Esther M. Pogatzki

A Multimodal Approach to Control Postoperative Pathophysiology and Rehabilitation in Patients Undergoing Abdominothoracic Esophagectomy

This two-armed study was designed to determine whether recovery after esophageal resection may be improved by introducing a new multimodal approach. For 8 mo after the new approach was introduced, all patients undergoing abdominothoracic esophageal resection were studied (Group 2; n = 42). For comparison, a retrospective analysis was also conducted using the data of all patients who had undergone this operation in the 8 mo before the introduction of the new regimen, when the traditional therapy was still in use (Group 1; n = 49). All patients received an epidural catheter at the level of T6-9 before the induction of general analgesia. Afterward, Group 1 patients were operated under general anesthesia. For postoperative pain relief, a mixture of bupivacaine 1.25 mg/mL and sufentanil 1 micro g/mL was administered during 5 days without titration of the quality of analgesia. Patients in Group 2 received a preoperative bolus of 10-15 mL bupivacaine 2.5 mg/mL and 20-30 micro g sufentanil. After sensory block up to T4 was confirmed, general anesthesia was introduced and intraoperatively combined with a continuous infusion of 5 mL/h of a solution containing bupivacaine 1.75 mg/mL and sufentanil 1 micro g/mL. Postoperatively, the epidural infusion rate was adjusted to the need of the individual patients, who were able to administer themselves additional bolus doses of 2 mL with a lockout time of 20 min. Early tracheal extubation and forced mobilization were pursued to improve recovery. Demographic data of both groups were comparable. The pain relief of Group 2 patients was superior to that of patients in Group 1. The nitrogen balance of a subgroup of nine matched pairs of patients with comparable nutritional status was less negative in Group 2 patients on Postoperative Days 1 and 2. Patients in Group 2 were tracheally extubated earlier (mean 6.7 vs 25.1 h after admission to the intensive care unit [ICU]), mobilized earlier (mean 1.2 vs 2.0 days after surgery), discharged from the ICU earlier (mean 1.7 vs 4.0 days), and fulfilled criteria for discharge from the ICU (mean 1.8 vs 4.1 days) and from the intermediate care unit earlier (4.9 vs 6.4 days). We conclude that the multimodal approach may improve recovery and thus reduce costs after abdominothoracic esophageal resection. Implications: Analgesia and blockade of the perioperative stress response, combined with other aspects of postoperative therapy, may improve recovery after surgery. The intensive care unit stay after esophageal resection was reduced by a new regimen (thoracic epidural analgesia, early tracheal extubation, forced mobilization). This approach may influence the cost of major surgery. (Anesth Analg 1998;86:228-34)

Epidural analgesia with local anesthetics after abdominal surgery : Earlier motor recovery with 0.2% ropivacaine than 0.175% bupivacaine

UNLABELLED The aim of this prospective, randomized, double-blinded study was to compare pain relief, side effects, and ability to ambulate during epidural anesthesia with ropivacaine 0.2% plus sufentanil versus bupivacaine 0.175% plus sufentanil after major gastrointestinal surgery. Epidural catheters were inserted at T8-11, and 30 microg of sufentanil with 15 mL of ropivacaine 0.75% (Group 1, n = 42) or bupivacaine 0.5% (Group 2, n = 44) was injected. General anesthesia was induced, a continuous epidural infusion (5 mL/h) was then begun with 1 microg/mL sufentanil plus ropivacaine 0.2% (Group 1) or bupivacaine 0.175% (Group 2). Postoperatively, the infusion rate was adjusted to individual requirements. Patients were also able to receive additional 2-mL bolus doses every 20 min. Demographic data (except for gender and height), analgesia, drug dosage, and side-effects, including motor blockade (Bromage score), were similar in both groups, but mobilization recovered more quickly in Group 1. Gender, age, ASA physical status, duration of surgery, and intraoperative blood loss had no effect on mobilization. We conclude that epidural analgesia is effective and safe with both regimens. There is not necessarily a correlation between the Bromage score and the desired outcome of mobilization. The ability to walk postoperatively is hastened if ropivacaine is used instead of bupivacaine. IMPLICATIONS Regarding pain relief and side effects, epidural analgesia with ropivacaine 0.2% and sufentanil 1 microg/mL yields pain scores and pain intensity comparable to those for the well evaluated combination of bupivacaine 0.175% and sufentanil 1 microg/mL. However, earlier recovery of the ability to walk unassisted in patients receiving the combination of ropivacaine and sufentanil may result in their earlier rehabilitation.

Effect of Pretreatment with Intrathecal Excitatory Amino Acid Receptor Antagonists on the Development of Pain Behavior Caused by Plantar Incision

Background Drugs that block spinal excitatory amino acid receptor activation may prevent pain after surgery. The authors previously studied the effect of excitatory amino acid receptor antagonists after incision. In the present study, we examined the role of N-methyl-d-aspartate (NMDA), non-NMDA, and metabotropic glutamate receptors (mGluRs) on the development of pain behavior after plantar incision. Methods Rats with lumbar intrathecal catheters were anesthetized with halothane. Fifteen minutes before an incision was made, drug [40 nmol MK-801; 20 nmol NBQX; or 200 nmol (+)-MCPG] or vehicle was injected intrathecally followed by an infusion of the same drug for 75 min. Withdrawal thresholds to calibrated von Frey filaments applied adjacent to the wound and response frequencies to a blunt mechanical stimulus applied directly to the wound were measured before incision and 1, 2, 4, and 6 h after incision and then once daily for 6 days. Results Preincision treatments with antagonists against the NMDA (MK-801) and group I and II metabotropic receptors [(+)-MCPG] did not inhibit the development of mechanical hyperalgesia caused by incision. Preincision treatment with the non-NMDA receptor antagonist NBQX increased withdrawal thresholds at 1 and 2 h and on postoperative day 1 compared with the vehicle group; response frequencies were reduced 1 and 2 h after incision and on postoperative day 2 (P < 0.05). In an additional group, postincision treatment with NBQX was similar to preincision treatment. Conclusion Spinal NMDA and mGluR antagonists may not be useful for preventing postsurgical pain. Spinal non-NMDA receptor antagonists reduced pain behaviors, but a preventive effect using preincision treatment was not apparent.

Effect of plantar local anesthetic injection on dorsal horn neuron activity and pain behaviors caused by incision

&NA; Hypersensitivity after tissue injury is an expression of neuronal plasticity in the central nervous system. This has been explored most extensively using in vitro preparations and animal models of inflammatory pain and chemical irritation. For pain after surgery, a similar process has been proposed. In the present study, we examined dorsal horn neuron (DHN) sensitization using the plantar incision model for post‐operative pain. In behavioral experiments, the effect of a local anesthetic injection (or saline vehicle) 15 min before plantar incision on pain behaviors several days after incision was studied. Bupivacaine injection before incision prevented pain behaviors until 4 h afterwards; injection after incision produced the same effect. One day after incision, pain behaviors were not different between rats injected with saline or bupivacaine. In neurophysiologic experiments, however, bupivacaine injection blocked activation of DHNs during incision. One hour after incision, expansion of receptive fields (RFs) to pinch and increased background activity occurred in 14 of 16 neurons in the saline group but only in two of 22 neurons in the bupivacaine group. The difference was not due to a systemic effect of bupivacaine. Ten sensitized neurons were studied using the injection of bupivacaine 90 min after incision. Increased background activity (n=7) and expanded RFs (n=7) were reversed by bupivacaine. Sensitization was re‐established in seven of eight neurons 2 h after injection as the local anesthetic dissipated. These results indicate that activation of DHNs during plantar incision and sensitization 1 h later are not necessary for subsequent pain behaviors. Because sensitization was reversed 90 min after plantar incision and then re‐established as the local anesthetic effect diminished, enhanced responsiveness of DHN requires ongoing afferent input during the first day after incision.

Lumbar catheterization of the subarachnoid space with a 32-gauge polyurethane catheter in the rat

Chronic catheterization of the subarachnoid space of rats is an important tool for intrathecal drug delivery in pharmacologic investigations of pain. We describe a technique using direct lumbar insertion of a small 32‐gauge polyurethane (PU) catheter without extensive surgery. Location of the catheter was confirmed with 2% lidocaine injection 1 day later, and methylene blue injection after 7–14 days. This method improved recovery of the rat after catheter implantation and reduced neurologic complications. Copyright 2000 European Federation of Chapters of the International Association for the Study of Pain

Spinal glutamate receptor antagonists differentiate primary and secondary mechanical hyperalgesia caused by incision

Secondary mechanical hyperalgesia has been demonstrated in postoperative patients indicating that central sensitization occurs after surgery. However, the underlying mechanisms are unknown. Here, we studied the role of spinal N‐methyl‐d‐aspartate and &agr;‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole‐propionic acid (AMPA)/kainate receptors for pain behaviors indicating secondary hyperalgesia caused by gastrocnemius incision in the rat. We further determined if Ca2+ permeable AMPA/kainate receptors are important for secondary hyperalgesia after gastrocnemius incision and for pain behaviors indicating primary hyperalgesia and guarding behavior after plantar incision. Withdrawal thresholds (WTs) to punctate mechanical stimuli were assessed by applying calibrated monofilaments to the plantar hind paw before gastrocnemius incision. WTs were tested again 2 h after gastrocnemius incision and again after intrathecal (IT) injection of either dizocilpine maleate (MK‐801), 2‐amino‐5‐phosphonovaleric acid (AP5), 1,2,3,4‐tetrahydro‐6‐nitro‐2,3‐dioxo[f]quinoxaline‐7‐sulfonamide (NBQX), or Joro spider toxin (JSTX). The doses used were: MK‐801 (vehicle, 15, 30, 40 nmol), AP5 (vehicle, 10, 30 nmol), NBQX (vehicle, 5, 10 nmol), and JSTX (vehicle, 2, 5, 9 nmol). In the same rats, WTs were tested on postoperative day 2 before and after the same drugs were injected again. In other rats, WTs to monofilaments and response frequencies to a non‐punctate mechanical stimulus or guarding behaviors were determined before, 1 h after plantar incision was made, and assessed again after JSTX (9 nmol or vehicle) was administered IT. Secondary mechanical hyperalgesia after gastrocnemius incision was dose‐dependently blocked by NBQX but was only marginally affected by AP5 or MK‐801. Only secondary mechanical hyperalgesia was reversed by JSTX; primary mechanical hyperalgesia and guarding behavior were unchanged. These results indicate that spinal sensitization contributing to behaviors for secondary hyperalgesia after incision requires Ca2+ permeable AMPA/kainate receptors. The data further demonstrate that behaviors for secondary mechanical hyperalgesia after incision can be inhibited without affecting behaviors for primary mechanical hyperalgesia and guarding. Mechanisms for central sensitization causing secondary hyperalgesia in postoperative patients may therefore be seperated from spontaneous pain and hyperalgesia that arises adjacent to the area of the incision.

Persistent secondary hyperalgesia after gastrocnemius incision in the rat

Secondary hyperalgesia, an exaggerated response to stimuli applied to undamaged tissue surrounding an injury, is a common consequence of tissue injury and inflammation. It is well established that the etiology of secondary hyperalgesia is sensitization of central neurons but the exact mechanism and its role in certain clinical pain states is unclear. In the present experiments, we studied responses to punctate and non‐punctate mechanical stimuli and to heat applied to the plantar aspect of the hindpaw remote to an incision in the gastrocnemius region of the rat hindlimb. Median withdrawal thresholds to von Frey filaments were reduced 2 h after incision of skin, fascia and muscle (gastrocnemius incision, n = 9) and remained reduced through postoperative day 6 (p < 0.05 vs sham). Only a transient reduction in withdrawal threshold occurred after incision of skin and fascia (skin incision, n = 10). No enhanced responsiveness to blunt mechanical stimulation or reduction in withdrawal latency to heat was present after gastrocnemius incision (p > 0.05 vs sham, n = 9 each group). Reduced withdrawal thresholds were blocked by i.t. administration of morphine and by local anesthetic injection at the test site 2 h and 2 days after gastrocnemius incision. These pharmacological data provide evidence that reduced withdrawal thresholds after gastrocnemius incision are nociceptive behaviors indicating persistent secondary hyperalgesia. Because the behaviors have a similar time course to secondary hyperalgesia in postoperative patients, the model will be useful to evaluate the mechanisms for secondary mechanical hyperalgesia after incision, its pharmacological characteristics and its potential role in persistent postoperative pain.

Mechanisms for pain caused by incisions.

Postoperative incisional pain is a unique and common form of acute pain. Because effective postoperative analgesia reduces morbidity after surgery, new treatments continue to be investigated. However, much of the scientific work to date on postoperative pain management has focused on regional analgesia and pharmacology. Much less effort has been dedicated toward studies of the mechanisms that subserve acute postoperative pain.1 Yet, it is through the study of mechanisms that a better understanding of incisional pain can be achieved and perioperative medicine will be advanced. There is ample evidence that pain caused by inflammation, nerve injury, or incision is based on different pathophysiologic mechanisms.2,3 This explains why many treatment strategies are efficacious only against specific types of persistent pain.2 Recognizing this gap between preclinical models of persistent pain and postsurgical pain, we have been interested in better understanding the mechanisms for pain caused by incisions. Therefore, we developed4 and characterized5 a rat model for postoperative pain. An incision made in the plantar aspect of the rat hindpaw causes persistent, reduced withdrawal thresholds to mechanical stimuli suggesting hyperalgesia (decreased pain threshold to suprathreshold stimuli). Primary hyperalgesia, enhanced pain to mechanical and thermal stimuli in the area of the incision, and secondary hyperalgesia, enhanced pain only to mechanical stimuli adjacent to the area of tissue injury, are present after a surgical incision in this model6 and in several clinical studies.7-9 Because primary hyperalgesia is caused by primary afferent nociceptor sensitization and secondary hyperalgesia is produced by sensitization of central neurons, peripheral and central sensitization likely contribute to pain after an incision. In agreement with this, Pogatzki et al.10 showed that A-delta and C fibers were sensitized by an incision and that the conversion of mechanical insensitive silent nociceptors to mechanically active fibers likely has a role in the maintenance of hyperalgesia after an incision. Furthermore, recording action potentials from dorsal horn neurons show that wide dynamic range neurons become sensitized after an incision and mediate the reduced withdrawal threshold observed in behavioral studies.11,12 In contrast to other more persistent and intense tissue injuries like inflammation or nerve injury, sensitization of dorsal horn neurons is maintained at least initially by excitation of primary afferents fibers (peripheral sensitization).13 We investigated the role of excitatory amino acid receptors (EAA), N-methyl-D-aspartate (NMDA) and non-NMDA (AMPA: alpha-amino-3-hydroxy5-methyl-4-isoxazole-propionic acid and kainate), for the development and maintenance of postoperative pain. Spinal NMDA receptor antagonists inhibit exaggerated pain behaviors in most models of persistent pain and are critical for activity-dependent plasticity, wind-up, and central sensitization. No effect on pain behaviors after plantar incision was observed14 in agreement with a recent clinical study.15 Surprisingly, intrathecal administration of non-NMDA receptor antagonists blocked painrelated behaviors after incision.16 Clinical studies have examined the effect of AMPA-kainate receptor antagonists in patients with persistent pain17; more studies on this group of EAA receptors will follow. Other spinally administered drugs producing analgesia in this model include L-type calcium channel receptor antagonists,18 alpha-2 adrenoceptor antagonists,19 and adenosine receptor agonists.20 Because central sensitization may be important for postoperative pain, many have proposed that a blockade of noxious input to the spinal cord before From the Department of Anesthesia and Intensive Care, University of Muenster, Muenster, Germany; and the University of Iowa, Iowa City, Iowa. Accepted for publication April 6, 2002. Reprint requests: Peter K. Zahn, M.D., Department of Anesthesia and Intensive Care Medicine, University of Muenster, Albert Schweitzer Str. 33, 48149 Muenster, Germany.

Role of the rostral medial medulla in the development of primary and secondary hyperalgesia after incision in the rat.

Background Descending influences from the rostral medial medulla (RMM) contribute to secondary hyperalgesia in persistent inflammatory, neuropathic, and visceral pain models. The current study examined if descending inhibition or facilitation from the RMM modulates primary and secondary hyperalgesia after incision in the rat hind limb. Methods Bilateral RMM lesions were produced using the soma-selective neurotoxin ibotenic acid, and the effect of RMM lesion was examined on primary and secondary hyperalgesia 5 days after a plantar or gastrocnemius incision, respectively. Results Plantar incision reduced withdrawal thresholds to von Frey filaments applied adjacent to the incision (primary punctate hyperalgesia). The withdrawal thresholds were the same in RMM-lesioned and sham-operated rats. The response frequency to a blunt mechanical stimulus after plantar incision was increased (primary nonpunctate hyperalgesia) in both groups. Nonpunctate hyperalgesia was greater in lesioned rats on postoperative day 2 only; all other measures were not different. Primary heat hyperalgesia after plantar incision was not modulated by RMM lesion. Secondary punctate hyperalgesia after gastrocnemius incision was not affected by RMM lesion. Gastrocnemius incision did not produce secondary nonpunctate or heat hyperalgesia in either RMM lesion or sham rats. Conclusion Primary and secondary hyperalgesia after an incision were not modulated by descending influence from the RMM. The lack of contribution of descending facilitatory influences from the RMM to secondary hyperalgesia after gastrocnemius incision supports the notion that incision-induced pain involves dissimilar mechanisms compared with inflammatory and neuropathic pain.

Ein modernes Konzept zur postoperativen Schmerztherapie

ZusammenfassungEine gute Analgesie ist Voraussetzung für weitere wichtige Therapiemaßnahmen nach einer Operation: z.B. Atemtherapie und Frühmobilisation. Die Schmerztherapie sollte daher Bestandteil eines multimodalen postoperativen Behandlungskonzepts sein. Es sollte ein Stufenkonzept der postoperativen Schmerztherapie eingeführt werden, das es dem Pflegepersonal ermöglicht, selbständig Schmerzen zu behandeln. Wenn diese Therapiemöglichkeiten nicht ausreichen bzw. wenn patientenkontrollierte intravenöse oder Regionalanalgesieverfahren benötigt werden, übernimmt der Akutschmerztherapiedienst die Betreuung, wobei zur Reduktion von Nebenwirkungen synergistische Effekte von Medikamentenkombinationen, d.h. balancierte Analgesieverfahren genutzt werden. Risikopatienten mit großen Operationen erhalten eine Kombination aus einem Opioid und einem Lokalanästhetikum über einen thorakalen Periduralkatheter. Dieses Verfahren sichert eine besonders gute Analgesie, erleichtert weitere wichtige Behandlungsmaßnahmen wie z.B. Frühmobilisation und begünstigt die postoperative Erholung im Vergleich zur patientenkontrollierten intravenösen Opioidanalgesie. Die Therapieanpassung muß unter Observationsbedingungen stattfinden, um Nebenwirkungen frühzeitig behandeln zu können. Später auf den Stationen sind tägliche Visiten zur weiteren Adaptation erforderlich. Dies ist nicht ohne sorgfältige Dokumentation möglich. Ein besonders wichtiger Aufgabenbereich der Mitarbeiter des Schmerzdienstes ist die Ausbildung und ständige Weiterbildung von Stationspersonal, da nur in enger Kooperation eine effektive Therapieanpassung, Reduktion von Nebenwirkungen und Verhütung von Komplikationen möglich sind.AbstractPain relief should be considered part of a multimodal postoperative approach. Combining patient-controlled pain therapy with other measures i.e. respiratory therapy or early mobilisation improves the outcome after surgery. In many patients adequate postoperative pain relief can be achieved by an optimal use of traditional pain management strategies. Therefore different levels of therapy should be introduced. On the first level nursing staff on surgical wards should treat pain. Patients undergoing extended surgery will need the advanced techniques of a postoperative pain service including balanced analgesia with antipyretic analgetics, patient-controlled intravenous opioids and epidural drug administration. Low dose combinations of local anaesthetiscs and opioids administered via thoracic epidural catheters result in excellent analgesia and provide the most effective means in improving outcome after surgery. For optimal adjustment of the patient-controlled techniques and early detection of side effects and complications nursing staff must be integrated into the pain service. Such a structured pain management program requires the training of nurses in the principles and techniques of postoperative pain treatment. Dosage of patient-controlled intravenous opioids or epidural drug combinations must be adjusted to the individual needs of the patients. Best results can only be achieved if the patient remains under observation by the pain service. This requires daily or twice daily rounds including an adequate documentation of pain relief, side effects and complications.