As aforementioned, the present study focused on the etiology of POI; the possible intervention approach was not investigated. Therefore, the question arises whether peritoneal CO or CO 2 exposure is able to avoid intestinal inflammation and POI compared to air exposure. This should be clarified in future experiments. In conclusion, our results suggest that the length of peritoneal air exposure is proportional to the degree of intestinal paralysis and the activation of intestinal inflammation, leading to POI.
In addition, increased oxidative stress response is linked to peritoneal air exposure, which may lead to systemic and local intestinal inflammatory responses.
Future studies should determine the exact molecular mechanism underlying the systemic and intestinal inflammation after peritoneal air exposure. Nevertheless, avoiding prolonged air exposure in open abdominal surgery should be encouraged in the clinical practice. This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Article of the Year Award: Outstanding research contributions of , as selected by our Chief Editors.
Read the winning articles. Journal overview. Special Issues. Academic Editor: Jyoti J. Received 08 Apr Revised 30 Jun Accepted 02 Jul Published 22 Jul Abstract Background. Introduction Postoperative ileus POI is a common and major iatrogenic complication after surgery, especially open abdominal surgery [ 1 ].
Materials and Methods 2. Table 1. Figure 1. Gastrointestinal transit. Figure 2. Figure 3. Figure 4. Figure 5. MPO activity in the tissues of ileum and colon. Figure 6. References J. Rychter and P. Vather, S. Trivedi, and I. Prasad and J. Asgeirsson, K. El-Badawi, A. Mahmood, J. Barletta, M. Luchtefeld, and A. Boeckxstaens and W. Stoffels, K. Hupa, S. Snoek et al. Gomez-Pinilla, F. Li, M. Cao, B.
Goetz et al. Kalff, T. Carlos, W. Schraut, T. Billiar, R. Simmons, and A. Kalff, W. Schraut, R. Augestad and C. Chen, S. Wexner, A. Iroatulam et al. Jiang, K. Yang, Q. Guan et al. Sammour, A. Kahokehr, S. Chan, R. Booth, and A. Lee, D. Feingold, J. Carter et al. Southall, S. Lee, M. Bessler, J. Allendorf, and R. Watson, H. Redmond, J. McCarthy, P.
Burke, and D. Ishibashi, H. Takeuchi, K. Fujii, N. Shiraishi, Y. Adachi, and S. Ooshiro, Y. Sugishita, H. Leukocyte-derived interleukin aggravates POI and in IL deficiency, neutrophil extravasation into the postsurgical bowel wall is reduced and protects mice from developing POI Stein et al. Lipid rich enteral nutrition is a physiologic approach to activate the cholinergic vagal anti-inflammatory pathway by stimulating cholecystokinin receptors Luyer et al.
In a randomized control trial, early enteral nutrition in patients undergoing major rectal surgery has been shown to reduce POI by improving recovery of gut motility, a reduction in the time to first defecation and length of hospital stay Boelens et al.
The contribution of mast cells to POI has been reviewed in experimental and clinical studies. Intestinal manipulation during surgery and mast cell degranulation releases pro-inflammatory mediators that can trigger formation of a localized infiltrate in the gut wall.
The inflammation plays a significant role in POI by disrupting GI motility that also includes non-manipulated bowel segments Peters et al. An earlier study provided proof of the concept that intestinal handling-induced mast cell activation and inflammation in human POI.
Mast cell activation tryptase release and inflammation were determined in peritoneal lavage fluid in patients undergoing conventional and minimal invasive surgery. The study showed that intestinal handling triggers mast cell activation and inflammation associated with prolonged POI, that may in part explain faster recovery with minimal invasive surgery, although other cells and mechanisms are likely to be involved as well The et al.
The role of mast cells in functional GI disorders was reviewed by Wouters et al. Similar approaches deserve consideration in POI. The effects of acupuncture on POI were also assessed in patients after colorectal resection and in colocolic anastomosis mice. Acupuncture also reduced high serum miRa level in patients with colorectal surgery. Carbon monoxide treatment was shown to ameliorate POI in mice Moore et al. More recent studies have shown that H 2 S is involved in cellular signaling and cytoprotection of the colonic mucosa and other organ systems Calvert et al.
A recent study in mice showed that the H 2 S-releasing naproxen derivative ATB and the slow releasing H 2 S donor GYY were effective in reducing intestinal inflammation and restoring transit in postoperative ileus Van Dingenen et al. A systematic review and meta-analysis revealed that NSAIDs reduce the time to recovery of gut function after elective colorectal surgery Milne et al. The underlying mechanisms by which H 2 S releasing compounds exert their beneficial effects in POI remain unknown.
In China, acupuncture has been traditionally used as an alternative treatment of GI disorders Takahashi, Even though several studies have determined the effectiveness of acupuncture in the prophylaxis against POI after colorectal surgery, current clinical evidence remains inconclusive Meng et al.
Additional randomized controlled studies are necessary to prove or disprove its effectiveness. Electroacupuncture EA is a modern way of delivering acupuncture used widely in various GI diseases around the world. EA administered at ST36 shortened the recovery time of GI and colonic transit and increased gastric emptying.
The beneficial effect of EA on POI was thought to be mediated by exciting neurons in the nucleus of the solitary tract NTS and activating the vagus efferent nerve pathway to improve GI tract transit, but not by activating the cholinergic anti-inflammatory pathway Fang et al. Inflammation in intestinal mesothelial cells in the abdominal cavity is an important pathogenic mechanism in clinical conditions such as POI and peritonitis.
Small bowel mucosal antimicrobial defense is disturbed in a gut manipulation mouse model of POI and it is accompanied by bacterial overgrowth and translocation. IL1R activation is involved in gene expression of mucosal antimicrobial peptides that serves to protect the epithelium from an increasing microbial challenge Stein et al. Data suggest that HuR is a potential candidate drug target for the mitigation of POI, and further studies are necessary to prove this.
A better understanding of the pathogenic mechanisms of POI and POGD in both experimental models and in the clinical setting are desperately needed. A cellular target of growing interest in the field of neurogastroenterology and motility is the enteric glial cell and in particular in GI disorders. Enteric neuropathies are a hallmark of GI Diseases and Disorders. A growing body of evidence supports the concept that enteric glia are involved in the pathogenesis Ochoa-Cortes et al.
There is great interest in enteric glia in the field of neurogastroenterology and motility—they are implicated in GI diseases and disorders including IBS, IBD, postoperative ileus, chronic morphine-induced constipation, and idiopathic constipation Ochoa-Cortes et al.
Enteric glia and neurons contribute to enteric neuropathies underlying these disorders Ochoa-Cortes et al. Disruption of glial cell activity leads to abnormal motility. Enteric glia is activated by mechanical forces encountered during peristalsis that are generated by coordinated movements of the gut.
Glial activation is involved in ongoing fine-tune modulation of motility through the ENS. Reactive glia contributes to neuroinflammation and abnormal motility associated with POI. Working hypothesis of proposed glial pathogenic mechanism of postoperative ileus—Enteric glia are very sensitive to mechanical stimulation and mechanical forces generated during peristalsis.
Touch, stretch, shear stress, pressure, compression, membrane perturbations and centrifugal forces all operate during peristalsis. Mechanosensation is a normal function of enteric glia in the modulation of motility through interactions with the ENS.
Abnormal mechanical forces encountered during GI surgery such as gut manipulation, surgical insult, fluid edema or high pressure pneumoperitoneum encountered in minimal invasive laparoscopic surgery, may activate enteric glia and immune cells in the muscularis externa contributing to the induction of a reactive enteric glial cell phenotype. Signs and symptoms include nausea, vomiting, Pain distention, bloating and constipation. Pain pathways also activate the sympathetic nervous system which has inhibitory effects on GI motility.
Edema and high-pressure pneumoperitoneum high PNP resulting from inflating the peritoneal cavity during laparoscopic surgery can also activate glia. In laparoscopic operations, patient positioning and gravity are used for mass movement, but abdominal contents are exposed to increased serosa pressure from carbon dioxide insufflation. In addition to such high PNP, edema from intravenous fluids causes swelling and stretch of glia to activate them Cooke et al.
Mechanogated channels are activated by such abnormal mechanical stimulation of the bowels during intestinal surgery—The types of channels involved are under investigation, but so far, the type of channel s linked to glial mechanosensation remain elusive.
Candidate channels include various transient receptor potential channels, Piezo 1, 2 channels, connexin hemichannels, pannexin channels, P2X7 channels and Aquaporin channels Kirischuk, ; Alcaino et al. Despite lower incidence of POI with a minimal invasive approach compared with open surgery laparotomy Behm and Stollman, ; Bragg et al.
High-pressure pneumoperitoneum PNP , may cause systemic inflammation and affect the immune response in the early postoperative period Schietroma et al. In order to overcome such adverse effects, low CO 2 PNP pressure could potentially be used to reduce the risk of POI and POGD by reducing postoperative inflammatory response circulating levels of inflammatory mediators or intestinal inflammation and immune suppression. To date, no clinical trials have tested whether low-pressure pneumoperitoneum is protective against intestinal and systemic inflammation, POI and POGD.
Our ongoing research has shown that intestinal glial cells are very sensitive to physiologic mechanical forces such as those occurring during peristalsis or excessive forces such as occur during surgical manipulation. During laparoscopic surgery, excessive external mechanical forces generated by high-pressure pneumoperitoneum may overcome the autoregulation capacity of the intestinal glia, and the constant increased intra-abdominal pressure IAP which result in bowel compression would induce a reactive glial phenotype.
In a recent retrospective study, lower pneumoperitoneum pressures were associated with a reduced incidence of POI and LOS in patients undergoing robotic-assisted radical prostatectomy Rohloff et al. Reactive glia together with other cells in the gut muscularis externa i. These are potential novel glial targets for future drug development that have been described in a recent review in IBD Ochoa-Cortes et al.
Therefore, they will only be given a brief mention here. Potential pathogenic mechanisms targeted in preclinical studies for POI are shown in Figure 3. Under normal physiological conditions, glial cells modulate motility by interacting with neural-motor components of the gut.
Gut surgical trauma and manipulation induces a reactive enteric glial phenotype that contributes to the overall neuroinflammation and GI dysmotility.
Experimental evidence in reactive glia suggests that a variety of glial molecular signaling mechanisms may be operating in POI. Edema alone can decrease intestinal contractile activity Uray et al. During abdominal surgery and surgical trauma, edema results in increased stretch of intestinal smooth muscle cells that was shown to down-regulate MLC phosphorylation Chu et al.
Therefore edema in the gut wall and increased intestinal wall stress Cox et al. Targeting this pathway might also be a promising target to prevent POI in surgical patients Hupa et al. This pathway is involved in ENS neural dysfunction. Testing PEA in a clinical trial for POI, a disease associated with acute inflammation of the muscularis externa may be possible since it is available as a nutritional supplement for the relief of intestinal symptoms of IBD.
Little is known about quality and functional recovery after surgery Feldman et al. It is not clear if POGD has a downstream effect on long-term recovery and quality of life.
For instance, we know that POCD is an important complication after surgery, especially in the elderly patient, with short term and long-term complications that significantly impact their quality of life Steinmetz et al.
It is also possible and quite probable that POGD may represent short- and long-term complications during the acute phase involving inflammation, and long term after inflammation has resolved and the patient leaves the hospital.
A recent study in neurogastroenterology and motility provided proof of concept, by showing for the first time that POI significantly decreases the quality of life at 3 and 6 months QoL Peters et al. Therefore, it would be prudent to incorporate quality of life questionnaires in the CERAS protocols and extending the timeline to a longer postoperative period to uncover potential complications occurring after intestinal or systemic inflammation has resolved to further investigate long-term outcomes and mechanisms in POGD.
ERAS involves a holistic, multimodal and articulate approach involving perioperative care. Even though the relative contribution of each element to the utmost outcomes has not been determined, reduced stress response and accelerated recovery have been consistently reported in patients undergoing surgery within ERAS protocols Varadhan et al.
In spite of the favorable perioperative outcomes reported in the first CERAS protocol in , these guidelines were not widely implemented until recent years Greco et al. Minimally invasive techniques are the cornerstone of ERAS protocols. A faster resolution of GI dysfunction and reduced length of hospital stay have been reported in patients undergoing laparoscopic surgery when compared to conventional open surgical approaches Schwenk et al.
However, when the open surgical approach is combined with ERAS protocols, POI incidence may be comparable between open and laparoscopic groups Lei et al. Nevertheless, a recent report suggests that in the context of ERAS, laparoscopic techniques are associated with better immunologic response and shorter duration of POI Wang et al. Nasogastric NG tube insertion along with liberal parenteral hydration were routinely indicated during the postoperative period of GI surgery. Traditionally, the common practice involved leaving the GI tract to rest after surgery expecting faster healing.
Therefore, the return of GI function was mandatory before the resumption of enteric nutrition Verma and Nelson, However, little evidence supported these methods. In contrast, a growing body of evidence suggested that early feeding was associated with a significant reduction in postoperative complications and length of hospital stay Lewis et al.
Postoperative pain management after abdominal surgery may be challenging for health care providers. Despite being effective analgesics, reduced GI motility is commonly reported in patients receiving opioids for postoperative pain management Viscusi et al.
Multimodal analgesia combines regional analgesia, non-opioid analgesics [acetaminophen, nonsteroidal anti-inflammatory drug NSAID or cyclooxygenase COX -2 specific inhibitor], lidocaine infusions, gabapentinoids and ketamine. Numerous studies have shown the opioid-sparing effect of this approach resulted in an accelerated GI recovery and improved outcomes. However, an optimal combination of these elements has not yet been elucidated Geltzeiler et al.
Thoracic epidural accelerates peristalsis by blocking pain afferents and efferent sympathetic inhibitory nerves. Epidural blocks are commonly used in patients undergoing open and complex abdominal surgeries Gustafsson et al. In , a Cochrane review of patients undergoing abdominal surgery reported a relevant association between epidural analgesia with an accelerated return of flatus and bowel movements Khan et al.
Transverse abdominis plane block TAP block is an effective alternative in patients undergoing abdominal surgeries. Torgeson et al. A significant reduction in LOS 2. Of note, the incidence of postoperative nausea and vomiting was higher in the TAP block group Nonsteroidal anti-inflammatory drugs NSAIDs such as ketorolac and ibuprofen, mainly block the cyclooxygenase COX enzyme inhibiting the prostaglandin biosynthesis with subsequent decreased pain receptor activation.
Similarly, an opioid-sparing effect and decreased opioid-related side effects have been reported after NSAIDs use Elia et al. Moreover, selective COX-2 inhibitors have a potent analgesic and anti-inflammatory effect but, its use in this patient setting has been associated with higher rates of anastomotic leak Klein et al. In contrast, acetaminophen may be an acceptable alternative therapy for pain management Apfel et al.
Oral, intravenous and rectal formulations are available. Lidocaine infusion is commonly known for its anti-inflammatory properties and opioid-sparing effect Knotkova and Pappagallo, ; Dunn and Durieux, In addition to reduced postoperative pain scores, lidocaine infusion may improve GI recovery and shorten LOS after open abdominal surgeries Sun et al.
Other adjuvant agents such as gabapentin and ketamine, are widely known by their anti-hyperalgesic effect and a subsequent reduction in opioid consumption that potentially decreases the incidence and duration of POGD Bell et al. Some pharmacologic agents decrease the incidence and duration of POI by selectively blocking the intestinal i.
There is an important body of evidence indicating that Alvimopan enhances GI recovery in patients who received high doses of opioids after open abdominal surgery Delaney et al. However, in light of ERAS protocols involving reduced opioids requirement, the usefulness of Alvimopan in minimally-invasive colorectal surgery has been recently questioned Keller et al.
Mechanical bowel preparation with oral antibiotics MBP-OAB is commonly indicated to prevent surgical site infection SSI , anastomotic leak and ileus after elective colorectal surgery Kiran et al.
However, a recent randomized clinical trial by Koskenvuo et al. The gut is highly susceptible to interstitial edema. However, in the context of CERAS programs with more conservative fluid therapies, the effects of edema may be importantly attenuated Srinivasa et al. Supportive treatment and symptom control are paramount during POGD management. The first step is to rule out any acute intra-abdominal condition or other surgical complications.
Serial radiographic imaging and computed tomography CT scan should be considered Sandrasegaran and Maglinte, Supportive care may include the removal of any potential triggers such as opioids and fluid overload. Moreover, bowel rest with NG tube insertion may be considered for gastric decompression and pulmonary aspiration risk Adiamah and Lobo, A search of Clinical Trials. Simethiocone is in a Phase IV clinical trial for POI that acts as an anti-bloating and anti-flatulence medication by reducing the surface tension of the gas.
Ulimovelin is a ghrelin agonist being tested as a prokinetic agent in a new Phase III clinical trial. Historically, prokinetic agents have been commonly used to treat POI. Drinking coffee and nicotine chewing gum are other approaches under investigation. Chewing gum was traditionally known to expedite GI recovery after abdominal surgery Li et al. However, most of the studies supporting this effect were published before the implementation of early postoperative feeding as part of the ERAS protocols Ho et al.
The effects of chewing gum are described in a systematic review Short et al. Caffeine is widely known as a stimulant to colonic motor activity in animals and humans Rao et al. Our review focused on recent advances and understanding in pathogenic mechanisms, treatment strategies, pipeline drugs and ongoing clinical trials and approved medications for those targets for POI and POGD.
Further clinical studies on 5HT 4 R agonists and vagal nerve stimulation are required to establish their usefulness as novel therapies, and more work needs to be done of short and long term impact of gut surgical manipulation on patient outcomes.
A key target of investigation should be to pinpoint the triggering mechanism s in various cells in the intestinal wall, and better understand the dynamic interactions between various cells implicated in the disease. Our review provides some examples of how targeting different cells in the gut wall, can potentially identify novel therapeutic targets for POI and POGD. Despite the implementation of enhanced recovery protocols for GI surgeries, there is still significant POI and POGD associated with prolonged hospitalizations, and increased morbidity and healthcare costs.
We cannot deny that significant progress has been made with ERAS protocols and other advances in the field to reduce the incidence and overall morbidity associated with this iatrogenic disorder.
Novel therapies in the pipeline offer some hope for better treatments, but a better understanding of the pathogenic mechanism s of POI is required to develop better therapeutic strategies Collins et al.
As food for thought, the NIH recently published its strategic plan. In that document, NIH reaffirmed its strong commitment for basic scientific discovery noting that many of the most important medical advances trace back to basic research, which had no explicit link [NIH, NIH-Wide Strategic Plan www.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. We wish to thank the Department of Anesthesiology for providing additional developmental funds to support studies on postoperative ileus.
In addition, we would like to thank the members of our Clinical Research Team in the Anesthesiology Department at The Ohio State University for their support of our clinical studies on POI, in scheduling and consenting patients to participate in the studies, providing regulatory support, and for procurement of viable surgical specimens from GI surgeries to study pathogenic mechanisms of postoperative ileus.
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Protein catabolism is stimulated by increased cortisol concentrations. Predominantly skeletal muscle is broken down, but some visceral muscle protein is also catabolized to release the constituent amino acids.
The liver also converts amino acids into other substrates, glucose, fatty acids or ketone bodies. Protein catabolism results in marked weight loss and muscle wasting in patients after major surgical and traumatic injury. The loss of protein can be measured indirectly by increased nitrogen excretion in the urine.
There has been much interest in the provision of nutritional supplements for patients with critical illness and those undergoing major surgery. Certain nutrients may have a beneficial influence on the immune status of stressed patients.
Studies of patients given enteral nutrition supplemented with arginine or glycine after major surgery benefited from a faster recovery of immunological parameters, fewer infectious complications and a shorter hospital stay. As a result of hormonal changes during surgery, fats stored as triglycerides are converted by lipolysis to glycerol and fatty acids.
Lipolytic activity is stimulated by cortisol, catecholamines and growth hormone and is inhibited in the presence of insulin. The net result is increased mobilization of triglyceride, although plasma concentrations of glycerol and fatty acids may not change markedly.
The glycerol produced by lipolysis is a substrate for gluconeogenesis in the liver. A number of hormonal changes occur in response to surgery which influence salt and water metabolism. These changes support the preservation of adequate body fluid volumes.
Arginine vasopressin, which is released from the posterior pituitary, promotes water retention and the production of concentrated urine by direct action on the kidney. Increased vasopressin secretion may continue for 3—5 days, depending on the severity of the surgical injury and the development of complications. Renin is secreted from the juxtaglomerular cells of the kidney, partly as a result of increased sympathetic efferent activation.
Renin stimulates the production of angiotensin II. The endocrine response is activated by afferent neuronal impulses from the site of injury. These travel along sensory nerve roots through the dorsal root of the spinal cord, up the spinal cord to the medulla to activate the hypothalamus. In classical experiments, Egdahl demonstrated the role of the nervous system in the activation of the stress response.
Blood samples were collected from the adrenal vein for assay of adrenal corticosteroid concentration. In animals with an intact sciatic nerve, operative injury and burns to the limb resulted in an immediate and sustained increase in adrenal hormone concentration in samples from the adrenal vein. If the nerve was cut after the injury, there was a rapid decline in the hormone response. In those animals in which the sciatic nerve was transected before operative or burn injury, there was no increase in adrenal hormone after the trauma.
This work did not provide evidence that local substances were released after injury which stimulated the pituitary—adrenal axis. The idea that local substances might influence some of the changes associated with surgery was advanced by the discovery of the cytokines.
They are produced from activated leucocytes, fibroblasts and endothelial cells as an early response to tissue injury and have a major role in mediating immunity and inflammation.
Details of the cytokine network and the activation of cytokines in response to surgery have been reviewed recently. The cytokines have a major role in the inflammatory response to surgery and trauma. They have local effects of mediating and maintaining the inflammatory response to tissue injury, and also initiate some of the systemic changes which occur.
This is a 26 kDa protein. Concentrations of circulating cytokines are normally low and may be undetectable. Cytokine production reflects the degree of tissue trauma, so cytokine release is lowest with the least invasive and traumatic procedures, for example, laparoscopic surgery. After these operations, cytokine concentrations are maximal at about 24 h and remain elevated for 48—72 h postoperatively.
Production of other proteins in the liver, for example, albumin and transferrin, decreases during the acute phase response. Concentrations of circulating cations such as zinc and iron decrease, partly as a consequence of the changes in the production of the transport proteins.
In patients after surgery, cytokines may augment pituitary ACTH secretion and subsequently increase the release of cortisol. A negative feedback system exists, so that glucocorticoids inhibit cytokine production. This suggests that stimuli for the stress response arise from visceral and peritoneal afferent nerve fibres in addition to those from the abdominal wall.
Anaesthesia has little effect on the cytokine response to surgery because it cannot influence tissue trauma. Although regional anaesthesia inhibits the stress response to surgery, it has no significant effect on cytokine production.
It has been known for many years that opioids suppress hypothalamic and pituitary hormone secretion. McDonald and colleagues demonstrated the suppressant effect of therapeutic doses of morphine on the hypothalamic— pituitary—adrenal axis in humans. The inhibitory effects of morphine occur at the hypothalamic level. In cardiac surgery, the effects of morphine and other opioids on the stress response to surgery have been well documented. In upper abdominal surgery, systemic opioids are relatively ineffective in preventing the stress response to upper abdominal surgery.
The synthesis of both aldosterone and cortisol is blocked. A single induction dose of the drug will suppress hormone production for 6—12 h, 48 while infusion for 1—2 h blocks cortisol synthesis for up to 24 h. The use of etomidate by infusion as part of intravenous sedation for critically ill patients was found to be associated with increased mortality.
A recent study has examined adrenocortical function in critically ill patients after induction of anaesthesia with etomidate or thiopental.
Cortisol concentrations before induction of anaesthesia were high, in keeping with other studies of adrenal function in critically ill patients.
Those patients who received etomidate tended to have a smaller cortisol response to stimulation by ACTH than the control thiopental group. Although assessment of adrenocortical function in critically ill patients using single cortisol concentrations and ACTH stimulation tests is the subject of great controversy, 34 this study suggests that etomidate may interfere with cortisol synthesis in these patients.
The benzodiazepine, midazolam, which has an imidazole ring in addition to the basic benzodiazepine structure, attenuates the cortisol responses to both peripheral and upper abdominal surgery.
Although Crozier and colleagues showed that subjects produced cortisol in response to exogenous ACTH, 9 thus confirming that the site of action of the benzodiazepine is at the hypothalamic—pituitary level, a direct inhibitory effect on steroid production cannot be excluded.
Extensive epidural analgesia with local anaesthetic agents will prevent the endocrine and metabolic responses to surgery in the pelvis and on the lower limbs.
Epidural blockade from dermatomal segment T4 to S5, established before the start of surgery, prevented increases in cortisol and glucose concentrations in response to hysterectomy. Thus the adrenocortical and glycaemic responses to surgery are abolished.
Less extensive neural blockade will not completely abolish the hormonal and metabolic changes. In upper abdominal or thoracic surgery, it is not possible to prevent pituitary hormone responses completely, even with extensive epidural local anaesthetic blockade. In a classical study by Bromage and colleagues, epidural block up to the C6 dermatome inhibited glycaemic changes but not the increases in cortisol concentrations in response to upper abdominal and thoracic surgery.
Many suggestions have been made to explain the failure to abolish completely the stress responses in these studies. Most of these centre around inadequate or incomplete afferent somatic and sympathetic neural blockade which allows pituitary activation and hence cortisol release from the adrenal cortex under the influence of ACTH, whilst efferent blockade of nerves to the adrenal medulla and the liver inhibits hyperglycaemic responses.
Attempts were made subsequently to improve on the afferent blockade using vagal blockade, splanchnic nerve block or continuous intraperitoneal local anaesthetic, but no technique has abolished consistently the stress responses to upper abdominal or thoracic surgery.
Perioperative thoracic epidural anaesthesia has been used successfully in the management of patients undergoing coronary artery bypass surgery. It is possible to prevent changes in catecholamine responses during CPB and up to 24 h after the start of cardiac surgery using thoracic epidural analgesia combined with general anaesthesia.
The cortisol responses to CPB may also be attenuated using thoracic epidural analgesia, although studies show variable results. Although there is no direct association between the attenuation of hormonal and metabolic responses and postoperative outcome, the use of thoracic epidural analgesia in cardiac surgery has many potential benefits in terms of improvements in organ function.
Thoracic epidural anaesthesia provides intense analgesia, avoids the use of systemic opioids and improves postoperative pulmonary function. Measurement of serum concentrations of the protein can be used to assess myocardial ischaemia. A recent study showed that thoracic epidural anaesthesia and general anaesthesia in cardiac surgery attenuated the myocardial sympathetic response and was associated with decreased myocardial damage as determined by less release of troponin T.
The sympatholytic effects of the blockade of cardiac sympathetic efferents and afferents may improve the balance of oxygen delivery and consumption.
The use of thoracic epidural anaesthesia in patients with heart disease has been the subject of a recent review. Despite the potential benefits of thoracic epidural anaesthesia, there are specific cautions about the use of regional neural blockade in patients who are given anticoagulants because of the risk of epidural haematoma formation.
Procedural guidelines may be used to minimize the risk of neurological complications. This may lead to arm weakness, and apnoea may occur if the diaphragm is affected by blockade of nerve roots C3—C5. Testing of arm movements has been advocated to monitor cephalad spread of thoracic epidural anaesthesia. There has been a great deal of interest in the modification of the stress response with respect to the potential beneficial effects on surgical outcome.
The extent to which the responses are modified depends on the choice of the analgesic techniques used. Inhibition of stress responses is greatest with neural blockade with local anaesthetics. Therefore attention has focused largely on the effects of regional anaesthetic and analgesic regimens, particularly epidural blockade with local anaesthetic agents. Individual studies show that provision of analgesia using neural blockade leads to improvements in physiological variables in specific organ systems.
Single investigations often cannot show benefits in morbidity and mortality because the incidence of serious complications after surgery is generally low, and the numbers of patients studied is small. It is well established that regional analgesic techniques reduce the incidence of thromboembolic complications following surgery of the pelvis and lower limbs.
Although it might be assumed that good analgesia with regional techniques should lead to decreased postoperative pulmonary complications, improvements in overall pulmonary outcome have not been demonstrated unequivocally. Regional analgesia is very effective in tempering some of the cardiovascular responses to surgery which result from sympathetic activation.
Whether neural blockade techniques are more beneficial in terms of overall cardiac morbidity and outcome compared with other methods of pain relief has not been established. Continuous epidural analgesia at the thoracic level decreases paralytic ileus following abdominal procedures. The elimination of ileus allows the early use of enteral nutrition which is an important factor in reducing the risk of infectious complications.
Despite evidence that regional analgesia confers beneficial effects on organ function, improvements in overall postoperative morbidity and length of hospital stay have not been demonstrated conclusively. This is disappointing in view of the widespread introduction of acute pain services which consume time and resources.
Of course, analgesia is provided for humanitarian reasons. Many factors other than analgesic regimens influence recovery from major surgery and the ability of the patient to return home and resume work. Other factors are also important, not least the expectations of patients and of the nursing and medical staff. Behavioural and subjective changes are part of the response to surgery. Feelings of malaise and postoperative fatigue have a strong influence on recovery from surgery and return to work.
Salmon and Hall have developed a theory of postoperative fatigue which encompasses psychological and cultural mechanisms as well as physiological changes. The use of minimally invasive surgical techniques, including laparoscopically assisted procedures, will reduce the effects of tissue injury. Postoperative nausea and vomiting and paralytic ileus should be avoided and enteral and oral feeding used.
Early mobilization must be encouraged and is facilitated by good analgesia and the avoidance of tubes and drains. A rapid return to normal function has to be encouraged. The stress response to surgery comprises a number of hormonal changes initiated by neuronal activation of the hypothalamic—pituitary—adrenal axis. The overall metabolic effect is one of catabolism of stored body fuels.
In general, the magnitude and duration of the response are proportional to the surgical injury and the development of complications such as sepsis. Other changes also occur following surgery, notably an increase in cytokine production which is triggered locally as a tissue response to injury.
Regional anaesthesia with local anaesthetic agents inhibits the stress response to surgery and can also influence postoperative outcome by beneficial effects on organ function. Principal hormonal responses to surgery.
Based on Desborough and Hall Features of the acute phase response. Based on Sheeran and Hall Acta Anaesthesiol Scand ; 37 : 1 — An epidural scoring scale for arm movements [ESSAM] in patients receiving high thoracic epidural analgesia for coronary artery bypass grafting. Anaesthesia ; 54 : — Adrenocortical function in critically ill patients 24 h after a single dose of etomidate. Anaesthesia ; 54 : —7. Anesth Analg ; 86 : — Anaesthesia ; 39 : 19 — Sepsis and cytokines: current status.
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