Faculty Bibliography

BACKGROUND: Early hemodynamic assessment of global parameters in critically ill patients fails to provide adequate information on tissue perfusion. It requires invasive monitoring and may represent a late intervention initiated mainly in the intensive care unit. Noninvasive monitoring of peripheral perfusion can be a complementary approach that allows very early application throughout the hospital. In addition, as peripheral tissues are sensitive to alterations in perfusion, monitoring of the periphery could be an early marker of tissue hypoperfusion. This review discusses noninvasive methods for monitoring perfusion in peripheral tissues based on clinical signs, body temperature gradient, optical monitoring, transcutaneous oximetry, and sublingual capnometry. DISCUSSION: Clinical signs of poor peripheral perfusion consist of a cold, pale, clammy, and mottled skin, associated with an increase in capillary refill time. The temperature gradients peripheral-to-ambient, central-to-peripheral and forearm-to-fingertip skin are validated methods to estimate dynamic variations in skin blood flow. Commonly used optical methods for peripheral monitoring are perfusion index, near-infrared spectroscopy, laser Doppler flowmetry and orthogonal polarization spectroscopy. Continuous noninvasive transcutaneous measurement of oxygen and carbon dioxide tensions can be used to estimate cutaneous blood flow. Sublingual capnometry is a noninvasive alternative for gastric tonometry.

INTRODUCTION: Severe sepsis is a dreaded consequence of infection and necessitates intensive care treatment. Severe sepsis has a profound impact on mortality and on hospital costs, but recent incidence data from The Netherlands are not available. The purpose of the present study was to determine the prevalence and incidence of severe sepsis occurring during the first 24 hours of admission in Dutch intensive care units (ICUs). METHODS: Forty-seven ICUs in The Netherlands participated in a point prevalence survey and included patients with infection at the time of ICU admission. Clinical symptoms of severe sepsis during the first 24 hours of each patient's ICU stay were recorded and the prevalence of severe sepsis was calculated. Then, the annual incidence of severe sepsis in The Netherlands was estimated, based on the prevalence, the estimated length of stay, and the capacity of the participating ICUs relative to the national intensive care capacity. RESULTS: The participating ICUs had 442 beds available for admissions, which was estimated to be 42% of the national ICU capacity. At the time of the survey, 455 patients were currently admitted and 151 were included in the analysis; 134 (29.5%) patients met criteria for severe sepsis. The most common failing organ system was the respiratory system (90%), and most patients were admitted following surgery (37%) and were admitted because of acute infection (62%). The most prevalent source of infection was the lung (47%). The estimated duration of ICU stay for severe sepsis patients was 13.3 +/- 1.1 days. CONCLUSION: The annual number of admissions for severe sepsis in Dutch ICUs was calculated at 8643 +/- 929 cases/year, which is 0.054% of the population, 0.61% of hospital admissions and 11% of ICU admissions.

Automated online tonometry displays a rapid, semicontinuous measurement of gastric-to-endtidal carbon dioxide (Pr-etCO2) as an index of gastrointestinal perfusion during surgery. Its use to predict postoperative outcome has not been studied in general surgery patients. We, therefore, studied ASA physical status III-IV patients operated on for elective surgery under general anesthesia and a planned duration of >2 h in a European, multicenter study. As each center was equipped with only 1 tonometric monitor, a randomization was performed if more than one patient was eligible the same day. Patients not monitored with tonometry were assessed only for follow-up. The main outcome measure was the assessment of postoperative functional recovery delay (FRD) on day 8. Among the 290 patients studied, 34% had FRD associated with a longer hospital stay. The most common FRDs were gastrointestinal (45%), infection (39%), and respiratory (35%). In those monitored with tonometry (n = 179), maximum Pr-etCO2 proved to be the best predictor increasing the probability of FRD from 34% for all patients to 65% at a cut-off of 21 mm Hg (2.8kPa) (sensitivity 0.27, specificity 0.92, positive predictive value 64%, negative predictive value 70%). We conclude that intraoperative Pr-etCO2 measurement may be a useful prognostic index of postoperative morbidity.

OBJECTIVE: Binding of bacterial cell wall components to CD14 and co-receptors on myeloid cells results in cellular activation and production of proinflammatory mediators. A recombinant anti-CD14 monoclonal antibody (IC14) has been shown to decrease lipopolysaccharide-induced responses in animal and human models of endotoxemia. This study was performed to evaluate the safety, pharmacokinetics, pharmacodynamics, and clinical pharmacology of IC14 in patients with severe sepsis. DESIGN: Randomized, double-blind, placebo-controlled, dose-ranging, multiple-center trial. SETTING: Six medical and surgical intensive care units located in Germany and The Netherlands. PATIENTS: Forty patients with severe sepsis. INTERVENTIONS: IC14 was administered intravenously to eight patients/cohort as single (1 mg/kg or 4 mg/kg) or multiple doses (4 mg/kg daily for 4 days, or 4 mg/kg on day 1 followed by 2 mg/kg daily for 3 days). A placebo group (two patients/cohort) was also included. MEASUREMENTS AND MAIN RESULTS: The overall incidence and types of adverse events were similar among treatment groups. One patient in the group receiving multiple-dose IC14 4 mg/kg daily for 4 days experienced an anaphylactic reaction after receiving the first dose of study drug. IC14 did not induce antibody formation or increase the incidence of secondary bacterial infection. A mean IC14 serum concentration of approximately 1 microg/mL was required to achieve 50% of maximum membrane-bound CD14 receptor occupancy on peripheral blood monocytes. The pattern of proinflammatory and anti-inflammatory cytokines, chemokine, soluble receptor, soluble E-selectin, and acute phase proteins in response to treatment was highly variable by patient and IC14 treatment group. CONCLUSIONS: Single and multiple doses of IC14 were generally well tolerated and did not induce antibody formation or increase the incidence of secondary bacterial infection. The results suggest that CD14 blockade with IC14 warrants further clinical investigation to determine its ability to attenuate the proinflammatory response due to infection.

Both in emergency and elective surgical patients increased blood lactate levels warn the physician that the patient is at risk of increased morbidity and decreased changes of survival. Prompt therapeutic measures to restore the balance between oxygen demand and supply are warranted in these patients.

OBJECTIVE: To assess the safety and efficacy of the nitric oxide synthase inhibitor 546C88 in patients with septic shock. The predefined primary efficacy objective was survival at day 28. DESIGN: Multiple-center, randomized, two-stage, double-blind, placebo-controlled, safety and efficacy study. SETTING: A total of 124 intensive care units in Europe, North America, South America, South Africa, and Australasia. PATIENTS: A total of 797 patients with septic shock diagnosed for <24 hrs. INTERVENTIONS: Patients with septic shock were allocated to receive 546C88 or placebo (5% dextrose) for up to 7 days (stage 1) or 14 days (stage 2) in addition to conventional therapy. Study drug was initiated at 0.05 mL.kg(-1).hr(-1) (2.5 mg.kg(-1).hr(-1) 546C88) and titrated up to a maximum rate of 0.4 mL.kg(-1).hr(-1) to maintain mean arterial pressure between 70 and 90 mm Hg while attempting to withdraw concurrent vasopressors. MEASUREMENTS AND MAIN RESULTS: Hemodynamic variables, organ function data, microbiological data, concomitant therapy, and adverse event data were recorded at baseline, throughout treatment, and at follow-up. The primary end point was day-28 survival. The trial was stopped early after review by the independent data safety monitoring board. Day-28 mortality was 59% (259/439) in the 546C88 group and 49% (174/358) in the placebo group (p <.001). The overall incidence of adverse events was similar in both groups, although a higher proportion of the events was considered possibly attributable to study drug in the 546C88 group. Most of the events accounting for the disparity between the groups were associated with the cardiovascular system (e.g., decreased cardiac output, pulmonary hypertension, systemic arterial hypertension, heart failure). The causes of death in the study were consistent with those expected in patients with septic shock, although there was a higher proportion of cardiovascular deaths and a lower incidence of deaths caused by multiple organ failure in the 546C88 group. CONCLUSIONS: In this study, the nonselective nitric oxide synthase inhibitor 546C88 increased mortality in patients with septic shock.

OBJECTIVE: To assess the safety and efficacy of the nitric oxide synthase inhibitor 546C88 in patients with septic shock. The predefined primary efficacy objective was resolution of shock, defined as a mean arterial pressure > or =70 mm Hg in the absence of both conventional vasopressors and study drug, determined at the end of the 72-hr treatment period. DESIGN: Multicentered, randomized, placebo-controlled, safety and efficacy study. SETTING: Forty-eight intensive care units in Europe, North America, and Australia. PATIENTS: A total of 312 patients with septic shock diagnosed within 24 hr before randomization. INTERVENTIONS: Patients were randomly allocated to receive either 546C88 or placebo (5% dextrose) by intravenous infusion for up to 72 hrs. Conventional vasoactive therapy was restricted to norepinephrine, dopamine, and dobutamine. Study drug was initiated at 0.1 mL/kg/hr (5 mg/kg/hr 546C88) and titrated according to response up to a maximum rate of 0.4 mL/kg/hr with the objective to maintain mean arterial pressure at 70 mm Hg while attempting to withdraw any concurrent vasopressor(s). MEASUREMENTS AND MAIN RESULTS: Requirement for vasopressors, systemic hemodynamics, indices of organ function and safety (including survival up to day 28) were assessed. The median mean arterial pressure for both groups was maintained >70 mm Hg. Administration of 546C88 was associated with a decrease in cardiac index while stroke index was maintained. Resolution of shock at 72 hr was achieved by 40% and 24% of the patients in the 546C88 and placebo cohorts, respectively (p =.004). There was no evidence that treatment with 546C88 had any major adverse effect on pulmonary, hepatic, or renal function. Day 28 survival was similar for both groups. CONCLUSIONS: In this study, treatment with the nitric oxide synthase inhibitor 546C88 promoted the resolution of shock in patients with severe sepsis. This was associated with an acceptable overall safety profile.

OBJECTIVE: To study whether the Short Form-36 questionnaire can be used to assess the patient's quality of life on admission to the ICU by use of proxies in both scheduled and emergency admissions. DESIGN AND SETTING: Prospective study involving direct interviews of patients and relatives before or during ICU stay in a 10-bed mixed intensive care unit in a 654-bed university affiliated hospital. PATIENTS AND PARTICIPANTS: Patients before major elective surgery ( n=55) or following emergency admissions ( n=57). MEASUREMENTS AND RESULTS: Patients and proxies completed a health questionnaire in the first 72 h following emergency admission or the day before a scheduled admission to the ICU. Internal consistency was evaluated by measurement of Cronbach's alpha. All dimensions of the SF-36 had adequate internal consistency. On all eight dimensions a significant correlation was found between the patient and their proxy. In general, proxies underestimated the patient's quality of life although differences were small (less than 5%). On most items a good to very good agreement was found (alpha>0.6). Quality of life assessment was not affected by the admission status of the patient (acute or elective admission and surgical or medical diagnosis). CONCLUSIONS: The SF-36 questionnaire completed by a proxy can reliable assesses the quality of life of the critically ill patient on admission to the ICU. Proxies underestimated the patient's quality of life, although the differences were small.

OBJECTIVE: Based on the results of the PROWESS trial the European Agency for the Evaluation of Medicinal Products has recently approved drotrecogin alfa (activated) for treatment of adult patients with severe sepsis and multiple-organ failure. We report study's data on efficacy and safety in patients with multiple-organ dysfunction. DESIGN AND SETTING: Randomized, double-blind, placebo-controlled, multicenter trial in 164 medical centers. PATIENTS: 1271 patients (75.2% of the intention-to-treat population, n=1690) with multiple-organ dysfunction at study entry. INTERVENTIONS: Drotrecogin alfa (activated) n=634, 24 micro g/kg per hour for 96 h or placebo ( n=637). RESULTS: Observed 28-day mortality was significantly lower with drug treatment than with placebo (26.5%vs. 33.9%), cardiovascular and respiratory organ dysfunction resolved more rapidly over the first 7 days, and serious bleeding events were more frequent (2.4% vs. 1.3%). CONCLUSIONS: Treatment with drotrecogin alfa (activated) significantly reduced 28-day mortality and more quickly resolved cardiovascular and respiratory organ dysfunction. The difference in serious bleeding event rates may be clinically significant; however, the overall benefit-risk profile appears favorable.