Edward M. Bender

Altered helper and suppressor lymphocyte populations in surgical patients. A measure of postoperative immunosuppression.

Although a wealth of evidence has suggested that cell-mediated immunity is suppressed after simple surgical trauma, there have been contradictory results using stimulation assays of lymphocyte function. We quantitated T-lymphocyte subsets in 11 patients undergoing routine cholecystectomy by immunofluorescence microscopy using specific monoclonal antibodies. T-helper to T-suppressor cell ratios were calculated on the preoperative day and the first postoperative day in all patients, and on the third or fourth postoperative day in five patients. Helper to suppressor ratios decreased in all patients on the first postoperative day (p greater than 0.01), but returned to within normal limits on subsequent days. Changes were due more to decreases in helper cells than to increases in suppressor cells, although changes in both populations were statistically significant. The measurement of T-cell subsets by antibody-specific labeling and immunofluorescence microscopy may prove to be a more sensitive, quantifiable, and reproducible assay of immune function in surgical or traumatized patients than use of stimulation assays. Measurements of specific helper and suppressor lymphocyte populations may prove useful in predicting morbidity and mortality, and may also help in studying the effect of immunomodulating agents on the immune response.

Characterization of the immunosuppressive effect of burned tissue in an animal model

The immunosuppressive effect of burned tissue was studied using a mouse burn model. To evaluate the immunologic status an in vivo measure of cell-mediated immunity (CMI) involving contact sensitization of mice by painting the skin with dinitrofluorobenzene was used; mice were challenged 5 days later by painting the ear with the same antigen. Ear swelling in response to antigenic challenge was used as a quantitative measure of CMI; diminution in ear swelling in treatment mice compared to sensitized, unburned control mice indicated the degree of immunosuppression. A full-thickness steam burn covering 20% body surface ares (BSA) was profoundly immunosuppressive as reflected by ear swelling of 45 to 60% of that found in normal mice; partial thickness burns and burns of 10% BSA extent were not significantly immunosuppressive. Transfer into unburned mice of burned skin equivalent in size to a 20% BSA burn eschar resulted in marked immunosuppression, but transfer of smaller amounts of burned skin, or of larger amounts of unburned skin and normal and burned liver tissue, did not produce immunosuppression. Mice receiving a very high-temperature (300 degrees C), dry burn were only slightly more suppressed than mice receiving a standard steam burn. Normal immunity was preserved in burned mice which received daily application of cerium nitrate to the wound for 7 days, but application of other topical agents commonly used in burn treatment did not preserve immunity. Postburn immunosuppression thus appears related quantitatively to toxic factors in burned skin, and these toxic factors can be abrogated in burned mice by the topical application of cerium nitrate.

Prevention of Alterations in Postoperative Lymphocyte Subpopulations by Cimetidine and Ibuprofen

Surgical procedures probably result in a temporary state of immunosuppression. Identification of functional lymphocyte subclasses using appropriate monoclonal antibodies appears to serve as a sensitive, accurate, and reproducible measure of immune status in patients in many disease states. Using monoclonal antibodies specific for lymphocyte surface markers and immunofluorescent assay, we quantitated lymphocyte subpopulations in patients undergoing surgical procedures. Cholecystectomy, colon surgery, and coronary bypass procedures all resulted in postoperative decreases in helper and inducer populations and increases in cytotoxic suppressor populations, with resultant depressions in the helper to suppressor lymphocyte ratio. Studies in an additional group of patients who underwent cholecystectomy demonstrated that these changes could be prevented by perioperative administration of ibuprofen and cimetidine. These results suggest that prostaglandins and histamines are involved in immunoregulatory events after major operation. The ability of specific pharmacologic therapy to prevent alterations in lymphocyte populations suggest that postoperative immunity may be preserved, hopefully leading to greater host resistance against infection and tumor dissemination.

Esophagogastrectomy for benign esophageal stricture. Fate of the esophagogastric anastomosis.

Eighty-nine patients who had resection of benign esophageal stricture with esophagogastrostomy were reviewed through medical records and by mailed questionnaire. The 30-day mortality rate was 8.9%. Seventy-six patients were available for follow-up for an average of 66.4 months (Group 1). Forty-three of these patients were followed up for longer than 5 years (Group 2). The incidence of postoperative heartburn in Groups 1 and 2 was 7.9% and 7.0%, respectively. The incidence of postoperative dysphagia in Groups 1 and 2 was 39.4% and 30.2%, respectively, with most episodes occurring within 2 years of operation. The vast majority of these patients required multiple esophageal dilatations over a long time. The high rate of restricture precludes support for the routine use of an esophagogastric anastomosis after resection of benign esophageal stricture.

Restoration of immunity in burned mice by cimetidine

We have previously described a mouse model of postburn suppression of cell-mediated immunity (CMI). Ear swelling (ES) in response to contact antigen challenge is depressed maximally 14 days following a 25% steam burn and recovers to control levels 3 weeks postburn. Splenic lymphocyte proliferation in response to Concanavalin A (Con A) is also depressed 14 days postburn. Splenic T-lymphocyte subset analysis with monoclonal antibodies for helper cells (Lyt 1.2) and suppressor cells (Lyt 2.2) reveals that T-helper cells reach a minimal level and T suppressor cells reach a maximum level 14 days postburn. The helper: suppressor ratio (HSR) reaches its nadir at day 14. Treatment of burned mice with low-dose cimetidine (2 or 10 mg/kg/day), but not high-dose (50 mg/kg/day), for 14 days restores CMI. Low-dose cimetidine also normalizes the HSR but does not effect postburn depression of mitogen responsiveness. Low-dose cimetidine probably restores CMI by inhibiting suppressor cells, whereas high doses provide more global inhibition. Recovery of mitogen responsiveness may require continued cimetidine presence in culture.

Contrast echocardiography: a method to visualize changes in regional myocardial perfusion in the dog model for CABG surgery.

The ability of contrast echocardiography to assess regional myocardial perfusion during cardiopulmonary bypass in a dog model for coronary artery bypass surgery was evaluated. Sonicated Renograffin-76 microbubbles (meglumin diatrigoate and sodium diatrigoate) were injected into an aortic root proximal to an aortic occlusion clamp root while dogs were on cardiopulmonary bypass, with the heart arrested in diastole. Echocardiographic contrast-enhanced regions of myocardial perfusion were easily visualized. Differences in contrast-enhanced myocardial regions depended on coronary artery occlusion or patency. The contrast-enhanced images of myocardial perfusion showed that, for a given myocardial segment of the supplying vessel, the presence or absence of contrast effect reliably predicted vessel occlusion or patency (P less than .01). In the future contrast echocardiography may allow the direct assessment of regional myocardial perfusion in the operating room.

The effect of histamine receptor antagonists on specific and nonspecific suppression of experimental contact sensitivity

We studied the effects of H1 and H2 histamine receptor antagonists on down regulation of contact sensitivity (CS) to dinitrofluorobenzene (DNFB). Two H2 receptor antagonists, cimetidine and ranitidine, reversed the nonspecific immunosuppression of CS induced by burns. On the other hand, these two drugs did not affect the antigen-specific suppressor T cell-mediated tolerance to DNFB induced by dinitrobenzene sulfonic acid. Two H1 antagonists did not affect the down regulation of CS induced by either tolerance or burning. The differential sensitivities to histamine 2-receptor antagonists indicate that the mechanisms for nonspecific burn-induced immunosuppression are different from those for hapten-specific tolerance to DNFB.

Prevention of suppressed cell-mediated immunity in burned mice with histamine-2 receptor antagonist drugs.

Abstract Thermal injury has been shown to suppress many aspects of both specific and nonspecific immune responses. We investigated the effect of two histamine H-2 antagonist drugs on cell-mediated immunity in burned mice, utilizing a method of quantitating the degree of contact sensitivity elicited to the antigen, 2,4-dinitrofluorobenzene (DNFB). Following sensitization by painting the abdomen with DNFB, animals were challenged 5 days later by painting the ears; subsequent ear swelling is a sensitive and reproducible measure of cell-mediated immunity. We have previously demonstrated that burned mice are maximally immunosuppressed 10 to 14 days following burn injury. In the present study we found that daily intraperitoneal administration of appropriate doses of the H-2 antagonists cimetidine (2 and 10 mg/kg/day) and ranitidine (2 and 10 mg/kg/day) resulted in maintenance of normal cell-mediated immunity in burned animals. Neither a lower dose of ranitidine (0.2 mg/kg/day) nor higher doses of cimetidine (20 and 50 mg/kg/day) restored immunity, and diphenhydramine, an H-1 antagonist, had no effect. There was no augmentation of contact sensitivity in unburned mice treated with cimetidine. The immunorestorative effect is probably secondary to antagonism of histamine H-2 receptors on suppressor T lymphocytes, and may reflect increased suppressor cell activity in burned mice; however, other mechanisms may be involved.

Rapid clinical evaluation: an early warning cardiac surgical scoring system for hand-held digital devices

OBJECTIVES The purpose of this study was to develop a new scoring system for the prompt recognition of clinical deterioration and early treatment in postoperative cardiac surgical patients. METHODS All consecutive adult patients undergoing cardiac surgery between 1st January 2007 and 31st December 2010 were included. The new score was calculated daily until intensive care unit (ICU) discharge. The score consists of 11 variables representing six different organ systems. Performance was assessed using receiver-operating characteristic (ROC) curves and calibration tests. RESULTS A total of 5207 patients with a mean age of 67.2 ± 10.9 years were admitted to the ICU after cardiac surgery. The operations performed covered the whole spectrum of cardiac surgery. ICU mortality was 5.9%. The mean length of ICU stay was 4.6 ± 7.0 days. The new score had an excellent discrimination with areas under the ROC curves between 0.91 and 0.96. Calibration was also excellent reflected by observed/expected mortality ratios ranging between 1.0 and 1.26. CONCLUSIONS The new score is a simple and reliable scoring system to assess organ dysfunction in cardiac intensive care patients. It is designed especially for personal digital assistants to simplify and accelerate the process of risk stratification in cardiac surgical ICUs.

Prevention of Suppressed Cell-Mediated Immunity in Burned Mice with Histamine-2 Receptor Antagonist Drugs

Thermal injury has been shown to suppress many aspects of both specific and nonspecific immune responses. We investigated the effect of two histamine H-2 antagonist drugs on cell-mediated immunity in burned mice, utilizing a method of quantitating the degree of contact sensitivity elicited to the antigen. 2,4-dinitrofluorobenzene (DNFB). Following sensitization by painting the abdomen with DNFB, animals were challenged 5 days later by painting the ears; subsequent ear swelling is a sensitive and reproducible measure of cell-mediated immunity. We have previously demonstrated that burned mice are maximally immunosuppressed 10 to 14 days following burn injury. In the present study we found that daily intraperitoneal administration of appropriate doses of the H-2 antagonists cimetidine (2 and 10 mg/kg/day) and ranitidine (2 and 10 mg/kg/day) resulted in maintenance of normal cell-mediated immunity in burned animals. Neither a lower dose of ranitidine (0.2 mg/kg/day) nor higher doses of cimetidine (20 and 50 mg/kg/day) restored immunity, and diphenhydramine, an H-1 antagonist, had no effect. There was no augmentation of contact sensitivity in unburned mice treated with cimetidine. The immunorestorative effect is probably secondary to antagonism of histamine H-2 receptors on suppressor T lymphocytes, and may reflect increased suppressor cell activity in burned mice; however, other mechanisms may be involved.