A. B. Johan Groeneveld

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.

Biomarkers of acute renal injury and renal failure

ABSTRACT Acute renal failure (ARF) is a frequent problem in the intensive care unit and is associated with a high mortality. Early recognition could help clinical management, but current indices lack sufficient predictive value for ARF. Therefore, there might be a need for biomarkers in detecting renal tubular injury and/or dysfunction at an early stage before a decline in glomerular filtration rate is noted by an increased serum creatinine. A MEDLINE/PubMed search was performed, including all articles about biomarkers for ARF. All publication types, human and animal studies, or subsets were searched in English language. An extraction of relevant articles was made for the purpose of this narrative review. These biomarkers include tubular enzymes (&agr;- and &pgr;-glutathione S-transferase, N-acetyl-glucosaminidase, alkaline phosphatase, &ggr;-glutamyl transpeptidase, Ala-(Leu-Gly)-aminopeptidase, and fructose-1,6-biphosphatase), low-molecular weight urinary proteins (&agr;1- and &bgr;2-microglobulin, retinol-binding protein, adenosine deaminase-binding protein, and cystatin C), Na+/H+ exchanger, neutrophil gelatinase-associated lipocalin, cysteine-rich protein 61, kidney injury molecule 1, urinary interleukins/adhesion molecules, and markers of glomerular filtration such as proatrial natriuretic peptide (1-98) and cystatin C. These biomarkers, detected in urine or serum shortly after tubular injury, have been suggested to contribute to prediction of ARF and need for renal replacement therapy. However, excretion of these biomarkers may also increase after reversible and mild dysfunction and may not necessarily be associated with persistent or irreversible damage. Large prospective studies in human are needed to demonstrate an improved outcome of biomarker-driven management of the patient at risk for ARF.

Splanchnic tonometry: a review of physiology, methodology, and clinical applications.

The objective of this article is to review splanchnic tonometry. The English literature, involving both animal and human studies, was used for review, with emphasis on papers on physiological and methodological principles and clinical applications. Tonometry involves the measurement of intraluminal PCO2 as a measure of mucosal PCO2 in the gastrointestinal tract via a catheter in, for instance, stomach or sigmoid colon, and the calculation, with help of the blood bicarbonate content and the Henderson-Hasselbalch equation, of the mucosal pH (pHi). The latter is considered as a relatively simple index of the adequacy of mucosal blood flow. Concerning methodology, it is still unclear whether acid secretion should be inhibited for proper assessment of PCO2 in the stomach. Buffering of bicarbonate by gastric acid may elevate the intraluminal PCO2 independently from mucosal PCO2, thereby confounding pHi as a measure of perfusion adequacy. This can be prevented by inhibition of acid secretion. Authors have raised doubts whether the composite variable pHi is of additive value to the acid-base status of arterial blood, so that it is unclear whether a subnormal pHi is a specific and sensitive indicator of mucosal ischemia, as suggested by others on the basis of a decline in the pHi along the gastrointestinal tract in animals subjected to vascular occlusion or circulatory shock. Moreover, tissue PCO2 depends on the PCO2 of supplying blood. Conversely, the bicarbonate concentration in ischemic mucosa may not equal that in arterial blood. Taken together, an elevated tonometer fluid arterial blood PCO2-gradient might be a more sensitive and specific indicator of mucosal ischemia than a decrease in the pHi, analogous to an increase in tissue PCO2 and widening of the venoarterial PCO2 gradient during various types of hypoperfusion, in animals and humans. Although splanchnic ischemia is an early event in shock, the sensitivity and specificity of this index for mucosal ischemia and its clinical value, relative to that of the pHi, have not been formally evaluated yet. Nevertheless, the pHi has been suggested to be of predictive value for gastrointestinal complications, multiple organ failure, success or failure of weaning from mechanical ventilation, and outcome in critically ill patients. Tonometry may be a useful monitoring technique to guide treatment and to improve survival. Splanchnic tonometry is a relatively simple, noninvasive, and thereby promising technique to monitor the critically ill. However, some aspects need further evaluation before the technique can be advocated for routine use.

Infusion of ultrafiltrate from endotoxemic pigs depresses myocardial performance in normal pigs.

We previously showed a beneficial effect of hemofiltration on hemodynamics of endotoxic shock pigs. To test the hypothesis that this effect of hemofiltration is caused by convective removal of factors that adversely affect hemodynamics during endotoxemia, we infused ultrafiltrate from endotoxic shock pigs into healthy pigs. Their hemodynamics were compared with those of pigs who were infused with ultrafiltrate from healthy pigs. Twelve anesthetized and ventilated pigs were hemodynamically monitored for 150 minutes following the infusion of 2 L of ultrafiltrate from 12 donor pigs. The acceptor pigs were randomly divided into two groups; group 1 received ultrafiltrate from pigs who were hemofiltered after the infusion of 0.5 mg/kg endotoxin over 30 minutes; group 2 served as a control group, receiving ultrafiltrate from healthy donor pigs. Group 1 showed a decrease in mean arterial pressure of 28 +/- 7 mm Hg (mean +/- SEM) versus an increase of 17 +/- 3 mm Hg in group 2 (P < 0.4). Mean pulmonary artery pressure increased more in group 1 than in group 2 (9 +/- 2 mm Hg versus 1 +/- 1 mm Hg, P < .04). The decrease in cardiac output in group 1 was greater than in group 2 (3.3 +/- 0.2 L/min v 0.3 +/- 0.3 L/min, P < .02) and was due to a decrease in stroke volume. The decrease in right ventricular ejection fraction was also greater (0.15 +/- 0.02 v 0.01 +/- 0.00, P < .01). Systemic vascular resistance, right atrial pressure, right ventricular end-diastolic volume, pulmonary wedge pressure and heart rate did not differ between groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Crystalloid or colloid fluid loading and pulmonary permeability, edema, and injury in septic and nonseptic critically ill patients with hypovolemia*

Objective: To compare crystalloid and colloid fluids in their effect on pulmonary edema in hypovolemic septic and nonseptic patients with or at risk for acute lung injury/acute respiratory distress syndrome. We hypothesized that 1) crystalloid loading results in more edema formation than colloid loading and 2) the differences among the types of fluid decreases at high permeability. Design, Setting, and Patients: Prospective randomized clinical trial on the effect of fluids in 24 septic and 24 nonseptic mechanically ventilated patients with clinical hypovolemia. Interventions: Patients were assigned to NaCl 0.9%, gelatin 4%, hydroxyethyl starch 6%, or albumin 5% loading for 90 minutes according to changes in filling pressures. Measurements and Main Results: Twenty-three septic and 10 nonseptic patients had acute lung injury/acute respiratory distress syndrome (p < 0.001). Septic patients had greater pulmonary capillary permeability, edema, and severity of lung injury than nonseptic patients (p < 0.01), as measured by the pulmonary leak index (PLI) for 67Gallium-labeled transferrin, extravascular lung water (EVLW), and lung injury score (LIS), respectively. Colloids increased plasma volume, cardiac index, and central venous pressure (CVP) more than crystalloids (p < 0.05), although more crystalloids were infused (p < 0.05). Colloid osmotic pressure (COP) increased in colloid and decreased in crystalloid groups (p < 0.001). Irrespective of fluid type or underlying disease, the pulmonary leak index increased by median 5% (p < 0.05). Regardless of fluid type or underlying disease, EVLW and LIS did not change during fluid loading and EVLW related to COP-CVP (rs = −.40, p < 0.01). Conclusions: Pulmonary edema and LIS are not affected by the type of fluid loading in the steep part of the cardiac function curve in both septic and nonseptic patients. Then, pulmonary capillary permeability may be a smaller determinant of pulmonary edema than COP and CVP. Safety factors may have prevented edema during a small filtration pressure-induced rise in pulmonary protein and thus fluid transport.

Vascular pharmacology of acute lung injury and acute respiratory distress syndrome.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) following sepsis, major trauma and surgery are leading causes of respiratory insufficiency, warranting artificial ventilation in the intensive care unit. It is caused by an inflammatory reaction in the lung upon exogenous or endogenous etiologies eliciting proinflammatory factors, and results in increased alveolocapillary permeability and protein-rich alveolar edema. The interstitial and alveolar inflammation and edema alter ventilation perfusion matching, gas exchange and mechanical properties of the lung. The current therapy of the condition is supportive, paying careful attention to fluid balance, relieving the increased work of breathing and improving gas exchange by mechanical ventilation, but in vitro, animal and some clinical research is done to evaluate the value of anti-inflammatory therapies on morbidity and outcome, including inflammatory cell-stabilizing corticosteroids, xanthine derivates, prostanoids and inhibitors, O(2) radical scavenging factors such as N-acetylcysteine, surfactant replacement, vasodilators including inhaled nitric oxide, vasoconstrictors such as almitrine, and others. None of these compounds has been proven to benefit survival in patients, however, even though carrying a physiologic benefit, except perhaps for steroids that may improve outcome in the later stage of ARDS. This partly relates to the difficulty to assess the lung injury at the bedside, to the multifactorial pathogenesis and the severity of comorbidity, adversely affecting survival.

Prediction of Microbial Infection and Mortality in Medical Patients with Fever: Plasma Procalcitonin, Neutrophilic Elastase-α1-Antitrypsin, and Lactoferrin Compared with Clinical Variables

Fever suggests the likelihood of severe microbial infection. Abnormal temperature, tachycardia, tachypnea, and abnormal white blood cell counts define the systemic inflammatory response syndrome (SIRS). In 300 hospitalized medical patients with fever, we determined clinical variables and procalcitonin, elastase-alpha1-antitrypsin, and lactoferrin levels in plasma. Of the patients, 71% had clinical infection (by clinical judgment) and 44% had microbial infection (by microbiological testing). SIRS occurred in 95%, and the 28-day mortality rate was 9%. The sensitivity for predicting microbial infection, bacteremia, and mortality was less but the specificity was greater for supranormal procalcitonin, elastase-alpha1-antitrypsin, and lactoferrin levels than for SIRS. The area under the receiver operating characteristic curve (AUC) for microbial infection was higher for procalcitonin and elastase-alpha1-antitrypsin levels than for clinical variables and lactoferrin level. The AUC for bacteremia was also higher for inflammatory factors (>0.70; P < .001) than for clinical variables. The AUC for mortality (P < .05) was 0.79 for the respiratory rate, 0.69 for elastase-alpha1-antitrypsin level, 0.65 for heart rate, 0.61 for procalcitonin level, and 0.60 for white blood cell count. In febrile medical patients, plasma procalcitonin and elastase-alpha1-antitrypsin levels may predict microbial infection and bacteremia better than (and mortality as well as) do clinical symptoms.

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)

High Volume Hemofiltration Improves Hemodynamics And Survival Of Pigs Exposed To Gut Ischemia And Reperfusion

This study assesses the influence of high volume continuous hemofiltration on hemodynamics of pigs subjected to bowel ischemia/reperfusion. Twelve anesthetized and ventilated pigs were studied for 60 min during clamping of the superior mesenteric artery (SMA) and subsequently for 90 min after release of the clamp, while measuring global hemodynamics, SMA flow, and jejunal pCO2. They were randomly divided into two groups: pigs in “control” group were subjected to SMA clamping only. Pigs in “hemofiltered” group received zero-balanced, high volume, veno-venous hemofiltration with the removal of 6000 ml of ultrafiltrate/h, starting 30 min before clamping until 90 min after removal of the SMA clamp. Thereafter, pigs were allowed to awake and sacrificed after 24 h for macroscopic assessment of bowel damage. The drop in cardiac output (CO) during SMA clamping in the hemofiltered group was 2.5 ± .3 L/min (mean ± SE) (1.1/4.0; 95% confidence interval) smaller than in the control group. At the end of the experiment, mean arterial pressure (MAP) in the hemofiltered group was 33 ± 6 (19/48) mmHg higher than in the control group, CO was 2.0 ± .2 (1.2/2.8) L/min higher in the hemofiltered group. After 60 min of SMA clamping, left ventricular stroke work in the hemofiltered group was 35 ± 4 (14/56) g higher than in the control group, and higher by 33 ± 3 (21/46) g at 90 min after release of the SMA clamp. The mean pulmonary artery pressure, right atrial pressure, pulmonary artery wedge pressure, SMA flow and bowel wall pCO2 at different time points did not differ between groups. None of the pigs in the control group survived until 24 after the start of the experiment, versus four pigs in the hemofiltered group. Macroscopic bowel damage at autopsy was less severe in the hemofiltered group than in the control group. We conclude that in this model, high volume veno-venous hemofiltration not only improves short-term hemodynamics, but also reduces bowel damage and improves survival after gut ischemia/reperfusion.

Quantitative Detection of Staphylococcus aureus and Enterococcus faecalis DNA in Blood To Diagnose Bacteremia in Patients in the Intensive Care Unit

ABSTRACT Direct detection of bacterial DNA in blood offers a fast alternative to blood culture and is presumably unaffected by the prior use of antibiotics. We evaluated the performance of two real-time PCR assays for the quantitative detection of Staphylococcus aureus bacteremia and for Enterococcus faecalis bacteremia directly in blood samples, without prior cultivation. Whole-blood samples for PCR were obtained simultaneously with blood cultures from patients admitted to the intensive care unit of our hospital. After the extraction of DNA from 200 μl of blood, real-time PCR was performed for the specific detection and quantification of S. aureus and E. faecalis DNA. The sensitivity for bacteremia of the S. aureus PCR was 75% and that of the E. faecalis PCR was 73%, and both tests had high specificity values (93 and 96%, respectively). PCR amplification reactions were positive for S. aureus for 10 (7%) blood samples with negative blood cultures, and 7 (4%) PCR reactions were positive for E. faecalis. The majority of these PCR results were likely (50%) or possibly (42%) related to infection with the specific microorganism, based on clinical data and radiological and microbiological investigations. PCR results were concordant for 95% of paired whole-blood samples, and blood culture results were concordant for 97% of the paired samples. We conclude that the detection of S. aureus and E. faecalis DNA in blood by real-time PCR enables a rapid diagnosis of bacteremia and that a positive DNAemia is related to proven or possible infection with the specific microorganism in the majority of patients with negative blood cultures.