine 24.4 ± 4.1 × 10−6 M at NR1/NR2A and 26.0 ± 2.4 × 10−6 M at NR1/NR2B). The combined application of Mg2+ and ketamine decreased the half-maximal inhibitory effect concentration >90% at both receptors. Isobolographic analysis demonstrated super-additive interactions. Ketamine and Mg2+ inhibit responses of recombinantly expressed NR1/NR2A and NR1/NR2B glutamate receptors, and combinations of the compounds act in a super-additive manner. These findings may explain, in part, why combinations of ketamine and Mg2+ are more effective analgesics than either compound alone.

Apoptosis induction by different local anaesthetics in a neuroblastoma cell line.

BACKGROUND Local anaesthetics are known to induce apoptosis in clinically relevant concentrations. Hitherto, it is unknown what determines the apoptotic potency of local anaesthetics. Therefore, we compared apoptosis induction by local anaesthetics related to their physicochemical properties in human neuronal cells. METHODS Neuroblastoma cells (SHEP) were incubated with eight local anaesthetics, two of the ester and six of the amide types. At least, five concentrations of each local anaesthetic were evaluated. After incubation for 24 h, rates of cells in early apoptotic stages and overall cell death were evaluated by annexin V and 7-amino-actinomycin D double staining by flow cytometry. The concentrations that led to half-maximal neurotoxic effects (LD50) were calculated and compared for all local anaesthetics. RESULTS All local anaesthetics were neurotoxic in a concentration-dependent manner. All drugs induced similar rates of early apoptotic cell formation at low concentrations, whereas at high concentrations, late apoptotic or necrotic cell death predominated. Comparison of LD50 values of the different local anaesthetics resulted in the following order of apoptotic potency from high to low toxicity: tetracaine>bupivacaine>prilocaine=mepivacaine=ropivacaine>lidocaine>procaine=articaine. The toxicity correlated with octanol/buffer coefficients and also with experimental potency of the local anaesthetic, but was unrelated to the structure (ester or amide type). CONCLUSIONS All commonly used local anaesthetics induce neuronal apoptosis in clinically used concentrations. The neurotoxicity correlates with lipid solubility and thus with the conduction blocking potency of the local anaesthetic, but is independent of the chemical class (ester/amide).

Modulation of NMDA receptor function by ketamine and magnesium. Part II: interactions with volatile anesthetics.

Mg2+ and ketamine interact superadditively at N- methyl-d-aspartate (NMDA) receptors, which may explain the clinical efficacy of the combination. Because patients are usually exposed concomitantly to volatile anesthetics, we tested the hypothesis that volatile anesthetics interact with ketamine and/or Mg2+ at recombinantly expressed NMDA receptors. NR1/NR2A or NR1/NR2B receptors were expressed in Xenopus oocytes. We determined the effects of isoflurane, sevoflurane, and desflurane on NMDA receptor signaling, alone and in combination with S(+)-ketamine (4.1 &mgr;M on NR1/NR2A, 3.0 &mgr;M on NR2/NR2B) and/or Mg2+ (416 &mgr;M on NR1/NR2A, 629 &mgr;M on NR1/NR2B). Volatile anesthetics inhibited NR1/NR2A and NR1/NR2B glutamate receptor function in a reversible, concentration-dependent, voltage-insensitive and noncompetitive manner (half-maximal inhibitory concentration at NR1/NR2A receptors: 1.30 ± 0.02 minimum alveolar anesthetic concentration [MAC] for isoflurane, 1.18 ± 0.03 MAC for desflurane, 1.24 ± 0.06 MAC for sevoflurane; at NR1/NR2B receptors: 1.33 ± 0.12 MAC for isoflurane, 1.22 ± 0.08 MAC for desflurane, and 1.28 ± 0.08 MAC for sevoflurane). On both NR1/NR2A and NR1/NR2B receptors, 50% inhibitory concentration for volatile anesthetics was reduced approximately 20% by Mg2+, approximately 30% by S(+)-ketamine, and approximately 50% by the compounds in combination. Volatile anesthetic effects on NMDA receptors can be potentiated significantly by Mg2+, S(+)-ketamine, or—most profoundly—both. Therefore, the analgesic effects of ketamine and Mg2+ are likely to be enhanced in the presence of volatile anesthetics.