Systemic and peritoneal host defense in peritonitis

Most of the work of host defense has been carried out in mixed patient populations. It is now clear that elective preoperative surgical patients have totally different host defense capabilities as compared to posttrauma patients or those suffering from peritonitis. Specific cell-mediated immune studies need to be repeated in these 2 patient groups as well. What will contribute clinical relevance to these studies will be the means to correct the defects. If these defects or—more correctly termed—abnormalities of host defense are, indeed, important and contribute to an increased sepsis rate and mortality from sepsis in affected patients, then correcting them should reduce these complications. This hypothesis can only be tested when such means become available. The issues of most interest in the next few years will be the significance of serum albumin in host outcome, the role of immunomodulators, the involvement of cytokines in the overall process of host defense, and the use of specific nutritional support regimens targeted to the immune system.

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Resumen La mayor parte del trabajo sobre los mecanismos de defensa del huésped ha sido realizada en poblaciones mixtas de pacientes. Actualmente aparece claro que los pacientes preoperatorios electivos poseen una capacidad de defensa de huésped totalmente diferente que la de los pacientes en estado posttrauma o de aquellos con peritonitis. Aparece necesario realizar estudios específicos de inmunidad celular en estos 2 grupos de pacientes; aquello que aporte pertinencia clínica en tales estudios habrá de representar medios para corregir estos defectos. Si tales defectos, mejor denominados anormalidades en las defensas del huésped, son de verdad importantes y contribuyen a mayores tasas de infección y de mortalidad por sepsis en los pacientes afectados, su corrección debe resultar en reducción de estas complicaciones. Esta hipótesis sólo puede ser puesta a prueba cuando tales medios se hallen disponibles. Los aspectos de mayor interés en los próximos años serán el significado de la albúmina sérica en la evolución final del huésped, el papel de los inmunomoduladores, la participación de las citocinas en el proceso general de defensa del huésped, y el uso de regimenes especificos de soporte nutricional dirigidos hacia el sistema inmune.

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Résumé La plupart des travaux sur les mécanismes de défense ont été faits sur les populations mixtes. Il est à présent certain que les patients opérés électivement ont des mécanismes de défense préopératoire totalement différents de ceux des traumatisés ou des patients ayant une infection péritonéale. Les études immunologiques sur la médiation cellulaire spécifique méritent d'être refaites chez ces deux populations. Ce qui ressortira de ces études donnera les moyens de corriger les défauts ou plutôt les anomalies des mécanismes de défense qui contribuent à augmenter septicité et mortalité en rapport avec l'état septique. Cette hypothèse ne peut être vérifiée qu'avec ces moyens. Les questions les plus intéressantes dans les années à venir sera peut-être de connaître l'influence de l'albumine sérique sur l'évolution, le rôle des immunomodulaterus, celui des cytokinines dans le procédé global des mécanismes de défense, et celui de l'utilisation de l'alimentation spécifique pour améliorer le système immune.

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Supported in part by grants from the Medical Research Council of Canada and the Fonds de recherche de Santé.     

Kupffer cell modulation of the systemic immune response

The effects of global hepatic injury and of Kupffer cell activation on systemic immunity were studied in an in vivo rat model, using the diameters of the delayed-type hypersensitivity (DTH) response to keyhole limpet hemocyanin and of a subcutaneous Staphylococcus aureus abscess as measures of systemic immunoresponsiveness. Hepatic injury with carbon tetrachloride resulted in significant suppression of the DTH score (5.5 +/- 0.7 vs 8.8 +/- 0.8 mm). Kupffer cell activation with intraportal Escherichia coli was likewise suppressive (DTH score, 4.4 +/- 0.5 vs 6.1 +/- 0.4 mm for animals receiving systemic E coli); the magnitude of this suppression correlated with the numbers of organisms extracted by the liver. Conversely, Kupffer cell ablation with carrageenan lessened the immunosuppressive effects of anesthesia and surgery (DTH score, 8.5 +/- 0.9 vs 6.8 +/- 0.6 mm for controls; S aureus abscess, 4.1 +/- 0.4 vs 5.7 +/- 0.4 mm for controls). These results indicate that Kupffer cells can modulate the systemic immune response and suggest that gram-negative portal bacteremia with resultant Kupffer cell activation may contribute to the immunologic derangements characteristic of trauma and critical surgical illness.     

In vitro polymorphonuclear neutrophil function in surgical patients does not correlate with anergy but with "activating" processes such as sepsis or trauma

We studied 199 preoperative patients admitted for esophagogastric, gastric, colonic, or rectal resections, 132 patients with severe blunt trauma, 180 surgical intensive care unit patients with major sepsis, and 95 laboratory controls in order to clarify the role of polymorphonuclear neutrophil (PMN) adherence and chemotaxis to outcome. Patients were also stratified by the delayed-type hypersensitivity response to five ubiquitous antigens. PMN adherence and PMN chemotaxis were not different in preoperative reactive or anergic patients and were equal to the control values, whereas both reactive patients and anergic patients showed altered PMN function after trauma or sepsis. There was no difference in PMN adherence or chemotaxis between patients who died and those who lived. Multiple logistic regression analysis showed that patient age, delayed-type hypersensitivity, and admission serum albumin level, not PMN adherence or chemotaxis, were significantly related to septic mortality. We concluded that altered circulating PMN adherence and chemotaxis is seen in all patients after an "activation" event such as trauma or sepsis. This is a nonspecific immune alteration not related to specific immune events such as delayed-type hypersensitivity; it does not correlate with patient outcome and should not be used as a predictive variable.     

Functional consequences of ROMK mutants linked to antenatal Bartter's syndrome and implications for treatment

The antenatal variant of Bartter's syndrome is an autosomal recessive kidney disease characterized by polyhydramnios, premature delivery, hypokalemic alkalosis and hypercalciuria. It is genetically heterogeneous, having been linked recently to mutations in an ATP- sensitive, renal outer medullary K+channel, ROMK, and earlier to mutations in the Na-K-2Cl co-transporter, NKCC2. We characterized four of the mutations reported in three heterozygous ROMK variants of antenatal Bartter's and found that each expressed a distinct phenotype in Sf9 cells. One mutation expressed normal function and appears to be an allelic polymorphism. The other three mutations produced channels with significantly reduced K+fluxes. However, the mechanisms in each case were different and reflected abnormalities in phosphorylation, proteolytic processing or protein trafficking. The different mechanisms may be important in the design of appropriate therapy for patients with this disease.      

Timing of recanalization after tissue plasminogen activator therapy determined by transcranial doppler correlates with clinical recovery from ischemic stroke

BACKGROUND: The duration of cerebral blood flow impairment correlates with irreversibility of brain damage in animal models of cerebral ischemia. Our aim was to correlate clinical recovery from stroke with the timing of arterial recanalization after therapy with intravenous tissue plasminogen activator (tPA). METHODS: Patients with symptoms of cerebral ischemia were treated with 0.9 mg/kg tPA IV within 3 hours after stroke onset (standard protocol) or with 0.6 mg/kg at 3 to 6 hours (an experimental institutional review board-approved protocol). National Institutes of Health Stroke Scale (NIHSS) scores were obtained before treatment, at the end of tPA infusion, and at 24 hours; Rankin Scores were obtained at long-term follow-up. Transcranial Doppler (TCD) was used to locate arterial occlusion before tPA and to monitor recanalization (Marc head frame, Spencer Technologies; Multigon 500M, DWL MultiDop-T). Recanalization on TCD was determined according to previously developed criteria. RESULTS: Forty patients were studied (age 70+/-16 years, baseline NIHSS score 18.6+/-6.2). A tPA bolus was administered at 132+/-54 minutes from symptom onset. Recanalization on TCD was found at the mean time of 251+/-171 minutes after stroke onset: complete recanalization occurred in 12 (30%) patients and partial recanalization occurred in 16 (40%) patients (maximum observation time 360 minutes). Recanalization occurred within 60 minutes of tPA bolus in 75% of patients who recanalized. The timing of recanalization inversely correlated with early improvement in the NIHSS scores within the next hour (polynomial curve, third order r(2)=0.429, P<0.01) as well as at 24 hours. Complete recanalization was common in patients who had follow-up Rankin Scores if 0 to 1 (P=0.006). No patients had early complete recovery if an occlusion persisted for >300 minutes. CONCLUSIONS: The timing of arterial recanalization after tPA therapy as determined with TCD correlates with clinical recovery from stroke and demonstrates a 300-minute window to achieve early complete recovery. These data parallel findings in animal models of cerebral ischemia and confirm the relevance of these models in the prediction of response to reperfusion therapy.