L. G. Thijs

Challenges in end-of-life care in the ICU

The jurors identified numerous problems with end of life in the ICU including variability in practice, inadequate predictive models for death, elusive knowledge of patient preferences, poor communication between staff and surrogates, insufficient or absent training of health-care providers, the use of imprecise and insensitive terminology, and incomplete documentation in the medical records. The jury strongly recommends that research be conducted to improve end-of-life care. The jury advocates a “shared” approach to end-of-life decision-making involving the caregiver team and patient surrogates. Respect for patient autonomy and the intention to honour decisions to decline unwanted treatments should be conveyed to the family. The process is one of negotiation, and the outcome will be determined by the personalities and beliefs of the participants. Ultimately, it is the attending physician’s responsibility, as leader of the health-care team, to decide on the reasonableness of the planned action. In the event of conflict, the ICU team may agree to continue support for a predetermined time. Most conflicts can be resolved. If the conflict persists, however, an ethics consultation may be helpful. Nurses must be involved in the process. The patient must be assured of a pain-free death. The jury of the Consensus Conference subscribes to the moral and legal principles that prohibit administering treatments specifically designed to hasten death. The patient must be given sufficient analgesia to alleviate pain and distress; if such analgesia hastens death, this “double effect” should not detract from the primary aim to ensure comfort.

Endotoxin and the hypothalamo-pituitary-adrenal (HPA) axis

Endotoxin is considered to be a systemic (immunological) stressor eliciting a prolonged activation of the hypothalamo-pituitary-adrenal (HPA) axis. The HPA-axis response after an endotoxin challenge is mainly due to released cytokines (IL-1, IL-6 and TNF-alpha) from stimulated peripheral immune cells, which in turn stimulate different levels of the HPA axis. Controversy exists regarding the main locus of action of endotoxin on glucocorticoid secretion, since the effect of endotoxin on this neuro-endocrine axis has been observed in intact animals and after ablation of the hypothalamus; however, a lack of LPS effect has been described at both pituitary and adrenocortical levels. The resulting increase in adrenal glucocorticoids has well-documented inhibitory effects on the inflammatory process and on inflammatory cytokine release. Therefore, immune activation of the adrenal gland by endotoxin is thought to occur by cytokine stimulation of corticosteroid-releasing hormone (CRH) production in the median eminence of the hypothalamus, which, in turn stimulates the secretion of ACTH from the pituitary. Acute administration of endotoxin stimulates ACTH and cortisol secretion and the release of CRH and vasopressin (AVP) in the hypophysial portal blood. During repeated endotoxemia, tolerance of both immune and HPA function develops, with a crucial role for glucocorticoids in the modulation of the HPA axis. A single exposure to a high dose of LPS can induce a long-lasting state of tolerance to a second exposure of LPS, affecting the response of plasma TNF-alpha and HPA hormones. Although there are gender differences in the HPA response to endotoxin and IL-1, these responses are enhanced by castration and attenuated by androgen and estrogen replacement. Estrogens attenuate the endotoxin-induced stimulation of IL-6, TNF-alpha and IL-1ra release and subsequent activation in postmenopausal women. There appears to be a temporal and functional relation between the HPA-axis response to endotoxin and nitric oxide formation in the neuro-endocrine hypothalamus, suggesting a stimulatory role for nitric oxide in modulating the HPA response to immune challenges.

Continuous Cardiac Output in Septic Shock by Simulating a Model of the Aortic Input Impedance A Comparison with Bolus Injection Thermodilution

BACKGROUND To compare continuous cardiac output obtained by simulation of an aortic input impedance model to bolus injection thermodilution (TDCO) in critically ill patients with septic shock. METHODS In an open study, mechanically ventilated patients with septic shock were monitored for 1 (32 patients), 2 (15 patients), or 3 (5 patients) days. The hemodynamic state was altered by varying the dosages of dopamine, norepinephrine, or dobutamine. TDCO was estimated 189 times as the series average of four automated phase-controlled injections of iced 5% glucose, spread equally over the ventilatory cycle. Continuous model-simulated cardiac output (MCO) was computed from radial or femoral artery pressure. On each day, the first TDCO value was used to calibrate the model. RESULTS TDCO ranged from 4.1 to 18.2 l/min. The bias (mean difference between MCO and TDCO) on the first day before calibration was -1.92 +/- 2.3 l/min (mean +/- SD; n = 32; 95% limits of agreement, -6.5 to 2.6 l/min). The bias increased at higher levels of cardiac output (P < 0.05). In 15 patients studied on two consecutive days, the precalibration ratio TDCO:MCO on day 1 was 1.39 +/- 0.28 (mean +/- SD) and did not change on day 2 (1.39 +/- 0.34). After calibration, the bias was -0.1 +/- 0.8 l/min with 82% of the comparisons (n = 112) < 1 l/min and 58% (n = 79) < 0.5 l/min, and independent of the level of cardiac output. CONCLUSIONS In mechanically ventilated patients with septic shock, changes in bolus TDCO are reflected by calibrated MCO over a range of cardiac output values. A single calibration of the model appears sufficient to monitor continuous cardiac output over a 2-day period with a bias of -0.1 +/- 0.8 l/min.

Plasma endothelin levels are increased during septic shock.

ObjectiveTo study whether serially measured plasma concentrations of endothelin (a novel, potent, endogenous vasoconstrictor derived from endothelium and macrophages) relate to the pathophysiology and severity of human septic shock. DesignProspective analysis. SettingMedical ICU of a university hospital. PatientsSix patients with septic shock, studied for 8 days after ICU admission. Measurements and Main ResultsThe initial plasma endothelin concentration was increased (14.2 ± 5.2 [SD] vs. normal 4.2 ± 0.7 pg/mL, p < .05) and correlated with the Acute Physiology and Chronic Health Evaluation II score (r2 = .79, p < .05). For pooled data, endothelin levels correlated poorly with leukocyte counts (r2 = .13), mean arterial pressure (MAP) (r2 = .16), and administered doses of dopamine (r2 = .26). In multiple regression analyses, plasma endothelin concentrations were predicted by dopamine doses and not by MAP. Plasma endothelin concentrations predicted the decrease in creatinine clearance, independently from MAP. The pooled value for correlations between endothelin levels and creatinine clearance, during the course of disease in individual patients, was statistically significant (r2 = .31). ConclusionsDuring septic shock, the release or production of endothelin may increase as a consequence of endothelial injury by activated leukocytes and the infusion of catecholamines, and this mechanism may relate to renal vasoconstriction and to the severity of disease. (Crit Care Med 1992; 20:1097–1101)

Coagulation disorders in septic shock

Abnormalities in coagulation and fibrinolysis are frequently observed in septic shock. The most pronounced clinical manifestation is disseminated intravascular coagulation. Recent studies in human volunteers and animal models have clarified the early dynamics and route of activation of both coagulation and fibrinolytic pathways. In healthy subjects subjected to a low dose of either endotoxin or TNF an imbalance in the procoagulant and the fibrinolytic mechanisms is apparent, resulting in a procoagulant state. Also in patients with septic shock a dynamic process of coagulation and fibrinolysis is ongoing with evidence of impaired fibrinolysis. These abnormalities have prognostic significance; the extent of disturbances of coagulation and fibrinolysis is related to the development of multiple organ failure and death.

Clinical and experimental studies on electromechanical dissociation.

Electromechanical dissociation (EMD) is the most frequent cause of unsuccessful cardiac resuscitation in critically ill patients. In a clinical study of cardiac arrest, including 54 episodes in 50 fully monitored patients, 14 episodes of ventricular fibrillation were observed and seven were reversed. In the remaining 40 instances, 36 cases of EMD were initially observed. Four patients had asystole. None of the patients with EMD or asystole were successfully resuscitated.For objective study of EMD and its treatment, we developed an experimental model in which ventricular fibrillation was induced in mechanically ventilated dogs. EMD was predictably observed when, after an interval of 120 seconds, ventricular fibrillation was reversed with an external countershock. Neither metabolic acidosis nor metabolic alkalosis modified the incidence of EMD. A few dogs were pretreated with glucose-insulin- potassium or pharmacologic doses of methylprednisolone, but this did not clearly reduce the incidence of EMD. However, the onset of EMD was delayed when the body temperature of the animal was spontaneously reduced.

Pulsatile hormone secretion during severe sepsis: Accuracy of different blood sampling regimens

The metabolic response to sepsis is dependent on the hormonal status. However, reported plasma hormone levels vary widely among studies. The persistence of pulsatile secretion, as occurs normally, may explain the observed variability. To study whether pulsatile hormone secretion persists during sepsis and how it affects assessment of the hormonal status from single measurements, we measured growth hormone (GH), prolactin, cortisol, insulin, and C-peptide at 20-minute intervals for 24 hours in eight consecutive patients with severe sepsis. Twenty-four-hour averages (mean +/- SD) were 3.3 +/- 2.5 ng/mL for GH, 640 +/- 461 nmol/L for cortisol, 18.2 +/- 4.8 mU/L for insulin, and 3.4 +/- 2.9 U/L for C-peptide, at a pulse frequency between 3.3 +/- 2.7 for C-peptide and 10.2 +/- 3.4 for insulin, and an increase of the maximal value in a pulse above the preceding nadir of 131% +/- 13% for cortisol and 376% +/- 386% for GH, as assessed with Cluster analysis. Prolactin levels were below the detection limit in all but one patient, probably due to the administration of dopamine. To determine the accuracy of less frequent blood sampling regimens, we simulated different sampling strategies and compared them with the 24-hour averages. The accuracy of single samples proved inadequate for all hormones. Sampling every 20 minutes for periods of 4, 8, or 12 hours improved accuracy, but intermittent sampling every 1, 2, 4, or 6 hours during a 24-hour period yielded even more accurate results.(ABSTRACT TRUNCATED AT 250 WORDS)

International sepsis trial (INTERSEPT) : Role and impact of a clinical evaluation committee

OBJECTIVE Several large clinical trials have recently evaluated a variety of potential therapeutic interventions for sepsis and have yielded negative results based on analyses of intention-to-treat cohorts. The present study was undertaken to evaluate the importance of a Clinical Evaluation Committee. DESIGN Prospective, double-blind evaluation of a prospective, controlled, double-blind, randomized, multinational trial. SETTING Forty medical centers. PATIENTS Five hundred fifty-three infused patients with severe sepsis and septic shock. METHODS As part of an international trial (INTERSEPT) of antitumor necrosis factor therapy, a Scientific Extramural Review Committee prospectively defined and excluded patients with confounding events that objectively interfered with the potential of any intervention for sepsis to exercise its therapeutic effect. These confounding events included inappropriate antimicrobial therapy, inadequate medical-surgical management, underlying disorders, and forgoing life-sustaining therapies before management had failed. Patients who met all inclusion and exclusion criteria and who had no confounding events were defined as the Scientific Extramural Review Committee group. MEASUREMENTS AND MAIN RESULTS Five hundred fifty-three patients were enrolled in INTERSEPT. Seventy-seven patients did not meet inclusion and exclusion criteria. Sixty patients had confounding events, including inappropriate antimicrobial therapy (n = 28), inadequate medical-surgical management (n = 16), underlying disorders (n = 17), and forgoing life-sustaining therapies (n = 7). Four hundred sixteen patients were in the Scientific Extramural Review Committee group and their mortality rates were different from the mortality rates of the intent-to-treat cohort. In the intent-to-treat analysis among shock patients, low-dose anti-tumor necrosis factor reduced 28-day mortality by 14.5% (p = .34), whereas in the Scientific Extramural Review Committee group, the study drug reduced mortality by 26.5% (p = .16). More patients in the high dose anti-tumor necrosis factor treatment arm (31/176) were in the invalid Scientific Extramural Review Committee group than in the other two arms (16/157 and 13/143, respectively, p < .05). CONCLUSIONS In large trials of sepsis, in addition to analyzing the intent-to-treat cohort, patients in compliance with the protocol and with no confounding events should also be analyzed. These results should assist in determining whether treatment groups are comparable and provide a greater likelihood of demonstrating the potential efficacy of a new therapy for sepsis. A Clinical Evaluation Committee is important to properly assess a clinical sepsis trial.

α-atrial natriuretic peptide, cyclic guanosine monophosphate, and endothelin in plasma as markers of myocardial depression in human septic shock

OBJECTIVE To assess the value of alpha-atrial natriuretic peptide (alpha-ANP), second messenger cyclic guanosine monophosphate (cGMP,) and endothelin as markers of myocardial depression in septic shock. DESIGN Prospective observational study. SETTING Medical intensive care unit (ICU) of a university hospital. PATIENTS Fourteen consecutive patients with septic shock and arterial and pulmonary artery catheters in place. MEASUREMENTS AND MAIN RESULTS Hemodynamic variables and plasma levels of alpha-ANP, cGMP, and endothelin were measured every 6 hrs for 3 days after admission. Eight patients died from shock in the ICU. The nadir left ventricular stroke work index (LVSWI) was below 35 g/m2 in all patients, and the median peak circulating alpha-ANP (n < 68 pg/mL) was 276 pg/mL (range, 79-1056), the median peak cGMP (n < 2.1 ng/mL) was 8.1 ng/mL (range, 3.2-29.7), and the median peak endothelin (n < 5.3 pg/mL) was 15.5 pg/mL (range, 8.5-33.9), supranormal in all patients. Outcome groups differed in the course of cardiac index and LVSWI, which were lower in nonsurvivors despite similar filling pressures and more intensive inotropic treatment (p < .01). The course of alpha-ANP, cGMP, and endothelin plasma levels also differed between groups, with higher levels in nonsurvivors (p < .05). As for pooled data, the mean daily or nadir LVSWI inversely related to mean daily or peak alpha-ANP, cGMP, and endothelin levels, respectively (p < .05). The area under the receiver operating characteristic curve for myocardial depression (LVSWI < 35 g/m2) was for alpha-ANP and endothelin 0.77, and for cGMP 0.85 (p < .01). The optimum cutoff values for alpha-ANP, cGMP, and endothelin were 172 pg/mL, 4.5 ng/mL, and 10.0 pg/mL, respectively. The sensitivity for myocardial depression of alpha-ANP, cGMP, and endothelin was 68%, 77%, and 72%, and the specificity was 82%, 93%, and 69%, respectively. CONCLUSIONS Circulating alpha-ANP, endothelin, and, particularly, cGMP may be markers of the myocardial depression of human septic shock, which is associated with mortality.

Continuous arteriovenous hemofiltration as an adjunctive therapy for septic shock.

The effects of continuous arteriovenous hemofiltration were studied in septic patients with acute renal failure and gross fluid overload. Hemofiltration was performed for a mean of 7 days per patient (range 1 to 14 days). The mean filtration volume was 3.64 L/day. The mean total ultrafiltration volume per patient was 25.5 L. The patients were hemodynamically stable during hemofiltration, as indicated by measurements of arterial blood pressure, CVP, pulmonary artery pressure, pulmonary artery wedge pressure, and cardiac output. Multiple simultaneous measurements in both serum and ultrafiltrate showed a very close correlation for sodium, potassium, phosphorus, urea and creatinine levels. There was no detectable protein in the ultrafiltrate. The calcium concentration in the ultrafiltrate was relatively low. Finally, antibiotic levels in the ultrafiltrate were almost equal to serum levels. There were no significant complications; in this series of patients hemofiltration was a safe and effective treatment of fluid overload.