Fluoroscopy-assisted epidural catheter placement: an exploratory analysis of 303 pre-operative epidurograms.

BACKGROUND: Epidural catheters that are placed for post-operative analgesia have a significant failure rate in the first 24 hours. Beginning in 2011, we have used fluoroscopic guidance to place all non-obstetrical epidural catheters. In this retrospective analysis, we hypothesized that the characteristics of dye distribution on an epidurogram obtained immediately after catheter placement would predict clinical catheter function after surgery. METHODS: The epidurograms and medical records of 303 consecutive patients who had epidural catheters placed for post-operative analgesia were reviewed. We extracted data on epidural dye distribution on the epidurograms and compared these results to the clinical function of the epidural catheters assessed on post-operative day 1 (POD1). RESULTS: The three-dimensional pattern of epidural dye distribution (cephalad-caudad, right-left, anterior-posterior) had significant correlations with clinical function of an epidural catheter after surgery. Increased cephalad-caudad and anterior dye spread both correlated with decreased epidural solution infusion rates on POD1, whereas right- or left-sided dye distribution correlated with unilateral sensory deficits. A higher catheter placement on the neuraxis correlated with lower pain scores after thoracic surgery. CONCLUSIONS: An epidurogram obtained immediately after epidural catheter placement may have clinical utility for predicting clinical function of the catheter after surgery.

Glucocorticoid regulation of the inflammatory response to injury.

During the first half of the 20th century, physiologists were interested in the adrenal glands primarily because adrenalectomized animals failed to survive even mild degrees of systemic stress. It eventually became clear that hormones secreted by the adrenal cortex were critical for survival and, in this context, adrenal cortical hormones were widely considered to support or stimulate important responses to stress or injury. With the purification and manufacture of adrenal cortical hormones in the 1930s and 1940s, clinicians suddenly discovered the potent anti-inflammatory actions of glucocorticoids (GCs). This dramatic, and unexpected, discovery has dominated clinical and laboratory research into GC actions throughout the second half of the 20th century. More recent research is again reporting GC-induced stimulatory effects on a variety of inflammatory response components. These effects are usually observed at low GC concentrations, close to concentrations that are observed in vivo during basal, unstimulated states. For example, GC-mediated stimulation has been reported for the hepatic acute-phase response, for cytokine secretion, expression of cytokine/chemokine receptors, and for the pro-inflammatory mediator, macrophage migration inhibition factor. It seems clear that the long-held clinical view that GCs act solely as anti-inflammatory agents needs to be re-assessed. Varying doses of GCs do not lead simply to varying degrees of inflammation suppression, but rather GCs can exert a full range of effects from permissive to stimulatory to suppressive.

The in vivo effects of general and epidural anesthesia on human immune function.

UNLABELLED: Impaired in vivo immunity is often observed after major surgery and is multifactorial. We conducted a randomized clinical study to determine the independent effects of general anesthesia (GA) and of lumbar epidural anesthesia (LEA) on human immune function in the absence of surgical trauma. Nineteen healthy volunteers were randomized to receive GA with thiopental and isoflurane, LEA with lidocaine, or no anesthesia (Control). Serial blood samples were tested for antibody responses to antigen inoculation, neutrophil and mononuclear cell antibody-dependent cell cytotoxicity (ADCC), natural killer cell cytotoxicity, and neutrophil phagocytic activity. Antibody responses were similar in the three groups. Mononuclear cell ADCC increased in the LEA group at the end of the anesthetic (P < 0.05 at effector/target [E/T] ratios of 10:1, 25:1, and 50:1). Natural killer cell cytotoxicity increased at the end of the anesthetic in both the LEA group (P < 0.05 at all E/T ratios) and the GA group (P < 0.05 at an E/T ratio of 5:1 and 10:1). No significant changes were observed for neutrophil ADCC or phagocytosis. General or epidural anesthesia alone, in the absence of surgery, seems to have only transient and minor effects on human immune function. IMPLICATIONS: General or epidural anesthesia alone, in the absence of surgery, seems to have only transient and minor effects on human immune function.

Trauma and inflammation modulate lymphocyte localization in vivo: quantitation of tissue entry and retention using indium-111-labeled lymphocytes.

OBJECTIVE: Determine the in vivo localization pattern of indium-111-labeled lymphocytes after a standardized extremity injury or standardized laparotomy and after sterile inflammation of the central nervous system. DESIGN: Prospective animal study with concurrent controls. SETTING: Animal research laboratory. SUBJECTS: Male Lewis rats weighing 150-175 g. INTERVENTIONS: Indium-111-labeled splenic lymphocytes were injected into animals after a standardized hind limb trauma or laparotomy and after induction of sterile central nervous system inflammation. MEASUREMENTS AND MAIN RESULTS: Lymphoid and non-lymphoid organs were removed at fixed intervals after lymphocyte injection and the proportion of injected lymphocytes/gram of tissue was determined using a quantitative radionuclide calculation. Results from treated animals were compared with results from untreated control animals. Muscle injury caused early localization of lymphocytes to injured hind limbs, liver, and spleen compared with controls, whereas laparotomy decreased lymphocyte localization in the thymus and colon. Encephalitis increased localization to the central nervous system with no effect on other tissues. CONCLUSIONS: These results identify a sensitive method to track in vivo leukocyte localization and specifically demonstrate that lymphocyte localization is altered in both traumatic and nontraumatic models of inflammation.

Cerebrospinal fluid cytokine levels after surgery with spinal or general anesthesia.

BACKGROUND AND OBJECTIVES: Studies show that pain may cause neuroinflammatory changes in the spinal cord. These inflammatory changes could be caused by circulating factors such as plasma cytokines or could be a primary neuroimmune response of the central nervous system following peripheral nerve injury. To identify the possible effects of peripheral trauma and pain on the cytokine environment of the spinal cord, interleukin-6 (IL-6) and interleukin-10 (IL-10) concentrations in plasma and cerebrospinal fluid (CSF) were measured before and after hip replacement surgery. METHODS: The investigation used a prospective, observational design to measure cytokine levels in samples of plasma and CSF by enzyme-linked immunosorbent assay (ELISA). Samples were taken from surgical patients before and after surgery under general anesthesia or spinal anesthesia performed with or without a spinal catheter. Reference samples were also obtained from healthy control subjects. RESULTS: Both plasma and CSF levels of IL-6 increased substantially after major surgery with either general or spinal anesthesia. No significant correlation was observed between plasma IL-6 and CSF IL-6 levels, suggesting a central origin for increased CSF cytokine levels. IL-10 did not change in plasma or CSF after surgery. Plasma and CSF IL-6 and IL-10 cytokine levels were very low or undetectable in healthy controls. CONCLUSIONS: Major orthopedic surgery leads to elevated CSF levels of the proinflammatory cytokine, IL-6. The origin of increased CSF IL-6 may be central because there was no significant correlation with plasma levels.

Insulin infusion improves neutrophil function in diabetic cardiac surgery patients.

UNLABELLED: Diabetic patients are at increased risk of wound infection after major surgery, but the effect of perioperative glucose control on postoperative wound infection rates after surgery is uncertain. We tested the effect of an insulin infusion on perioperative neutrophil function in diabetic patients scheduled for coronary artery bypass surgery. Participants (n = 26) were randomly allocated to receive either aggressive insulin therapy (AIT) or standard insulin therapy (SIT) during surgery. Blood was drawn for neutrophil testing before surgery, 1 h after the completion of cardiopulmonary bypass, and on the first postoperative day. Neutrophil phagocytic activity decreased to 75% of baseline activity in the AIT group and to 47% of baseline activity in the SIT group (P < 0.05 between groups). No important differences in neutrophil antibody-dependent cell cytotoxicity were found. This study documents a potentially beneficial effect of continuous insulin therapy in diabetic patients who require major surgery. IMPLICATIONS: A continuous insulin infusion and glucose control during surgery improves white cell function in diabetic patients and may increase resistance to infection after surgery.

Dissociation of microglial activation and neuropathic pain behaviors following peripheral nerve injury in the rat.

Peripheral nerve injury commonly leads to neuropathic pain states fostered, in part, by neuroimmunologic events. We used two models of neuropathic pain (L5 spinal nerve cryoneurolysis (SPCN) and chronic constriction injury (CCI)) to assess the role of spinal glial activation responses in producing pain behaviors. Scoring of glial responses subjectively encompassed changes in cell morphology, cell density and intensity of immunoreactivity with specific activation markers (OX-42 and anti-glial fibrillary acidic protein (GFAP) for microglia and astrocytes, respectively). Glial responses were compared with tactile sensitivity (mechanical allodynia) at 1, 3 or 10 days following SPCN and with thermal hyperalgesia at 10 days in the CCI group. Neuropathic pain behaviors preceded and did not closely correlate with microglial responses in either model. Perineural application of bupivacaine prior to SPCN prevented spinal microglial responses but not pain behaviors. Spinal astrocytic responses to SPCN were early, robust and not altered by bupivacaine. The current findings support the use of bupivacaine as a tool to suppress microglial activation and challenge the putative role of microglia in initiating or potentiating pain behaviors which result from nerve injury.

Effects of anesthetic technique on myocardial wall motion abnormalities during abdominal aortic surgery.

OBJECTIVE: To assess the impact of regional supplemented general anesthesia (RSGEN) on regional myocardial function during abdominal aortic surgery (AAS). DESIGN: Prospective randomized study. SETTING: Single academic medical center. PARTICIPANTS: Seventy-three patients scheduled for infrarenal aortic aneursymectomy. INTERVENTIONS: Patients received standardized intraoperative anesthetic management consisting of either general anesthesia (GA; n = 37) or general anesthesia supplemented by epidural anesthesia (RSGEN; n = 36). MEASUREMENTS AND MAIN RESULTS: Hemodynamic measurements and transesophageal echocardiograms (TEE) were obtained at eight intraoperative times. The electrocardiogram (ECG) was continuously recorded using Holter monitoring. Of the 56 patients with interpretable TEE recordings, 8 of 30 (27%) GA patients and 7 of 26 (27%) RSGEN patients developed new segmental wall motion abnormalities (SWMAs). There was no treatment effect on either the incidence (p = 0.23) or the intensity (p = 0.34) of SWMAs. Cross-clamping of the aorta was associated with the onset of new SWMAs (odds ratio, 8.2; 95% CI, 1.1 to 64; p = 0.04). Among the 63 patients with interpretable Holter recordings, 9 of 34 (26%) GA patients and 9 of 29 (31%) RSGEN patients exhibited intraoperative ischemia. There was no treatment effect on the incidence (p = 0.22) or intensity (p = 0.67) of ECG ischemia. CONCLUSION: Despite providing modest hemodynamic depression, RSGEN did not reduce the incidence or intensity of either regional myocardial dysfunction or ECG ischemia. New SWMAs were temporally associated with cross-clamping of the aorta and tended to resolve with unclamping.

Intrathecal catheterization alone induces neuroimmune activation in the rat.

Intrathecal (i.t.) catheterization in the rat has been used extensively for drug delivery in various experimental paradigms. These indwelling i.t. catheters have been associated with inflammatory processes and tissue reactions external to the spinal cord in numerous clinical and animal studies. The purpose of this study was to determine whether i.t. catheter placement produced glial activation and changes in specific cytokine expression, i.e. neuroimmune activation, within the spinal cord which might cause altered sensory processing. Rats underwent i.t. catheterization or sham surgery and were killed at 3 or 14 days postsurgery (n> or =3 per group). Spinal cord segments were taken at the cervical level, tip of the catheter and distal to the catheter (thoracic levels). Immunohistochemistry was used to examine spinal localization of the cytokines, interleukin (IL)-6, IL-10 and glial activation (OX-42 for microglia and anti-glial fibrillary acidic protein for astrocytes). At 3 and 14 days after i.t. catheterization, there was an elevation in OX-42 and GFAP expression as compared to control (n=3) and sham surgery (n=4) groups. IL-10-like immunoreactivity was significantly increased in both the dorsal and ventral horns 14 days after i.t. placement as compared to the sham and normal groups. Conversely, IL-6-like immunoreactivity was not significantly different from sham or normal groups. These cytokine findings are discussed in the context of a differential role of specific cytokines in the potential generation of pain states or in the production of analgesia. This study demonstrated that i.t. catheterization induces robust neuroimmune activation that manifests as increases in glial markers and specific cytokine expression. This method should be controlled for, or alternate methods used for, drug delivery in nociceptive animal models that require spinally administered agents.

Morphine inhibits spontaneous and cytokine-enhanced natural killer cell cytotoxicity in volunteers.

BACKGROUND: Opioids are used by patients who have conditions ranging from the acute pain of surgery and chronic cancer pain to substance abuse. Despite their widespread use and considerable experimental data about them, little is known about how opioids may alter in vivo immunity in humans. This study was designed to evaluate the in vivo effect of morphine on human peripheral blood immune functions. METHODS: Healthy volunteers underwent continuous exposure to morphine for 36 h including a 24-h intravenous infusion in the hospital. Peripheral blood was drawn for immune function studies at five measurement times before, during, and after morphine exposure. Peripheral blood mononuclear cells were tested for acute and gamma-interferon-stimulated natural killer cell cytotoxicity (NKCC), antibody-dependent cell cytotoxicity, antibody Fc receptor expression, and human immunodeficiency virus infectivity. RESULTS: Significant suppression of NKCC was observed at 2 and 24 h after the onset of intravenous morphine exposure. Suppression of NKCC persisted for 24 h after termination of morphine infusion in a "high"-dose study group. gamma-Interferon-stimulated NKCC and antibody-dependent cell cytotoxicity were also decreased after 24 h of intravenous morphine exposure. No effect on Fc receptor expression was observed. Mean virus antigen production after lymphocyte infection with human immunodeficiency virus was not increased (p24 100 ng/ml after morphine vs. 43 ng/ml before morphine; P = 0.17). CONCLUSIONS: These results suggest that morphine administration, at doses within the range of analgesic use, can cause measurable suppression of some components of the human cellular immune system.

Perioperative immunomodulation in cancer surgery.

Despite undergoing a curative resection, many patients with colorectal cancer will develop and die of metastatic disease. It has been shown clinically and experimentally that surgery causes a transient period of immunosuppression, and it is postulated that this may encourage both the implantation of surgically disseminated tumor cells and the growth of existing micrometastases. The present study used natural killer cell cytotoxicity (NKCC) and tumor burden to evaluate perioperative modulation of immunocompetence in a murine model. We measured NKCC and tumor burden responses to a standardized surgical stress (SSS) alone, and to either morphine sulfate (MS) (15 mg/kg subcutaneously x 4 doses), ketorolac (a prostaglandin synthetase--prostaglandin E2--inhibitor) (2.5 mg/kg subcutaneously x 4 doses), or interleukin 2 (2,000 units intraperitoneally x 3 doses) administration with the SSS. In this model, we found that both low-dose interleukin-2 (IL-2) and ketorolac reversed the NKCC suppression associated with surgery, whereas morphine resulted in further depression of NKCC. In addition, IL-2 significantly decreased tumor incidence, whereas continuous MS exposure markedly increased tumor burden after surgery. These data suggest that IL-2 and ketorolac may be effective agents for the restoration of perioperative immune competence, whereas the use of continuous morphine might have significant deleterious effects.

Effect of morphine and beta-endorphin on human Fc receptor-dependent and natural killer cell functions.

Interactions between opiates and the human immune system have important clinical implications. To further evaluate these interactions, we studied in vitro and in vivo effects of morphine sulfate (morphine) and beta-endorphin (Bend) on antibody-dependent cell cytotoxicity (ADCC), natural killer cell cytotoxicity (NKCC), and effector cell expression of antibody Fc receptors. Morphine and Bend had no potent in vivo or in vitro effect on FcR expression nor did they have a significant in vitro effect on ADCC by monocytes or polymorphonuclear cells. Bend enhancement of NKCC in vitro was inhibited by coincubation of effector cells with morphine. After taking 90 to 150 mg of oral morphine, study volunteers demonstrated a significant decrease in ADCC by peripheral blood mononuclear cells. The same individuals demonstrated a consistent increase in NKCC and no change in the expression of Fc receptors. Effector cells from these individuals responded normally to in vitro incubation with interferon-gamma (IFN-gamma).

The effect of ibuprofen on cardiac performance during abdominal aortic cross-clamping.

Decreased cardiac output and increased plasma thromboxane have been observed during aortic cross-clamping under general anesthesia. Amelioration of these changes has been reported by preoperative administration of cyclooxygenase inhibitors, but heterogeneity in patients' intravascular volume status has confounded analysis of the drugs' effects in previous studies. We studied hemodynamic conditions in 24 volume-loaded (pulmonary capillary wedge pressure greater than 10 mm Hg) patients undergoing abdominal aortic aneurysm repair under general plus epidural anesthesia, after preoperative double-blind administration of either ibuprofen 800 mg (n = 12) or placebo (n = 12). The hemodynamic response to aortic cross-clamping was similar in both groups. Pulse and mean arterial pressure remained unchanged; cardiac index decreased after aortic cross-clamping from 2.4 +/- 0.1 (mean +/- standard error of the mean [SEM]) to 2.1 +/- 0.1 1/min/m2 in the ibuprofen group and from 2.5 +/- 0.1 to 2.3 +/- 0.2 1/min/m2 in the placebo group (p less than 0.01 versus preclamp values in both groups, multivariate analysis of variance [MANOVA]), but improved after declamping. Both left and right ventricular stroke work indexes followed a similar pattern. Plasma 6-keto prostaglandin Fl alpha (6-k-PGF1 alpha) increased transiently from a baseline level of 304 +/- 44 to 2083 +/- 698 pg/ml plasma in mixed venous blood 30 minutes after incision in the placebo group (p less than 0.05), but no other significant change in plasma 6-keto prostaglandin Fl alpha or in thromboxane B2 occurred in either group at any other time.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of morphine on growth of metastatic colon cancer in vivo.

Control of colon cancer depends, in part, on intact immune defense mechanisms. Since opiates are known to affect some components of immune function, this study was conducted to determine the effect of high-dose subcutaneous morphine sulfate and of low-dose intrathecal morphine on the postoperative growth of metastatic colon cancer. Five groups of 15 Fischer 344 rats were given intraportal injections of colon cancer cells as follows: group 1, control; group 2, daily subcutaneous injections of 20-mg/kg morphine the day before and for 2 days after colon cancer cell inoculation; group 3, daily subcutaneous injections of saline; group 4, daily intrathecal injections of 20 micrograms of morphine; and group 5, daily intrathecal injections of saline. There was a significant decrease in the hepatic tumor burden in group 2 compared with groups 1 and 3 and a significant increase in the hepatic tumor burden in groups 4 and 5 compared with group 1. This study demonstrates that intermittent injections of a narcotic may decrease the growth of tumor cells that gain access to the circulation during a surgical procedure. In addition, the results support the concept that tumor cells entering the circulation during a vulnerable period of postoperative immunosuppression are more likely to survive as metastatic tumor.

Epidural anesthesia and analgesia in high-risk surgical patients.

The authors conducted a randomized controlled clinical trial to evaluate the effect of epidural anesthesia and postoperative analgesia (EAA) on postoperative morbidity in a group of high-risk surgical patients. A total of 53 patients were admitted to the study, 28 received EAA, and 25 received standard anesthetic and analgesic techniques without EAA. Surgical "risk" was evaluated preoperatively and found to be comparable in the two groups. When compared to control patients, patients who received EAA had a reduction in the overall postoperative complication rate (P = 0.002) and in the incidence of cardiovascular failure (P = 0.007) and major infectious complications (P = 0.007). Urinary cortisol excretion, a marker of the stress response, was significantly diminished during the first 24 postoperative hours in the group receiving EAA (P = 0.025). Finally, hospital costs were significantly reduced for patients who received EAA (P = 0.02). The authors conclude that EAA exerted a significant beneficial effect on operative outcome in a group of high risk surgical patients.

Effect of cimetidine on biotransformation of enflurane in man.

This study was designed to test the hypothesis that administration of clinical doses of cimetidine could affect the metabolic degradation of enflurane to inorganic fluoride via inhibition of the mixed function oxidase enzyme (MFOE) system. In Part 1 of the study 38 female patients undergoing gynaecologic surgery received, double blind, either cimetidine, 300 mg PO the night prior to surgery and 300 mg IV 30 minutes prior to anaesthesia induction or a placebo. In Part 2, 24 patients received either cimetidine as in Part 1, but with continued administration for 24 hours into the postoperative period, or a placebo. Anaesthesia in all cases was with enflurane in oxygen, via a closed circuit. In both Parts 1 and 2 of the study there were no statistically significant differences between the two groups in serum fluoride levels at baseline, four hours or 24 hours postoperatively, or in the total urinary fluoride excretion during the first or second postoperative days. The authors speculate that this is due either to separate interactions of cimetidine and enflurane with the MFOE system or to the relatively low rate of enflurane metabolism.