Perioperative Pathophysiology Research Articles

Volatile Anesthetic Sevoflurane Attenuates Toll-Like Receptor 1/2 Activation.

Although immunomodulatory effects of anesthetics have been increasingly recognized, their underlying molecular mechanisms are not completely understood. Toll-like receptors (TLRs) are one of the major receptors to recognize invading pathogens and danger signals from damaged host tissues to initiate immune responses. Among the TLR family, TLR2 and TLR4 recognize a wide range of ligands and are considered to be important players in perioperative pathophysiology. Based on our recent finding that volatile anesthetics modulate TLR4 function, we tested our hypothesis that they would also modulate TLR2 function. The effect of anesthetics isoflurane, sevoflurane, propofol, and dexmedetomidine on TLR2 activation was examined by reporter assays. An anesthetic that affected the activation was subjected to in silico rigid docking simulation on TLR2. To test our prediction that sevoflurane and a TLR1/TLR2 ligand Pam3CSK4 would compete for the same pocket of TLR2, we performed Pam3CSK4 competitive binding assay to TLR2 using HEK cells stably transfected with TLR2 (HEK-TLR2) with or without sevoflurane. We examined the effect of different anesthetics on the functions of human neutrophils stimulated with TLR2 ligands. Kruskal-Wallis test and Mann-Whitney U test were used for statistical analysis. We observed that the attenuation of TLR1/TLR2 activation was seen on sevoflurane exposure but not on isoflurane, propofol, or dexmedetomidine exposure. The attenuation of TLR2/TLR6 activation was not seen in any of the anesthetics tested. The rigid docking simulation predicted that sevoflurane and Pam3CSK4 bound to the same pocket of TLR1/TLR2 complex. The binding of Pam3CSK4 to HEK-TLR2 cells was impaired in the presence of sevoflurane, indicating that sevoflurane and Pam3CSK4 competed for the pocket, as predicted in silico. The stimulation of neutrophils with Pam3CSK4 induced L-selection shedding but did not affect phagocytosis and reactive oxygen species production. L-selectin shedding from neutrophils was attenuated only by sevoflurane, consistent with the result of our reporter assays. We found that TLR1/TLR2 activation was attenuated by sevoflurane, but we found no evidence for attenuation by isoflurane, propofol, or dexmedetomidine at clinically relevant concentrations. Our structural analysis and competition assay supported that sevoflurane directly bound to TLR2 at the interphase of the TLR1/TLR2 complex. Sevoflurane attenuated neutrophil L-selectin shedding, an important step for neutrophil migration.

Challenges in optimising recovery after emergency laparotomy.

Standardised peri-operative care pathways for patients undergoing emergency laparotomy or laparoscopy for non-traumatic pathologies have been shown to be inadequate and associated with high morbidity and mortality. Recent research has highlighted this problem and showed that simple pathways with 'rescue' interventions have been associated with reduced mortality when implemented successfully. These rescue pathways have focused on early diagnosis and surgery, specialist surgeon and anaesthetist involvement, goal-directed therapy and intensive or intermediary postoperative care for high-risk patients. In elective surgery, enhanced recovery has resulted in reduced length of stay and morbidity by the application of procedure-specific, evidence-based interventions inside rigorously implemented patient pathways based on multidisciplinary co-operation. The focus has been on attenuation of peri-operative stress and pain management to facilitate early recovery. Patients undergoing emergency laparotomy are a heterogeneous group consisting mostly of patients with intestinal perforations and/or obstruction with varying levels of comorbidity and frailty. However, present knowledge of the different pathophysiology and peri-operative trajectory of complications in these patient groups is limited. In order to move beyond rescue pathways and to establish enhanced recovery for emergency laparotomy, it is essential that research on both the peri-operative pathophysiology of the different main patient groups - intestinal obstruction and perforation - and the potentially differentiated impact of interventions is carried out. Procedure- and pathology-specific knowledge is lacking on key elements of peri-operative care, such as: multimodal analgesia; haemodynamic optimisation and fluid management; attenuation of surgical stress; nutritional optimisation; facilitation of mobilisation; and the optimal use and organisation of specialised wards and improved interdisciplinary collaboration. As such, the future challenges in improving peri-operative patient care in emergency laparotomy are moving from simple rescue pathways to establish research that can form a basis for morbidity- and procedure-specific enhanced recovery protocols as seen in elective surgery.

Second Generation of a Fast-track Liver Resection Programme.

Recent developments in perioperative pathophysiology and care have documented evidence-based, multimodal rehabilitation (fast-track) to hasten recovery and decrease morbidity and hospital stay in several major surgical procedures. The aim of this study was to investigate the effect over time of a modified previously published fast-track programme in unselected patients undergoing open or laparoscopic liver resection. A prospective study includes the first 121 consecutive patients following an updated fast-track programme for liver resection. High-dose methylprednisolone was given to all patients before surgery, catheters and drains were systematically removed early, and patients were mobilized and started eating and drinking from the day of surgery. An opioid-sparing multimodal pain treatment was given for the first week. The discharge criteria were (1) pain sufficiently controlled by oral analgesics only; (2) patient comfortable with discharge; (3) no untreated complications. The median length of stay (LOS) for all patients was 4days, with 2days after laparoscopic vs. 4days for open resections. The median LOS after major hepatectomies (≥3 segments) was 5days. The readmission rate was 6% and the 30-day mortality zero. The LOS decreased compared to our first-generation fast-track programme with LOS 5days. Fast-track principles for perioperative care and early discharge are safe even after major liver resection. The introduction of high-dose steroids preoperatively might have facilitated a shorter LOS. Routine discharge on POD 1 or 2 after laparoscopic resection and on POD 4 after open liver resection has proven to be feasible.

Henrik Kehlet, M.D., Ph.D., recipient of the 2014 Excellence in Research Award.

Henrik Kehlet, M.D., Ph.D., recipient of the 2014 Excellence in Research Award.

Fast-track surgery: A new concept of perioperative management of surgical patients

In the past few decades, surgery has advanced greatly because of an improved understanding of perioperative pathophysiology, development of minimally invasive operative techniques and advanced anaesthetic techniques. Fewer operations are requiring extended periods of hospital stay and a growing number of procedures are performed on an ambulatory basis. The pressure on medical systems is continuously growing as a result of economic constraints, increasing numbers of patients undergoing surgical procedures and greater patient autonomy. Patient awareness is steadily increasing along with their participation in their own care, leading to expectations of a higher standard of care. This has led to the development of a new concept of fast-track surgery.

Evaluation of a fast-track programme for patients undergoing liver resection

Recent developments in perioperative pathophysiology and care have documented evidence-based, multimodal rehabilitation (fast-track) to hasten recovery and to decrease morbidity and hospital stay for several major surgical procedures. The aim of this study was to investigate the effect of introducing fast-track principles for perioperative care in unselected patients undergoing open or laparoscopic liver resection. This was a prospective study involving the first 100 consecutive patients who followed fast-track principles for liver resection. Catheters and drains were systematically removed early, and patients were mobilized and started eating and drinking from the day of surgery. An opioid-sparing multimodal pain treatment was given for the first week. Discharge criteria were: pain sufficiently controlled by oral analgesics alone, patient comfortable with discharge and no untreated complications. Median length of stay (LOS) for all patients was 5 days, with 2 days after laparoscopic versus 5 days following open resection (P < 0·001). Median LOS after minor open resections (fewer than 3 segments) was 5 days versus 6 days for major resections (3 or more segments) (P < 0·001). Simple right or left hemihepatectomies had a median LOS of 5 days. The readmission rate was 6·0 per cent and 30-day mortality was zero. Fast-track principles for perioperative care were introduced successfully and are safe after liver resection. Routine discharge 2 days after laparoscopic resection and 4-5 days after open liver resection may be feasible.

Effect of smoking on perioperative pathophysiology and anesthesia

Background Smoking is common and millions of cigarette smokers require surgery and anesthesia ever year.Many anesthesiologists are not sufficiently aware that smoking in the perioperative period is harmful.Objective To improve anesthetic management and surgical outcomes,the paper review the effect of smoking on perioperative pathophysiology and anesthesia.Content Smoking increases not only the risk of some postoperative complications,including pulmonary,cardiovasular and wound-related complications, but also anesthetic related complications, such as hypoxemia, cough, laryngospasm,bronchospasm,and haemodynamic response to tracheal intubation. Even temporary smoking cessation may reduce the risk of these complications and improve surgical outcome. However,smoking status can be helpful in some area,e.g.,reducing postoperative nausea and vomiting . It is controversial that smoking status can reduce postoperative pain. The mechanism of nicotine's effect on analgesia is not fully understood. Smoking changes the potency of many anesthetic drugs including sedatives,analgesic and neuromuscular blockers. Trend The preoperative smoking cessation is beneficial to surgical patients' short-and long-term outcomes.Anesthesiologists should actively persuade their patients to quit smoking. Key words: Smoking; Perioperative; Anesthesia; Complication; Analgesia

New insights into the pathophysiology of postoperative cognitive dysfunction

There is evidence that postoperative cognitive dysfunction (POCD) is a significant problem after major surgery, but the pathophysiology has not been fully elucidated. The interpretation of available studies is difficult due to differences in neuropsychological test batteries as well as the lack of appropriate controls. Furthermore, there are no internationally accepted criteria for defining POCD. This article aims to provide an update of current knowledge of the pathogenesis of POCD with a focus on perioperative pathophysiology and possible benefits achieved from an enhanced postoperative recovery using a fast-track methodology. It is concluded that the pathogenesis of POCD is multifactorial and future studies should focus on evaluating the role of postoperative sleep disturbances, inflammatory stress responses, pain and environmental factors. Potential prophylactic intervention may include minimal invasive surgery, multi-modal non-opioid pain management and pharmacological manipulation of the inflammatory response and sleep architecture.

Intestinal effects of thoracic epidural anesthesia

Thoracic epidural anesthesia (TEA) is most frequently used after major surgery. However, despite ongoing research, the influence of TEA on the intestinal perioperative pathophysiology is not fully understood. According to recent results, the splanchnic sympathetic activity is reduced during TEA both in animal models and in clinical TEA. The splanchnic sympathetic activity during high TEA is still unknown. Intestinal perfusion effects of TEA are still unclear as the technique and extent of TEA, hemodynamic alteration and size of measurement result in--seemingly--conflicting reports. Postoperative ileus after laparotomy is ameliorated by TEA. Recent findings suggest beneficial effects also after major laparoscopic procedures. Finally, the impact of TEA on the intestinal pathophysiology in critical illness is an area of growing clinical and scientific interest, although this knowledge is just at its beginning. Further research concerning the use of TEA in major laparoscopic procedures and its potential to improve or endanger anastomotic healing is warranted. The experimental studies of TEA in critical illness should be expanded.

Future perspectives and research initiatives in fast-track surgery

Major surgery is still followed by a risk of morbidity, a need for hospitalisation and convalescence. Fast-track surgery has been introduced as a coordinated effort to combine unimodal evidence-based principles of care into a multi-modal effort to enhance recovery. The aim of this article was to update recent data on fast-track abdominal surgery and outline future strategies for research. The data from fast-track colonic resection support the validity of the concept because pain, ileus, cardiopulmonary function and muscle function were all improved, compared with traditional treatment and with reduced post-operative fatigue and convalescence. Although less data is available, similar positive results may be achieved in other types of major surgery. Current research initiatives include improved multi-modal non-opioid analgesia, rational principles for perioperative fluid management, pharmacological reduction of surgical stress responses and the role of laparoscopic procedures within the fast-track concept. Fast-track surgery has evolved as a valid concept to improve post-operative outcome. Further progress may be expected based upon intensified research within perioperative pathophysiology and a multi-disciplinary collaboration between surgeons, anaesthesiologists and surgical nurses.

New approaches and old controversies to postoperative pain control following cardiac surgery

To evaluate the effect of postoperative pain control in cardiac surgical patients on morbidity, mortality and other outcome measures. New approaches in pain control have been introduced over the past decade. The impact of these interventions, either alone or in combination, on perioperative outcome was evaluated in cardiac surgical patients. We searched Medline for the period of 1980 to the present using the key terms analgesics, opioid, non-steroidal anti-inflammatory drugs, cardiac surgery, regional analgesia, spinal, epidural, fast-track cardiac anaesthesia, fast-track cardiac surgery, myocardial ischaemia, myocardial infarction, postoperative care, accelerated care programmes, postoperative complications, and we examined and discussed the articles that were identified to be included in this review. Pain management in cardiac surgery is becoming more important with the establishment of minimally invasive direct coronary artery bypass surgery and fast-track management of conventional cardiac surgery patients. Advances have been made in this area and encompass specific techniques, such as central neuraxial blockade or selective nerve blocks, and drugs (opioids, sedative-hypnotics and non-steroidal anti-inflammatory drugs). Ideally, these therapies provide not only patient comfort but also mitigate untoward cardiovascular responses, pulmonary responses, and other inflammatory and secondary sympathetic responses. The introduction of these newer approaches to perioperative care has reduced morbidity, but not mortality, in cardiac surgical patients. Understanding perioperative pathophysiology and implementation of care regimes to reduce the stress of cardiac surgery, will continue to accelerate rehabilitation associated with decreased hospitalization and increased satisfaction and safety after discharge. Reorganization of the perioperative team (anaesthesiologists, surgeons, nurses and physical therapists) will be essential to achieve successful fast-track cardiac surgical programmes. Developments and improvements of multimodal interventions within the context of 'fast-track' cardiac surgery programmes represents the major challenge for the medical professionals working to achieve a 'pain and risk free' perioperative course.

Paradigmas e evidências da nutrição peri-operatória

Understanding perioperative pathophysiology and implementing care regimes, through a multimodal approach, to reduce the organic response to stress after surgery and the related postoperative ileus, are major challenges. Multimodal surgical strategies such as pre-operative intake of a carbohydrate drink, instead of the usually recommended 2- to 6-hour period of nothing-bymouth, together with patient's education of the postoperative care plan, plus efficacious analgesia and early postoperative nutrition, among others, have been described to significantly impact on the previous variables. Therefore, these strategies accelerate rehabilitation and, as a consequence, decrease complications and hospital length of stay and, its related costs.

Einführung der „Fast-track”-Kolonchirurgie in den klinischen Alltag

A multimodal perioperative concept ("fast-track"-surgery) may decrease the incidence of general complications following elective colonic resections, accelerate rehabilitation and shorten postoperative hospital stay. During the introduction of this new "clinical pathway" several obstacles have to be overcome. This manuscript describes a practical way to establish "fast-track"-colonic surgery in the clinical routine. After discussion of the many aspects of perioperative pathophysiology following abdominal surgery a "fast-track"-concept for colonic surgery was defined. Since 11.10.2001 the "fast-track" concept was applied to all patients treated by one attending surgeon. Experience with establishing this concept in the clinical routine was analysed. "Fast-track"-colonic surgery was established in close cooperation between surgeons, anesthesiologists and nurses. A written-down concept, the use of checklists and letters of information for patients, their relatives and general practicioners will simplify the introduction of the new perioperative treatment. Traditional practice (i. e. types of incisions, use of drainage, postoperative oral feeding) have to be modified. In 74 "fast-track"-colonic resections postoperative hospital stay was reduced to a median of 4 days, regardless of the way of access to the abominal cavity (laparoscopic or conventional). Postoperative morbidity was acceptable (local complications: 7 %; general complications: 7 %, but only 1 % without local complication). Establishing "fast-track"-colonic surgery requires close cooperation between surgery, anestehsiology and nursing personal. Most important is a surgeon prepared to overcome traditional concepts of perioperative care.

The impact of early nutrition on metabolic response and postoperative ileus.

Early nutrition has been evaluated and used as a possible strategy to decrease the negative impact of the metabolic response to injury and postoperative ileus. The metabolic response to injury, be it surgical or traumatic, is a physiological mechanism that, according to the magnitude and duration of the event, can impact on the patient's morbidity and survival. The adequate initial approach is a determinant factor that might influence its outcome. Simultaneously, gastrointestinal tract motility is transiently impaired, leading to the so-called postoperative ileus. The latter not only causes patient discomfort, but is also related to abdominal complications and worsening of the nutritional status, as well as increased length of hospital stay and costs. Multimodal surgical strategies such as preoperative intake of a carbohydrate drink, together with patient education of the postoperative care plan, efficacious analgesia and early nutrition have been described to significantly decrease the stress response and improve the ileus. Therefore, these strategies accelerate rehabilitation and, as a consequence, decrease complications and length of hospital stay and its related costs. Understanding perioperative pathophysiology and implementing care regimes through a multimodal approach in order to reduce the stress of the operation and the related postoperative ileus are major challenges. These factors will certainly impact on patient outcomes.

Effect of postoperative epidural analgesia on patient outcomes

The overall benefits of perioperative epidural anesthesia and analgesia for decreasing morbidity and mortality is controversial. However, perioperative epidural anesthesia and analgesia will attenuate detrimental perioperative pathophysiology, which, in turn, may diminish the incidence of adverse patient outcomes. There are increasing experimental and clinical data to support the use of perioperative epidural anesthesia and analgesia for decreasing postoperative pulmonary, gastrointestinal, and cardiovascular complications. One of the primary reasons that the “regional versus general anesthesia” question has not been answered is due to the significant methodological issues present in every available trial, which affect the interpretation and limit the applicability of the trial results. A major issue in the overall interpretation of results from trials examining the effect of postoperative epidural analgesia on patient outcomes is that “epidural analgesia” is commonly viewed as a generic term. There are clinical and outcome implications for various inputs into what constitutes “epidural analgesia,” including the duration of epidural analgesia, analgesic contents (eg, local anesthetics versus opioids), and location of catheter placement. We will examine these issues along with the role of epidural analgesia in the multimodal approach for patient recovery.

Physiological, Metabolic, and Immunological Responses after Intestinal Resection

Major surgery leads to an activation of inflammatory and endocrine responses resulting in catabolism, immunosuppression, and adverse physiological effects in various organ systems. In addition, hypothermia, opioid administration, immobilization, and semistarvation may amplify the negative effects of the stress responses on perioperative organ physiology. Currently available options to modify the stress response activation per se are epidural local anesthetics, minimally invasive surgery, and a single high-dose glucocorticoid. Recent studies indicate that the stress-induced perioperative impairment in various organ functions may be profoundly reduced by multimodal rehabilitation programs aiming to control perioperative pathophysiology and thereby improve recovery.

Effect of post-operative analgesia on patient morbidity

The pathophysiology that commonly follows surgery results in detrimental physiological effects and may be associated with post-operative mortality and morbidity. The use of post-operative epidural analgesia, but not systemic opioids, may attenuate some of these adverse physiological effects and result in a decrease in patient-related morbidity post-operatively. Randomized trials suggest that the perioperative use of epidural analgesia may facilitate return of gastrointestinal function, attenuate hypercoagulable events and diminish post-operative pulmonary complications. A multimodal approach incorporating the use of epidural analgesia to control perioperative pathophysiology will facilitate the patient's recovery.

Multimodal strategies to improve surgical outcome.

To evaluate the effect of modifying perioperative care in noncardiac surgical patients on morbidity, mortality, and other outcome measures. New approaches in pain control, introduction of techniques that reduce the perioperative stress response, and the more frequent use of minimal invasive surgical access have been introduced over the past decade. The impact of these interventions, either alone or in combination, on perioperative outcome was evaluated. We searched Medline for the period of 1980 to the present using the key terms fast track surgery, accelerated care programs, postoperative complications and preoperative patient preparation; and we examined and discussed the articles that were identified to include in this review. This information was supplemented with our own research on the mediators of the stress response in surgical patients, the use of epidural anesthesia in elective operations, and pilot studies of fast track surgical procedures using the multimodality approach. The introduction of newer approaches to perioperative care has reduced both morbidity and mortality in surgical patients. In the future, most elective operations will become day surgical procedures or require only 1 to 2 days of postoperative hospitalization. Reorganization of the perioperative team (anesthesiologists, surgeons, nurses, and physical therapists) will be essential to achieve successful fast track surgical programs. Understanding perioperative pathophysiology and implementation of care regimes to reduce the stress of an operation, will continue to accelerate rehabilitation associated with decreased hospitalization and increased satisfaction and safety after discharge. Developments and improvements of multimodal interventions within the context of "fast track" surgery programs represents the major challenge for the medical professionals working to achieve a "pain and risk free" perioperative course.

Reply

Associate Professor of Anesthesia and Surgery, Director, Fellowship in Critical Care Medicine, Department of Anesthesia, University of Pennsylvania Medical Center, 3400 Spruce Street, Philadelphia, Pennysylvania 19104–4283.In Reply:-Kempen maintains that “the single most cost effective preoperative evaluation likely occurs when competent surgeons thoroughly evaluate and prepare their patients regarding perioperative needs…” He later bemoans the concern that Stanford's surgeons “never develop necessary skills…” Implicit in these, and other statements, is an assumption that appropriate preparation of patients for the perioperative period is something best performed by either surgeons or primary care physicians. This is simply not true.The goal of surgical training is learning when and how to perform surgery. The emphasis is, as it should be, on the diagnosis of surgical disease, selection of the appropriate operation, and skilled performance of that operation. Similarly, primary care physicians and medical subspecialists are trained to deal with disorders within the context of everyday life at home or recovery from a severe medical problem in the hospital. Neither surgeons, primary care physicians, nor medical subspecialists are trained to understand the interactions between perioperative pathophysiology and intrinsic medical conditions. In contrast, anesthesiologists are specifically and intensively trained in just such issues. Therefore, in a sense, Kempen's statement regarding the need for surgeons to develop “necessary skills” is key. Surgeons, primary care physicians, and medical subspecialists will need to develop additional skills to deal with patients in the perioperative period, just as some anesthesiologists may need to enhance their skills in this area, also. However, an anesthesiologist trained in a modern department that emphasizes perioperative medicine possesses these skills in abundance and is, therefore, the appropriate individual to evaluate and prepare a patient for the perioperative period. An analogy to postoperative pain management can be made; the anesthesiologist understands the physiologic source of pain, is versed in management modalities, and is trained to manage these in the context of the response to surgery. Clearly, the anesthesiologist is best equipped to manage this issue, and the failure of classical methods of postoperative pain management emphasizes this point.Let's put this in completely practical terms. It is the rare anesthesiologist who has not been confronted with a medical consultation for “preoperative clearance,” wherein a well meaning primary care physician, untrained in the implications of perioperative pathophysiology, has neglected an essential component of preoperative management. Similarly, most of us have been faced with a consultation on a significantly ill patient who is “cleared but only for spinal anesthesia,” indicating ignorance of the issues involved. Surgeons tend to treat such consultations as license to proceed and are angered when an unaddressed issue leads to cancellation or postponement. The result is often the ordering of all tests on all patients. Appropriate preoperative evaluation by a competent anesthesiologist, or a physician extender supervised by that anesthesiologist, can avoid these problems. We anesthesiologists are trained to do this, we are better aware than anyone of the issues involved, and anesthesia preoperative evaluation clinics such as that at Stanford will serve to institutionalize this essential role. This may not be the best approach for all places; the private practitioner in a small hospital may accomplish the same thing simply by being available for informal consultation and by developing a professional and personal relationship with his surgical colleagues. The point is, this service is appropriate, and best provided by a well-trained anesthesiologist. Embracing this role is good for anesthesiologists, surgeons, hospitals, and, most importantly, patients.Clifford S. Deutschman, M.S., M.D., Associate Professor of Anesthesia and Surgery, Director, Fellowship in Critical Care Medicine, Department of Anesthesia, University of Pennsylvania Medical Center, 3400 Spruce Street, Philadelphia, Pennsylvania 19104–4283.(Accepted for publication September 11, 1996.)

Surgery in immunosuppressed patients with emergency or elective indications

Immunosuppressive therapy and its influence on perioperative pathophysiology present special challenges in the event of surgical intervention. Immunosuppressive agents alter the patient's response to surgical stress and infectious complications. The often masked signs, even in the case of severe infection, require a high index of suspicion to establish the diagnosis. This may result in a fatal delay of therapy. In addition, the immunosuppressed state increases the patient's susceptibility to infection and leads to an impairment of wound healing. Therefore, careful perioperative clinical monitoring of the patient and complete control of the immunosuppressive therapy are mandatory. Elective operations in immunosuppressed patients should be performed with special caution regarding the potential perioperative risks for the patient and the graft. On the other hand, if there is evidence of, for example, an acute abdominal event, a more aggressive approach is required to rapidly establish the diagnosis and institute appropriate therapy. From the surgical point of view, special emphasis should be placed on wound closure and on anastomotic sutures when operating on a patient receiving immunosuppressive therapy.