Heterogeneity and prediction of hemodynamic responses to dobutamine in patients with septic shock.

OBJECTIVE: To establish the heterogeneity of hemodynamic responses to dobutamine in patients with septic shock and to identify the predictive factors of these hemodynamic responses. DESIGN: Prospective study. SETTING AND PATIENTS: A total of 12 patients with septic shock in a tertiary medical intensive care unit. INTERVENTIONS: A 20-min dobutamine infusion at 5 microg.kg(-1).min(-1) with subsequent increments to 8, 12.6, and 20 microg.kg(-1).min(-1), on two consecutive days. Responses were dichotomized into changes in heart rate (HR) or stroke volume index (SVI) of >10% and < or =10% at the maximal dobutamine infusion. MEASUREMENTS AND MAIN RESULTS: No differences were found in survival, Acute Physiology and Chronic Health Evaluation II score, maximal dobutamine doses, or pharmacokinetics of dobutamine between HR and SVI groups. In DeltaHR > 10% vs. DeltaHR < or = 10%, baseline HR was lower, and baseline mixed venous oxygen tension and saturation were higher. During dobutamine infusion, mean arterial pressure decreased in DeltaHR > 10%. Cardiac index and the systemic oxygen delivery index increased and the systemic vascular resistance index decreased at unchanged SVI. Pressure work index increased and the ratio of the diastolic to systolic aortic pressure time indices decreased but not to <0.6. In DeltaHR < or = 10%, systemic vascular resistance index and the ratio of the diastolic to systolic aortic pressure time indices decreased (but remained >0.6) without changes in SVI or cardiac index. Baseline hemodynamic and metabolic variables did not differ between SVI groups. In DeltaSVI > 10%, cardiac index increased with dobutamine, but Pao2 and the systemic oxygen delivery index decreased. In DeltaSVI < or = 10%, HR and the systemic oxygen delivery index increased; mean arterial pressure, left ventricular stroke work index, systemic vascular resistance index, and the ratio of the diastolic to systolic aortic pressure time indices decreased. CONCLUSIONS: Patients with a positive chronotropic response to dobutamine had lower baseline HR values, and a chronotropic rather than inotropic response predicted an increase in cardiac index and systemic oxygen delivery index. Incremental dosages of dobutamine did not compromise indirectly measured myocardial oxygen balance.

Population pharmacodynamic modelling of lorazepam- and midazolam-induced sedation upon long-term continuous infusion in critically ill patients.

OBJECTIVE: The objective of the present investigation was to develop a population pharmacodynamic model for midazolam- and lorazepam-induced sedation upon long-term continuous infusion in critically ill patients. METHODS: The study was conducted in 59 patients receiving lorazepam and 54 patients receiving midazolam by continuous infusion for at least 24 h. Repeated blood samples were obtained for determination of the concentrations of lorazepam and midazolam. The level of sedation was assessed using a 5-point sedation scale. RESULTS: The pharmacokinetics of lorazepam and midazolam was described with previously proposed pharmacokinetic models. For the pharmacodynamics, the probability that the sedation was equal to or more than a specific score was described using a sigmoid E(max) model. The EC(50) values of lorazepam for the sedation scores equal or larger than 2-5 were 6.1, 57, 184 and 529 ng/ml, respectively. The corresponding values for midazolam were 216, 483, 1,100 and 2,200 ng/ml. Inter-individual variability in the EC(50) values was relatively high with a CV of 68% for lorazepam and 86% for midazolam (p=0.035). No covariates explaining part of the observed inter-individual variability were identified. CONCLUSION: The population pharmacodynamic model shows a similarly wide intra- and inter-individual variability in the pharmacodynamics of both lorazepam and midazolam. Thus, the previously observed differences in "ease of titration" between lorazepam and midazolam are unrelated to pharmacodynamic factors.

Population pharmacokinetics of lorazepam and midazolam and their metabolites in intensive care patients on continuous venovenous hemofiltration.

BACKGROUND: The objective is to study the population pharmacokinetics of lorazepam and midazolam in critically ill patients with acute renal failure who are treated with continuous venovenous hemofiltration (CVVH). METHODS: Twenty critically ill patients with acute renal failure on CVVH therapy were administered either lorazepam (n = 10) or midazolam (n = 10) by continuous infusion. CVVH was performed with an ultrafiltrate flow of 2 L/h with filtrate substitution in the predilution or postdilution mode. Blood flow through the 1.9-m 2 cellulose triacetate membrane filter was 180 mL/min. For 48 hours, multiple blood and ultrafiltrate samples were obtained for determination of concentrations of the drug and its metabolites. RESULTS: The pharmacokinetics of lorazepam is described best by a 1-compartment model. No significant covariates were identified. Total-body clearance was 6.4 L/h, and volume of distribution was 376 L. Ultrafiltration clearance was 0.31 L/h, equivalent to approximately 5% of total clearance. Average degree of plasma protein binding was 82.9% for lorazepam, with a sieving coefficient of 0.16 +/- 0.03. For lorazepamglucuronide, degree of plasma protein binding was 39.5%, and sieving coefficient was 0.48 +/- 0.07. The pharmacokinetics of midazolam is described best by a 1-compartment model. No significant covariates were identified. Total-body clearance was 8.5 L/h, and volume of distribution was 157 L. Clearance by ultrafiltration was 0.055 L/h, equivalent to approximately 0.7% of total clearance. Average degree of plasma protein binding was 95.8%, with a sieving coefficient of 0.04 +/- 0.03. For the metabolite 1-hydroxymidazolamglucuronide, average degree of plasma protein binding was 43.4%, with a sieving coefficient of 0.45 +/- 0.06. CONCLUSION: Neither lorazepam nor midazolam is removed efficiently by CVVH. CVVH contributes significantly to the removal of the glucuronide metabolites lorazepamglucuronide and 1-hydroxymidazolamglucuronide.

The immunoneuroendocrine axis in critical illness: beneficial adaptation or neuroendocrine exhaustion?

PURPOSE OF REVIEW: Over the last years, endocrinology has been incorporated in critical care medicine, and acknowledgment of the complex neuro-endocrine adaption of critical illness has led to new insights and major breakthroughs in clarifying pathophysiological mechanisms and the targeting of therapeutic strategies. This review focuses on the important role of the hypothalamic-pituitary-adrenal (HPA) axis during critical illness and the occurrence of neuroendocrine failure. RECENT FINDINGS: The distinction between acute (activated anterior pituitary function and inactivated peripheral anabolic pathways) and prolonged (reduced neuroendocrine stimulation) critical illness as different neuroendocrine paradigms has brought a new approach to the critically ill patient. The HPA adaptation in the prolonged phase is characterized by hypercortisolism induced by non-ACTH driven pathways as ACTH levels are low. In spite of the high-normal (total) cortisol levels, HPA insufficiency appears to be quite common. On the other hand, there is a marked depletion of corticosteroid-binding globulin (CBG) in the acute phase of critical illness, resulting in increased free and biologically active cortisol. There is a persistent marked depletion of dehydroeplandrosterone sulfate, possibly indicating adrenal exhaustion, while macrophage inhibitory factor is upregulated in sepsis, affecting and contraregulating the biological effects of glucocorticoids. SUMMARY: The endocrine system is highly interrelated with the immune and neural systems, the neuroimmunoendocrine axis is subject to clear biphasic changes in the acute and chronic phases of critical illness, most likely reflecting a beneficial adaptation. These neuroendocrine dynamics should be considered when assessing the neuroendocrine system, in particular the HPA axis.

Challenges in end-of-life care in the ICU: statement of the 5th International Consensus Conference in Critical Care: Brussels, Belgium, April 2003: executive summary.

OBJECTIVE: The purpose of the conference was to provide clinical practice guidance in end-of-life care in the ICU via answers to previously identified questions relating to variability in practice, inadequate predictive models for death, elusive knowledge of patient preferences, poor communication between staff and surrogates, insufficient or absent training of healthcare providers, the use of imprecise and insensitive terminology and incomplete documentation in the medical record. PARTICIPANTS: Presenters and jury were selected by the sponsoring organizations (American Thoracic Society, European Respiratory Society, European Society of Intensive Care Medicine, Society of Critical Care Medicine, Société de Réanimation de Langue Française). Presenters were experts on the question they addressed. Jury members were general intensivists without special expertise in the areas considered. Experts presented in an open session to jurors and other healthcare professionals. EVIDENCE: Experts prepared review papers on their specific topics in advance of the conference for the jury's reference in developing the consensus statement. CONSENSUS PROCESS: Jurors heard experts' presentations over 2 days and asked questions of the experts during the open sessions. Jury deliberation with access to the review papers occurred for 2 days following the conference. A writing committee drafted the consensus statement for review by the entire jury. The 5 sponsoring organizations reviewed the document and suggested revisions to be incorporated into the final statement. CONCLUSIONS: Strong recommendations for research to improve end-of-life care were made. 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 honor 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 team, to decide on the reasonableness of the planned action. If a conflict cannot be resolved, an ethics consultation may be helpful. The patient must be assured of a pain-free death. The jury 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.

Challenges in end-of-life care in the ICU. Statement of the 5th International Consensus Conference in Critical Care: Brussels, Belgium, April 2003.

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.

Comparative population pharmacokinetics of lorazepam and midazolam during long-term continuous infusion in critically ill patients.

AIMS: It is well established that there is a wide intra- and interindividual variability in dose requirements for lorazepam and midazolam in intensive care patients. The objective of this study was to compare the population pharmacokinetics of lorazepam and midazolam after long-term continuous infusion in mechanically ventilated critically ill patients. METHODS: Forty-nine critically ill patients randomly received either lorazepam (n = 28) or midazolam (n = 21) by continuous infusion for at least 24 h. Multiple blood samples were obtained for determination of the drug and metabolite concentrations by HPLC. Population pharmacokinetic models were developed using the Non-Linear Mixed Effect Modelling (NONMEM) program. The influence of selected covariates was investigated. The prospective performance of the models was evaluated on the basis of results in separate groups of patients for lorazepam (n = 31) and midazolam (n = 33). RESULTS: The pharmacokinetics of lorazepam were best described by a two-compartment model. Alcohol abuse, positive end expiratory pressure (PEEP) and age were identified as significant covariates. Total body clearance for patients without alcohol abuse was 4.13 - (PEEP - 5) x 0.42 l h-1, and 0.74 l h-1 for patients with alcohol abuse. The volume of distribution was 0.74 l, the steady state volume of distribution was 56 - (age - 58) x 2.1 l and the intercompartmental clearance was 10 l h-1. The proportional residual error was 15% and the median absolute prediction error was 13.6% with a bias of 1.5%. The pharmacokinetics of midazolam were best described by a two-compartment model with alcohol abuse, APACHE score and age as significant covariates. Total body clearance for patients without alcohol abuse was 11.3 - (age - 57) x 0.14 l h-1, and 7.27 - (age -57) x 0.14 l h-1 for patients with alcohol abuse. The volume of distribution was 7.15 l, the steady state volume of distribution was 431 l, and the intercompartmental clearance was 40.8 - (APACHE score - 26) x 2.75 l h-1. The proportional residual error was 31% with an additive residual error of 32 ng ml-1. The median absolute prediction error was 12.9% with a bias of 1.2%. The prospective performance in the lorazepam evaluation group was better with the covariate adjusted model, but in the midazolam evaluation group it was not better than with the simple model. In all models a tendency to overestimate the lower plasma concentrations was observed. CONCLUSIONS: The pharmacokinetics of both lorazepam and midazolam were well described by a two-compartment model. Inclusion of alcohol abuse and age as covariates improved both models. PEEP was identified as an additional covariate for lorazepam, and the APACHE score for midazolam. For both drugs there is a large interindividual variability in their pharmacokinetics when used for long-term sedation in critically ill patients. However, the intra-individual variability is much lower for lorazepam.

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.

Decreased levels of dehydroepiandrosterone sulphate in severe critical illness: a sign of exhausted adrenal reserve?

INTRODUCTION: Dehydroepiandrosterone (DHEA) and its sulphate (DHEAS) are pleiotropic adrenal hormones with immunostimulating and antiglucocorticoid effects. The present study was conducted to evaluate the time course of DHEAS levels in critically ill patients and to study their association with the hypothalamic-pituitary-adrenal axis. MATERIALS AND METHOD: This was a prospective observational clinical and laboratory study, including 30 patients with septic shock, eight patients with multiple trauma, and 40 age- and sex-matched control patients. We took serial measurements of blood concentrations of DHEAS, cortisol, tumour necrosis factor-alpha and IL-6, and of adrenocorticotrophic hormone immunoreactivity over 14 days or until discharge/death. RESULTS: On admission, DHEAS was extremely low in septic shock (1.2 +/- 0.8 mol/l) in comparison with multiple trauma patients (2.4 +/- 0.5 micromol/l; P < 0.05) and control patients (4.2 +/- 1.8; P < 0.01). DHEAS had a significant (P < 0.01) negative correlation with age, IL-6 and Acute Physiology and Chronic Health Evaluation II scores in both patient groups. Only during the acute phase did DHEAS negatively correlate with dopamine. Nonsurvivors of septic shock (n = 11) had lower DHEAS levels (0.4 +/- 0.3 micromol/l) than did survivors (1.7 +/- 1.1 micromol/l; P < 0.01). The time course of DHEAS exhibited a persistent depletion during follow up, whereas cortisol levels were increased at all time points. CONCLUSION: We identified extremely low DHEAS levels in septic shock and, to a lesser degree, in multiple trauma patients as compared with those of age- and sex-matched control patients. There appeared to be a dissociation between DHEAS (decreased) and cortisol (increased) levels, which changed only slightly over time. Nonsurvivors of sepsis and patients with relative adrenal insufficiency had the lowest DHEAS values, suggesting that DHEAS might be a prognostic marker and a sign of exhausted adrenal reserve in critical illness.

Glutamine-enriched enteral nutrition increases HLA-DR expression on monocytes of trauma patients.

The aim of this study was to investigate the effect of glutamine-(Gln)-enriched enteral nutrition (EN) on human leukocyte antigen (HLA)-DR and FcgammaR1/CD64 expression on monocytes and plasma glutamine concentrations in multi-trauma patients. HLA-DR expression on monocytes is crucial in the presentation of foreign antigen to the immune system and is severely reduced in trauma patients. In vitro monocyte HLA-DR and FcgammaRI/CD64 expression is dependent on glutamine availability. To study the effect of glutamine supplemented enteral nutrition on HLA-DR and FcgammaRI/CD64 expression on CD14(+) monocytes, 55 multi-trauma patients were studied in a randomized, double-blinded, controlled trial. Trauma patients received either a Gln-enriched EN (glutamine group, n = 28) or an isocaloric, isonitrogenous control EN (control group, n = 27) and were compared with a group of age-matched healthy volunteers (healthy volunteers, n = 53). On d 1, 5, 9 and 14 after trauma, expressions of HLA-DR and FcgammaRI/CD64 were determined on CD14(+) monocytes using FACS analysis. Plasma glutamine levels were measured using HPLC. Plasma glutamine was lower in both trauma patient groups compared with healthy volunteers and from d 3 to d 5; glutamine was higher in the glutamine group than in the control group. On d 1, HLA-DR expression was much lower in both trauma patient groups than in healthy volunteers. HLA-DR expression was greater on d 5, 9 and 14 in the glutamine group than in the control group. FcgammaRI/CD64 expression on monocytes of trauma patients was not different than the expression of healthy volunteers. This study showed that glutamine-enriched enteral nutrition was associated with a higher HLA-DR expression on CD14(+) monocytes of trauma patients. No difference in monocyte FcgammaRI/CD64 expression was detected between patients that received the two enteral diets and between trauma patients and the healthy volunteers. Increased HLA-DR expression may improve cellular immune function and may be involved in the beneficial effect of glutamine on the occurrence of infections in trauma patients.