Université Libre de Bruxelles Faculté de Médecine
STUDIES IN PATIENTS WITH SEPSIS AND ORGAN FAILURE: DIAGNOSTIC AND THERAPEUTIC
ASPECTS
Dr. Yasser Sakr
Thèse présentée en vue de l’obtention du grade d’agrégé l’enseignement supérieur
(grade scientifique)
I Dedicate This Work to You, My Great Love;
EGYPT
I Owe You Not Only My Success but My very Existence:
One Day I will be back
ACKNOWLEDGEMENTS
It is very hard to recall all who helped and supported me during the preparation of this work. I am lucky enough to have had an immense amount of help and
encouragement since I started my fellowship in Brussels. I would like to express my gratitude not only to the team on the Department of Intensive Care but to the whole staff of Erasme Hospital who made my stay in Brussels one of the most pleasant and productive experiences I have ever had.
It is almost impossible for me to find appropriate words to express my gratitude towards Prof. Jean Louis Vincent. I feel indebted to his continuous and unlimited support. I will always be proud that I have had the chance to work beside this pioneer, who has so enriched the field of critical care medicine with his
contributions. His enthusiasm was the main drive, and his support the main reason for the success of this work. He converted my stay in Brussels into a process of continuous development and refinement in my knowledge, and my capabilities and performance in this field have progressed steadily under his guidance. The center of excellence he heads in Brussels is a true model of how critical care medicine
should be practiced. I thank him wholeheartedly for all he has done both professionally and personally.
I also feel indebted to Prof Konrad Reinhart (Jena, Germany) who made the completion of this work possible. He has provided me with a pleasant working environment and kind support during the final stages of this work, for which I am very grateful.
I would like to express my gratitude to Dr. Daniel De Backer for his support and his kind help with my research on the microcirculation. His competent knowledge and professional insight were behind this distinguished research. I would like also to thank Dr. Marc-Jacques Debois and Dr. Jacques Crèteur for their helpful
contribution to the microcirculatory studies.
I would like also to express my sincere gratitude to Dr. Karen Picket for her critical revisions of our manuscripts and for her kind and friendly support during my stay in Brussels.
The steering committee of the “SOAP Study” and all the Investigators who have contributed to this enormous work must also be mentioned as without them there would have been no results! This experience has been a real turning point in my professional life. I also thank Prof. Francis Cantraine for his advice during data management, for his outstanding efforts in data handling, and for his competent counsel and critical revision of the statistical analyses of the “SOAP Study”. I wish him a long and happy retirement.
I am also thankful to Dr Akram Gharbi, Mrs. Marie-Rose André, Mrs. Colette Dutillieu and Miss Véronique De Vlaeminck for their kind support.
Finally, I cannot find words enough to express my gratitude to my wife for her continuous support and to my daughter for her marvellous inspiration; their input has sustained me through the completion of this work.
Content
List of Abbreviations 5
CHAPTER 1. Introduction 8
CHAPTER 2. Aim of the study 30
Part 1: Sepsis in a cohort of ICU patients in Europe; epidemiology, disease interactions, therapeutic and prognostic implications
CHAPTER 3. Sepsis in European intensive care units: Results of the SOAP study 34 CHAPTER 4. High tidal volume and positive fluid balance are associated with
worse outcome in acute lung injury
54
CHAPTER 5. Use of pulmonary artery catheter is not associated with worse outcome in the ICU
71
CHAPTER 6. Does dopamine administration in shock influence outcome? 91 CHAPTER 7. Is albumin administration in the acutely ill associated with increased
mortality?
109
CHAPTER 8. Effects of hydroxyethyl starch administration on renal function in critically ill patients
221
Part 2: Time course and influence of therapeutic interventions on microcirculatory Perfusion
CHAPTER 9. Persistent microcirculatory alterations are associated with organ failure and death in patients with septic shock
135
CHAPTER 10. Microvascular response to RBC transfusion in patients with severe Sepsis
151
CHAPTER 11. The effects of dobutamine on microcirculatory alterations in patients with septic shock are independent of its systemic effects
164
CHAPTER 12. General discussion and future prespectives 176
CHAPTER 13. Summary and conclusions 180
CHAPTER 14. French summary 185
References 192
Appendix 230
List of Abbreviations
ALI: Acute lung injury
ANOVA: Analysis of variance
APACHE: Acute physiology and chronic health evaluation ARDS: Acute respiratory distress syndrome
AUC: Area under the curve CDC: Center for disease control CI: Confidence interval
COPD: Chronic obstructive pulmonary disease CRF: Case report form
CVP: Center venous pressure
EPIC: European prevalence of infection in intensive care DO2: Oxygen delivery
FiO2: Fraction of inspiration of oxygen concentration Hb: Hemoglobin concentration
HES: Hydroxyethyl starch ICU: Intensive Care Unit
ICD-9-CM: International classification of diseases, ninth revision, clinical modifications
IQ: Interquartile range
LDF: Laser Doppler fluxumetry LOS: Length of stay
MOF: Multiorgan failure Mw: Molecular weight
O2ER: Oxygen extraction ratio
OPS: Orthogonal Polarization Spectral OR: Odds ratio
PAC: Pulmonary artery catheter PaCO2: Partial pressure of CO2
PAOP: Pulmonary artery balloon-occluded pressure PaO2: Partial pressure of oxygen
PEEP: Positive end-expiratory pressure PgCO2: Gastric mucosal PCO2
PgCO2gap: Gastric to arterial PCO2 gradient pHi: Gastric intramucosal pH
PslCO2: Sublingual PCO2 RBC: Red blood cell
ROC: Receiver operator charcteristic RRT: Renal replacement therapy
SAFE: saline versus albumin fluid evaluation SaO2: Arterial oxygen saturation.
SAPS: Simplified acute physiology score
SIRS: systemic inflammatory response syndrome SOFA: Sequential organ failure assessment SOAP: Sepsis Occurrence in Acutely ill Patients SvO2: Mixed venous oxygen saturation
VO2: Oxygen consumption
CHAPTER 1 Introduction
Sepsis is a common problem in the ICU with high mortality and morbidity rates.
Understanding the pathophysiologic dynamics underlying sepsis is crucial, generating hypotheses for future therapies and clarifying possible adverse or
beneficial effects of currently applied therapeutic interventions. On the other hand, epidemiologic and cohort-based studies offer a global view of the magnitude of sepsis-related morbidity and mortality, provide preliminary answers to some important questions concerning possible interactions with other disease groups or therapeutic interventions in the intensive care unit (ICU), and set the stage for future randomized controlled trials.
Recent years have seen several studies providing important national and international epidemiological data on the frequency, associated factors, and even costs of sepsis. However, in view of the dynamicity of sepsis as a multifactorial syndrome and the presence of controversies related to the management of patients with sepsis, repeated updating of our knowledge concerning etiologic, diagnostic, therapeutic, and prognostic issues related to sepsis is of utmost importance.
Microcirculatory alterations are common in patients with sepsis. These alterations were found to be more severe in non-survivors than in survivors but were not related to global hemodynamic status or administration of vasopressor agents. These observations were obtained early in the course of disease, so that their time course has not been well characterized. In addition it may be interesting to identify patients in whom further interventions may eventually be useful to improve their microcirculation, or therapeutics that might have deleterious effects on microvascular perfusion with subsequent adverse outcomes in terms of
multiorgan failure and death. The recently developed, non invasive, Orthogonal
Polarization Spectral (OPS) imaging technique can be applied to investigate the human microvasculature and is particularly convenient for studying tissues protected by a thin epithelial layer, such as mucosal surfaces. This technique has been validated as an effective method of microvascular imaging in animals and in humans.
Pathophysiologic and clinical aspects are complementary in obtaining a multidimensional view of this important health problem and could guide bedside management and future research.
I) Microcirculatory alterations during sepsis
As early as 1952, Thomas [1] described the progression of vascular changes in the microcirculation after endotoxin administration, including intense arteriolar
constriction followed by extreme vasodilation and marked slowing of blood flow.
Early studies [2] reported striking phenomena: large rigid red blood cell (erythrocyte) aggregates were seen in all vessels, concentrated "sludge" was observed in plugged vessels which accounted for obstructed blood flow, and bacteria were trapped in impacted vessels so that phagocytosis was interrupted, providing an opportunity for multiplication of bacteria at the site of obstruction.
Several alterations were subsequently identified and summarized as follows:
1. Disseminated Intravascular Coagulation (DIC)
DIC is a coagulation disturbance accompanied by the slowing of capillary blood flow associated with arterial hypotension, arteriolar vasoconstriction, capillary dilation, and the opening of arteriovenous shunts. In 1995, Astiz et al. [3]
emphasized the association of DIC with the deposition of fibrin and
microthrombosis during human septic shock. The effect of DIC on microvascular
blood flow and its role in the development of multiple organ failure in human septic shock is, therefore, detrimental [4].
2. Decreased Red Blood Cell Deformability
Red blood cell deformability depends on the viscoelastic properties of the cell membrane, the viscosity of the cytoplasm, and the surface area/volume ratio, all of which may change during shock [4]. When red blood cell deformability is
decreased, the time required for red cell passage through capillaries is increased and the cells may block the capillaries. The causes of deformability in circulatory shock include acidosis, hypothermia, and changes in red cell geometry [5]. The presence of leukocytes is responsible for conformational changes in the
cytoskeletal proteins of red blood cells induced by endotoxin and is associated with the degree of red cell deformability [6].
Decreases in deformability during endotoxin-induced shock in animals and during septic shock in patients are believed to produce stagnation and plugging of the microcirculation [4]. Increased rigidity of red blood cells promotes arteriovenous shunting of blood, which decreases microcirculatory flow during septic shock [6].
Hemolysis resulting from the destruction of red blood cells has been observed regularly in the plasma of animals during endotoxin/live organism-induced shock and would be expected to disrupt flow of blood in the microcirculation because of the release of fragments of hemoglobin [7].
3. Increased Microvascular Permeability and edema formation
Continuous fluid transfer from intravascular to extravascular compartments during shock accounts for the progressive loss of circulating blood leading to depression of cardiac output. Reports [8, 9] provided evidence that loss of fluid and albumin occurs during human septic shock; however, there is no evidence that plasma
extravasation affects all organs similarly. Endotoxin increases capillary permeability in the skin and muscle tissues independently from changes in hydrostatic and colloid osmotic pressures, thereby implicating alterations in cell membrane structure [10].
Loss of fluid from the vascular bed occurs in the form of edema in the lungs,
kidneys, skin and muscle, heart, and brain during septic/endotoxic shock. Causes of edema formation include protein leakage, separation of tight junctions between endothelial cells, dysfunctional rather than destructive changes of vascular endothelium, release of vasoactive agents, defective endothelial cell volume regulation, and the presence of circulating neutrophils [4].
4. Congestion and Hemorrhage
Congestion of blood in the lungs and adrenal glands of baboons given E. coli has been observed histologically by Archer [11]. Adrenal hemorrhage has been
reported by McGovern [12] and Siegel et al [13] in human sepsis, probably due to the anatomical arrangements in the adrenal glands which make them susceptible to hemorrhage: a rich, subcapsular arteriolar plexus draining into single central veins [4]. Shock reduces forward flow and, when combined with increased venular back pressure, leads to hemorrhage. Adrenal thrombosis occurs because stasis and increased catecholamine concentrations in the adrenal vein contribute to platelet adhesion.
5. Altered Microvascular Blood Flow and Vascular Resistance
Abnormalities in the general (macrocirculatory) circulation are evident in septic shock and it is important to determine how the large and small (microcirculatory) vessel compartments interact [4]. During E. coli-induced shock, regional arteriolar constriction of the small intestine occurs and microvascular blood flow decreases
markedly [14], whereas vascular tone of the skeletal muscle bed is decreased in both hyper- and hypodynamic septic shock [15], constriction of large arterioles and dilation of small arterioles occurring simultaneously. Sustained vasodilation of the skeletal muscle vascular bed, however, may prevent fine adjustments to metabolic needs, because of overperfusion of this relatively low oxygen requiring tissue and hypoperfusion of others, such as the intestines, which have higher oxygen
requirements [8]. Animals that develop intestinal mucosal lesions experience periods of intense vasoconstriction and hypoperfusion of the intestine during early sepsis, even when blood pressure and cardiac output are normal [14]. Local
vasoconstriction, if prolonged, would be detrimental under these conditions.
The microcirculation is affected by adrenergic receptor responses to endotoxin [16]. The threshold dosage for norepinephrine administered to test a given level of adrenergic receptor responsiveness after endotoxin progressively increases and microvessel sensitivity to norepinephrine is reduced. This effect is adverse in that the adrenergic system is eventually incapable of maintaining constriction due to depression of the active state of vascular smooth muscle to changes in muscle fiber length or to alterations in sympathetic alpha-adrenergic activity [16]. The ultimate result is significant loss of control over perfusion of the microcirculation.
6. Viscosity Alterations and disturbance of red and white blood cell rheology During low-flow states, blood viscosity increases because of a decrease in shear stress, augmenting postcapillary resistance; blood flow thereby diminishes, and transcapillary fluid leakage occurs as a result [17]. Increases in permeability also depend on the increased microvascular accumulation of neutrophils [18]. The reduction in velocity suggests that vasoconstriction and changes in vascular
pathways, together with red blood cell aggregation, combine to impede the flow of circulating red blood cells in plasma flowing around the aggregated cells through
different vascular channels [19]. Leukocyte entrapment during low-flow states may cause red blood cells to accumulate behind white cells, thus increasing
microvascular resistance to flow and contributing to maldistribution of
microcirculatory flow [20]. The duration of leukocyte plugging in shock increases when microcirculatory flow is low and, at low flows, the frequency of leukocyte plugging increases [21].
7. Intravascular Pooling and Redistribution of Organ Blood Flow
Intravascular pooling has been reported to occur in the intestinal bed of animals after endotoxin [22, 23], resulting from arteriolar relaxation and venous
constriction. This action increases capillary blood volume, trapping blood, thereby effectively removing it from the general circulation, resulting in decreased venous return and lowered cardiac output. About 50% of the blood resides in the
microcirculation and the latter is an effective site for increased sequestration of blood after endotoxin, accounting for the drop in arterial pressure and decline in cardiac output [4]. Severe peripheral intravascular pooling of circulating blood ultimately leads to death [24]. Redistribution of hepatic microvascular flow within liver lobules occurrs in rat livers during bacteremia despite an increased cardiac output [4]. It is believed that ischemia in the poorly perfused areas of the liver leads to cellular damage contributing to multiple organ failure. In a rat model of
hyperdynamic sepsis, a 20% increase in cardiac output was demonstrated within 1 hr; however, microvascular flow to the small intestine decreased by 27% during the same time period, independent of the changes in cardiac output [14].
8. Opening of Arteriovenous Shunts
Cronenwett and Lindenauer [25] found evidence of arteriovenous shunting of blood in the septic canine limb during the hyperdynamic period using a microsphere
technique. In contrast, Archie [26] found that arteriovenous shunting occurred only in the splanchnic circulation in the cecal ligation shock model and only in the kidney in the endotoxin shock model. A study by Hurd et al. [27] found that nutrient blood flow to the liver, kidneys, and muscles was markedly decreased in early sepsis despite increases in cardiac output, an observation consistent with the early opening of arteriovenous shunts.
9. Multiple Actions of the Endothelium
During the development of septic shock, the vascular smooth muscle is
metabolically deranged and the endothelium lining the entire vascular system is adversely affected [4]. During septic and endotoxic shock, vasoactive agents are released and the balance between systemic and local controls is altered [4]; the cytokines may perform major roles in these changes. Endothelial cells modulate vascular tone, control local blood flow, influence the rates of leakage of fluids and plasma proteins into tissues, modulate the accumulation and extravasation of leukocytes into tissues, and influence leukocyte activation [28].
II) Assessment of the microcirculation
The microcirculation can be assessed indirectly by several methods, principally reflecting the degree of regional dysoxia, or can be directly visualized using special imaging techniques.
Clinical techniques
Lactate levels are thought to be an indicator of anaerobic metabolism due to the unavailability of oxygen. Lactate is generated from pyruvate in a reversible
reaction by the cytosolic enzyme, lactate dehydrogenase; it increases when the rate
of pyruvate production in the cell exceeds its utilization in the mitochondria [29].
Beside global (shock, hypoxia) or regional (small bowel infarction) causes of anaerobic lactate production, non-hypoxic causes of increased lactate production also exist. Decreased lactate clearance, accelerated aerobic glycolysis (e.g., by sympathomimetic drugs), or a dysfunction of the pyruvate-dehydrogenase enzyme complex which brings pyruvate into the mitochondria and converts it to acetyl CoA as a substrate for the citric acid cycle, may decrease the prognostic value of lactate measurement [30]. Furthermore, intact metabolic capabilities of the liver make a significant increase in lactate unlikely, so any individual organ failure may pass undetected [31].
Mixed venous oxygen saturation (SvO2), a global parameter that reflects the balance between oxygen supply and consumption, can be readily measured with intermittent blood gas analyses from a pulmonary artery catheter (PAC) or by continuous measurement with a fiberoptic PAC. The SvO2 is an average of the venous effluents from all perfused vascular beds. High flow, low extraction vascular beds (e.g., kidney, gut) have a larger influence than organs with a high oxygen extraction such as the heart. Furthermore, a critical value of SvO2 that defines an inadequate regional oxygen delivery (DO2) is difficult to determine. In sepsis, microcirculatory shunting mechanisms can cause persisting high global as well as regional venous oxygen saturations, while regional tissue dysoxia is present [32]. In principle, regional venous oxygen saturation can be measured from any organ of interest. Since the introduction of fiberoptic oximetry catheters, hepatic (ShvO2) and jugular venous hemoglobin saturations (SjvO2) have been measured in both experimental and clinical studies [33].
Intestinal regional capnography
Regional capnography relies on the principle that CO2 generated in tissues diffuses freely across tissue and cell membranes. The classic intestinal tonometry technique described by Fiddian-Green and Baker [34] uses a nasogastric tube with a saline- filled silicone balloon for the intraluminal determination of PCO2 in the gastric mucosa. Measurement of arterial bicarbonate (HCO3-) and use of the Henderson- Hasselbalch equation allows, with certain assumptions, the calculation of intestinal mucosal pH (pHi). The original assumption that arterial HCO3- is in equilibrium with gut mucosal bicarbonate is not always correct. Decreased gastric mucosal blood flow in states of shock or following administration of sodium bicarbonate may lead to a significant difference between intestinal tissue and systemic HCO3- , and would therefore overestimate the gastric pHi [35]. The systemic arterial PCO2
also influences the piCO2 and thus the pHi. The intestinal and arterial PCO2 gap has thus been proposed as a more accurate value describing the correlation between regional tissue blood flow and oxygenation, as it corrects for systemic
abnormalities altering intestinal PCO2 [36].
Intestinal capnography has been extended to analyze PCO2 from an air-filled balloon in a conventional capnometer [36, 37]. The in vitro bias, precision and reproducibility of air tonometry are consistent with a clinically reliable device. In a study in mechanically ventilated, septic patients, the accuracy of this method was close to that of conventional saline tonometry; values measured at 10-min intervals showed a short response time and correlated well with conventional tonometry [37]. Despite the value of intestinal tonometry in the prediction of mortality and morbidity, its usefulness for guiding therapy is still under debate.
Oxygen electrodes
Oxygen electrodes for measurement in tissue and in the microcirculation are
conventionally based on the classical Clark electrode [38] from a noble metal (e.g., silver, gold, or platinum) which reduces oxygen due to a negative polarizing
voltage. The change in voltage between the reference electrode (anode) and the measuring electrode (cathode) is proportional to the number of oxygen molecules being reduced on the cathode [33]. Calibration of these oxygen electrodes in a solution of known oxygen tension is needed prior to each measurement. Needle tip oxygen electrodes measure PO2 at a single point. Oxygen electrodes can also be applied on the surface of the tissue to avoid tissue damage by electrode penetration.
The distribution of PO2 values measured is a combination of the spatial distribution under the electrode and the temporal distribution during the measurement [33].
The area of tissue which is effectively measured by oxygen electrodes has been estimated to be about 15-20 mm deep [32]. This small penetration depth is a major limitation in the interpretation of oxygen electrode derived data. Mechanical forces produced by the tip and shaft of needle electrodes, or the high pressure applied by surface electrodes, may cause tissue damage as well as alterations in microvascular flow which lead to irregular histograms and low PO2 readings [39, 40]. A further limitation of oxygen electrodes is, paradoxically, their sensitivity to oxygen.
Vessels carrying high PO2 blood in the catchment volume of the electrode will bias the electrode value despite the surrounding tissue remaining hypoxic; these tissue oxygen electrodes are thus sensitive to changes in arterial PO2 [41].
Optode sensors
Optodes are used to measure concentrations of substances by photochemical reactions creating changes in optical properties of indicator compounds [39, 42].
Changes in the concentration of H+ ions or CO2 produces altered fluorescence or absorbance in indicators. pH-sensitive, photochemical dyes absorb light of a certain wavelength from a reference light source [43] or alter the intensity of fluorescence proportional to the concentration of hydrogen ions. Oxygen-dependent quenching of fluorescence of indicator substances (e.g. ruthenium) has been used for optical sensing of PO2 and has been incorporated into catheters [43, 44]. Such optical sensors have been included in intravascular catheters for the on-line measurement of PCO2 and pH to provide continuous monitoring of oxygenation. Their use as alternatives to conventional ex vivo arterial blood gas has been shown in patients during long-term application [36, 45]. Optode technology has also been used for real-time measurement of intestinal PCO2 [33]. Although preliminary results are promising, the influence of the relatively small catchment area of these optical sensors in relation to the whole organ remains to be determined.
Near-infrared spectroscopy
Near-infrared spectroscopy (NIRS) is a non-invasive, optical technique applying the principles of light transmission and absorption for the measurement of
oxygenated and deoxygenated haemoglobin or cytochrome aa3 (cyt aa3) in tissues [46]. Oxygenation of haemoglobin results in less red light and more infrared absorption than deoxygenated haemoglobin. Cyt aa3, has a different absorption band than the other cytochromes arising from its central copper atom in the near- infrared region between 800 and 900 nm. Monitoring the redox state of cytochrome aa3 in this way could potentially be of particular importance for the assessment of cellular oxidative metabolism and tissue dysoxia.
Although NIRS can be used in virtually any organ, it has mainly been applied to studies of cerebral oxygenation [33]. The use of NIRS in adults during coronary artery bypass surgery, as well as in patients with acute brain disease, has
indicated conventional SjvO2 to be a better monitor of cerebral oxygenation than NIRS [47-49]. Blood flow in extracranial tissues had no significant influence on either cerebral hemoglobin concentration or saturation measurements [49, 50].
Bearing the difficulties of the technique in mind, NIRS does seem to offer new information on tissue oxygenation, not only of the brain but also of other organs [51, 52]. In general, NIRS measurements of hemoglobin saturation and
concentration appear more accurate than estimations of intracerebral blood flow and volume [33].
Reflectance Spectrophotometry
Light absorption of reflected visible light on the tissue surface can also provide information about hemoglobin saturation, although its catchment area will be restricted to the tissue surface. Reflectance spectrophotometry can either measure discrete wavelengths or whole reflectance spectra. The reflected spectra can be fitted with known spectra of fully oxygenated and fully deoxygenated hemoglobin to determine the relative saturation of microvascular hemoglobin. The signal intensity at the isobestic points of hemoglobin allows an evaluation of capillary hemoglobin concentration representing the tissue blood volume [33].
In open-heart surgery this technique has shown improved microcirculatory oxygenation after completed revascularization [33]. Application to the fetal scalp during delivery [33] showed development of critically low hemoglobin saturations, indicating that local oxygen reserves are almost exhausted. Reflectance
spectroscopy has also been applied during neurosurgical arteriovenous
malformation operations [33], in plastic surgery [53, 54] and for the evaluation of skin hemoglobin oxygenation in patients with chronic venous insufficiency and peripheral arterial occlusive disease [55, 56]. In transplantation of tissue flaps, reflectance spectroscopy provided useful information about oxygenation of the
different transplant regions [54], whereas evaluation of tissue blood flow by hydrogen clearance was not as accurate [53].
NADH fluorescence
Metabolic pathways such as pyruvate oxygenation, fat oxidation and the citric acid cycle produce reduced equivalents of nicotinamide adenine dinucleotide (NADH) and H+ to maintain oxidative phosphorylation by reducing molecular oxygen for the production of ATP. NADH/NAD+ is the main source of energy transfer from the citric acid cycle to the respiratory chain in the mitochondria [57]. During tissue dysoxia, NADH accumulates as less NADH is oxidized to NAD +. Because the redox state of mitochondrial NADH/NAD+ directly reflects the mitochondrial energy state, it can be considered as a direct indicator of dysoxia in mammalian cells. The main limitation of the NADH fluorescence technique for studying tissue energy state is the current inability to quantify NADH levels from measured
fluorescence [33].
Palladium (Pd)-porphyrin phosphorescence
The technique is based upon the principle that a Pd-porphyrin molecule, when excited by a pulse of light, can either release this absorbed energy as light
(phosphorescence) or transfer it to molecular oxygen. After porphyrin is excited by light, the decay in phosphorescence is dependent on the amount of oxygen present [33]. The advantage of this water-soluble compound is that it can be injected intravenously to measure oxygen concentrations predominantly of the
microvascular compartment [58, 59]. In vivo, Pd-porphyrin phosphorescence has been used to assess the arteriolar, venular and capillary PO2 in hamster and mouse skinfold models and in skeletal muscle and intestine of rats [33].
Laser Doppler Fluxmetry
Laser Doppler fluxmetry (LDF) utilizes the Doppler shift to give a value of the mean erythrocyte flux found in the investigated tissue [60]. The LDF technology is very easy to apply and requires only a few minutes to obtain readings. However, the probe has to be attached to the tissue and movement of the fiber optic during measurements can result in artifacts that may make the interpretation of the results difficult, thus limiting some applications. LDF measures the temporal variation of tissue perfusion in a very small area. Large spatial and temporal fluctuations in tissue blood flow occur over small areas of skin and, thus, influence the LDF signal [60, 61]. Furthermore, the depth of penetration of the laser light is limited to a few millimeters and since the signal originates mainly from the arterio-venous
anastomoses in the skin it does not reflect the nutritious blood flow of the skin.
Though a linear correlation between LDF signal and blood flow could be
demonstrated [60], no calibration for absolute values is currently available, which very much restricts the clinical use of LDF.
LDF has been used to study microcirculatory changes in chronic venous insufficiency (CVI) and chronic venous ulceration [60]. Ubbink et al. [62] tested the usefulness of LDF in assessing the severity of lower limb ischemia and concluded that it could be a suitable addition to standard macrocirculatory techniques. LDF has also been suggested to be a useful microvascular monitor during surgery. Belboul and al-Khaja [63] evaluated the effect of coronary
revascularization on the epicardial microcirculation by LDF and found a positive correlation between the flux signal and blood flow after coronary artery bypass grafting.
A recent development of LDF is laser Doppler perfusion imaging (LDI) in which a laser beam scans a certain area of the tissue to form an image of perfusion [60]. Conventional LDF records perfusion continuously at one point only.
Investigations of a larger area can integrate different local flow readings over a specified area rather than temporal variation at a single point and assesses the spatial distribution of microvascular perfusion. Since LDI is a scanning technique, the probe does not come into contact with the investigated tissue, enabling new applications of the laser Doppler technique.
Imaging of the microcirculation
In addition to measurement of tissue oxygenation, a method for direct visualization of the microcirculation in humans would be expected to give sensitive insights into the pathogenesis of various acute and chronic diseases. Such a method could also elucidate the influence of vascular tone, oxygenation, cytokines and local humoral factors on the distribution of microcirculatory blood flow [33].
Until recently, information regarding the dynamics of microcirculatory blood flow during different pathological conditions has only been available from
intravital microscopic studies in animal models. In humans suffering from
peripheral vascular disease, the measurement of nailfold microcirculation by direct capillaroscopy has been the only available clinical technique to study
morphological and dynamic changes in the microcirculation.
Intravital Microscopy
Intravital microscopy is the methodology required to visualize the living tissue and particularly the microcirculation. In general it comprises some means of bringing light to the tissue under observation, and obtaining a magnified image via an objective in a conventional microscope configuration. One of the requirements is the illumination of the tissue under study, a process accomplished by either trans- illumination, epi-illumination, or causing specific structures contained within the tissue to emit light by phosphorescence techniques [64]. Thin tissues make it
possible to implement conventional condenser objective configurations. In extremely thin tissues, such as the mesentery, omentum, and chamber window preparations, the optical conditions are such that full advantage can be taken of the combined resolving power afforded by the combination of both optical elements.
Thick tissues that cannot be penetrated by light require epi-illumination, which can be accomplished by directing light to the area under observation from a light source near the objective, or directly through the objective. The surfaces of organs and the human skin are studied in this way [64].
Intravital microscopy has been used for many years to make quantitative observations of the microcirculation. Because of the high image contrast achieved when using fluorochromes, intravital microscopy could be performed on more solid tissues such as the liver and brain. However, the use of fluorescent dyes also has several disadvantages. The binding of the dye to the cell could have undesired side effects such as altering the cell function or even killing the cell through some
toxicity reaction. The presence of a fluorochrome and the high light intensities used in epi-illumination can themselves lead to so called phototoxic effects that may lead to the production of reactive oxygen species [65-67]. Fluorescent dyes are, in addition, themselves toxic and there is only a single dye which has been approved for use in humans. Because of the risk of phototoxic effects, it is used very
sparingly. Measurements of the human microcirculation can be made through the capillary nailfold bed without the use of fluorescent dyes, but this procedure has only limited application and has yet to find widespread clinical acceptance [68].
Orthogonal Polarization Spectral Imaging
Direct observation of the vascular beds of other organs in humans has been prohibited by the need for transillumination, fluorescent dyes for contrast enhancement, or by the size of instrumentation required to acquire images,
especially during surgery. Further, even in the best cases when reflected light is used, good image contrast and detail have been difficult to obtain due to surface scattering and turbidity of the surrounding tissue.
The use of polarized light, and particularly the realization that the illuminated objects obey Beer’s law of light absorption is a novel concept [69]. With this
method, deeper regions where light has undergone multiple scattering become depolarized. When the illuminated region is viewed through a cross polarized optics the depolarized light is only partially blocked, thus illuminating the surrounding deep structures. Conversely, light reflected from shallower regions having undergone a lesser degree of depolarization is blocked by the polarizer.
In OPS imaging, taking advantage of the phenomenon of cross- polarization, mitigates these effects. As shown in Figure 1, polarized incident light is projected through a beam splitter onto the subject. While most of the reflected light retains its polarization, light that has penetrated the subject more deeply undergoes multiple scattering events and is depolarized before being remitted back towards the surface.
When looking at the subject through a second polarizer (analyzer), oriented
precisely orthogonal to that of the first polarizer, an image is seen that looks as if it were back-illuminated [69]. OPS imaging technology can be incorporated into a small, portable, and easy to use handheld device (Fig. 2). A typical sublingual image from a human obtained using OPS technology is shown in Figure 3. Small blood vessels, individual red blood cells, and white blood cells (WBC) are clearly visible [69].
Fig.1. OPS imaging: optical schematic [69].
Fig. 2. CYTOSCAN A/R imaging probe [69].
Visualization of Blood with OPS imaging
To image the blood, a wavelength region, centered at an isosbestic point of oxy- and deoxyhemoglobin (548 nm), was chosen. This represented a compromise
between using an isosbestic point in the Soret region (about 420 nm),where hemoglobin absorption is maximum but the scattering length is shorter, and an isosbestic point in the near IR region (810 nm), where multiple scattering occurs deep in the tissue, but absorption for hemoglobin is lower. It is also possible to image WBC in the human sublingual microcirculation using the Cytoscan.
However, OPS imaging hardware and software have not yet been optimized for imaging WBC at this time. The ability to visualize leukocytes in the
microcirculation alone is not sufficient to determine the systemic WBC count because it is not clear what the relationship is between the number of WBC seen in microcirculation and the WBC count in a sample obtained by venipuncture and measured using an in vitro clinical analyzer [69].
Fig. 3. OPS image of sublingual human microcirculation. WBC (arrows), either rolling or stationary, can be visualized in sublingual venules of a human subject [69].
OPS vs. intravital microscopy
The ability of OPS imaging to provide quantitative measurements of relevant physiological parameters and pathophysiological changes in the microcirculation was shown by measurement of functional capillary density (FCD) in the dorsal skinfold chamber of the awake Syrian golden hamster [5]. FCD is defined as the length of red blood cell perfused capillaries per observation area and is given in cm/cm2. As the capillaries must contain flowing red blood cells to be counted in the measurement, FCD is a direct measure of nutritional tissue perfusion and an
indirect measurement of oxygen delivery to tissue [70]. The hamster dorsal skinfold model is standardized and has been used extensively to study ischemia/
reperfusion injury [70, 71]. As the measurement of FCD is a dynamic event, not all capillaries can be clearly seen in the static images, although some typical capillary structures can be seen. Thus, although one may actually see many capillaries in the picture that are filled with the fluorescent dye, this does not necessarily mean that they will be counted in the FCD measurement, unless a red blood cell (in this case a small dark spot) can be seen moving through it. Importantly, contrast obtained by OPS imaging without the use of dyes was equivalent to that obtained with contrast enhancement by fluorescence [69].
OPS imaging of human microcirculation
Intravital imaging by transmission microscopy is not possible in humans or animals for inaccessible sites or solid organs. The OPS imaging method uses a small-sized probe and produces clear images of the microcirculation by reflectance from the surface of solid organs and from sites such as the sublingual area in the awake human. OPS imaging could thus show differences between normal and pathological microvascular structure and function non-invasively. The diagnosis and progression
of disease and the effectiveness of treatment could be monitored for disorders in which altered microvascular function has been found. Additional applications of OPS imaging, originally described by Winkelman [69], are to use images of the microcirculation to measure directly and compute key elements of the complete blood count. The combination of OPS imaging, image processing, reflectance spectroscopy and algorithmic calculation, can yield a rapid determination of
hemoglobin concentration, hematocrit and WBC count without withdrawing blood samples from the body. Non-invasive blood testing will have substantial utility in medical practice.
OPS imaging has been used to study the microcirculation of many organs including the brain [72], burn wounds [73], the liver [74], the gut and the skin of neonates. Recently pathological microcirculation of brain tumors has been
demonstrated with this technique and differences in the structure were revealed for meningiomas, glioblastomas and metastases [72]. Using OPS imaging, Vollebregt et al. [75] found impaired local skin microcirculation in pre-eclamptic women, which was not detectable with LDF. OPS imaging allows identification of ischemic regions of the epicardium [60]. With a specific stabilizing technique even images of the beating heart can be obtained and quantitative measurements of diameter and flow can be made.
To make clinical use of this technology, a fast and easy to use software analysis is needed giving absolute values of microvascular perfusion. So far most clinical studies with OPS imaging have used a well validated but cumbersome manual analysis software routine [60]. A recently developed software [60] enables the fast measurement of microvascular diameter, red cell velocity and flow as well as functional capillary density in a semi-automated fashion. Due to the clearly defined statistical margins of this analysis it may be used in future for a fully automated bedside analysis of the OPS images. OPS imaging also allows for a
visualization of leukocytes where they appear as spacing within the red cell
column. The typical slow rolling movement along the postcapillary venule can be identified. Using OPS imaging, we regularly saw rolling and sticking leukocytes in images obtained during cardio-pulmonary bypass (CPB) as well as after strenuous exercise in healthy volunteers.
Technical problems with OPS imaging in critically ill patients
Movement artefacts due to the patient or the operator are of the most challenging problems. Operator-related movements can be limited by the use of fixation devices. Patient movements are more difficult to avoid. Full cooperation or light sedation of the patient is required to limit movement but also to avoid biting of the instrument. Transmission of respiratory movements is more difficult to avoid, and often prevents the use of the available software measuring capillary blood flow.
One should also be very cautious not to apply pressure with the device against the tissue as this could lead to compression of the vessels. Finally, various secretions, including saliva and blood, could impair the visualization of the microcirculation [69].
CHAPTER 2 Aim of the study 9 Hypothesis:
Part 1:
1. The epidemiology of sepsis is variable in ICUs all over Europe with the presence of several factors that modify outcome in patients with sepsis.
2. Sepsis, co-morbid diseases, degree of organ dysfunction, fluid loading and violation of the ARDSNet protective ventilatory strategy could worsen outcome of patients with acute lung injury (ALI).
3. The use of the pulmonary artery catheter may influence outcome in patients with sepsis.
4. Dopamine administration may be associated with worse outcome in patients with shock due to any cause and in septic shock.
5. Administration of hydroxyethyl starch solutions may impair renal function in critically ill patients with or without severe sepsis.
6. Albumin administration may be associated with worse outcome.
Part 2:
1. The evolution of microcirculatory alterations over time in patients with septic shock might be an important determinant of outcome in terms of multiorgan failure and ICU survival.
2. Transfusions may have beneficial effects in the septic patients with possible alterations in the microvascular perfusion.
3. Dobutamine may improve the sepsis-related alterations in microcirculatory blood flow, independent of its systemic effects.
9 Aim of the work:
Part 1:
In this section we conducted a large prospective, multicenter, observational study, the Sepsis Occurrence in Acutely Ill Patients (SOAP) study, with the following objectives:
1. To assess the frequency of sepsis syndromes in various European countries and the report on the pattern of infections in this cohort.
2. To identify predictors of worse outcome in patients with sepsis.
3. To investigate the possible contribution of sepsis as an aggravating factor in patients with ALI.
4. To determine whether or not dopamine administration is associated with a poor outcome in patients with shock due to any cause and in a subgroup of septic shock patients, and identify other factors associated with a poor outcome in these patients.
5. To investigate the epidemiology of pulmonary artery catheter use, as a frequently applied monitoring procedure in patients with sepsis, and its relation to outcome.
6. To investigate the possible effects of hydroxyethyl starch solutions on renal function in critically ill patients especially those with severe sepsis.
7. To determine whether or not albumin administration is associated with a poor outcome in critically ill patients, especially those with severe sepsis.
Part 2:
In this section we used the OPS technique to study the sublingual microcirculation, with the following objectives:
1. To determine the time course of microvascular alterations in patients with septic shock and its relation to disease severity. We also investigated whether
the technique may help to identify patients at risk of death despite the apparent resolution of shock.
2. To evaluate sublingual microvascular perfusion in response to RBC transfusion, to identify patients who are likely to benefit from RBC transfusion, and to evaluate its possible correlation with RBC storage time in patients with sepsis.
3. To evaluate the effect of dobutamine administration on microvascular perfusion and its relation to dobutamine-induced hemodynamic alterations.
Part 1: Sepsis in a cohort of ICU patients in Europe;
epidemiology, disease interactions, therapeutic and
prognostic implications
CHAPTER 3
Sepsis in European intensive care units: Results of the SOAP study
Jean-Louis Vincent, Yasser Sakr, Charles L Sprung, V Marco Ranieri, Konrad Reinhart, Herwig Gerlach, Rui Moreno, Jean Carlet, Jean-Roger Le Gall, and Didier Payen
on behalf of the “Sepsis Occurrence in Acutely Ill Patients” investigators
Crit Care Med. 2006; 34(2): 344-53
Recent years have seen several studies providing important, national and international epidemiological data on the frequency, associated factors, and even costs of sepsis [76-82]. Angus and coworkers [76] analyzed more than 6 million hospital discharge records from seven states in the USA and estimated that 751,000 cases of severe sepsis occur annually in the US, with a mortality rate of 28.6%, and leading to average costs per case of $22,100. Using the National Hospital
Discharge Survey database, Martin et al. [77] identified 10,319,418 cases of sepsis from an estimated 750 million hospitalizations in the United States over a 22-year period, with an increase in frequency from 82.7 cases per 100,000 population in 1979 to 240.4 cases per 100,000 population in 2000. Alberti and colleagues [78]
examined 14,364 patients in six European countries and Canada, with more than 4500 documented infectious episodes and reported a hospital mortality rate of 16.9% for non-infected patients and 53.6% for patients who had repeated courses of infection while in the ICU.
The European Prevalence of Infection in intensive Care (EPIC) study [83], now more than 10 years old, demonstrated how international collaboration can succeed in providing valuable information regarding disease prevalence and
demographics of critically ill patients. In that prevalence study, data were collected on all patients present in the participating ICUs on a single day. For the present sepsis occurrence in acutely ill patients (SOAP) study, we collected a large amount
of data on all patients admitted to the ICU during a 2-week period, to identify the frequency of sepsis in European ICUs, and identify various etiologic, diagnostic, therapeutic, and prognostic factors in this population.
METHODS Study design
The SOAP study was a prospective, multicenter, observational study, designed to evaluate the epidemiology of sepsis and other characteristics of ICU patients in European countries and was endorsed by the European Society of Intensive Care Medicine. Institutional recruitment for participation was by open invitation, and was voluntary, with no financial incentive. Since this observational study required no deviation from routine medical practice, institutional review board approval was either waived or expedited in participating institutions and informed consent was not required. All adult patients (> 15 years) newly admitted to the ICU of a participating center (see the “Appendix” for a list of participating countries and centers) between May 1 and May 15, 2002 were included. Patients were followed up until death, hospital discharge, or for 60 days. Those who stayed in the ICU for
< 24 hours for routine postoperative observation were excluded. Patients who were readmitted and had been included on their first admission were not included for a second time.
Data management
Data were collected prospectively using preprinted case report forms (CRFs).
Detailed instructions, explaining the aim of the study, instructions for data collection, and definitions for various items were available for all participants at www.intensive.org before starting data collection and throughout the study period.
The steering committee was easily accessible to the investigators and processed all queries during data collection.
Data were entered centrally by medical personnel using the SPSS v 11.0 for Windows (SPSS Inc, Chicago, IL). A sample of 5% of data was re-entered by a different encoder and revised by a third one; a consistency of more than 99.5% per variable and 98.5% per patient was observed during the whole process of data entry. In cases of inconsistency, data were verified and corrected. Daily frequency tables were revised for all variables and the investigators were queried when data values were either questionable or missing for required fields. Data collection on admission included demographic data and comorbid diseases. Clinical and
laboratory data for SAPS II score [84] were reported as the worst value within 24 hours after admission. Microbiologic and clinical infections were reported daily as well as the antibiotics administrated. A daily evaluation of organ function that was based on a set of laboratory and clinical parameters according to the SOFA score [85] was performed, with the most abnormal value for each of the six organ systems (i.e., respiratory, renal, cardiovascular, hepatic, coagulation and neurological) being collected on admission and every 24 hours thereafter. For single missing values, a replacement was calculated using the mean value of the results on either side of the absent result [86]. When first or last values were missing, the nearest value was carried backward or forward respectively. When more than one consecutive result was missing, it was considered to be a missing value in the analysis. Missing data represented less than 6% of the collected data, of which only 2% were replaced.
Definitions
Infection was defined as the presence of a pathogenic microorganism in a sterile milieu (such as blood, abscess fluid, cerebrospinal or ascitic fluid), and/or clinically
documented infection, plus the administration of antibiotics (Figure 1). Sepsis was defined according to the ACCP/SCCM consensus conference definitions, by infection plus two systemic inflammatory response syndrome (SIRS) criteria [87].
Severe sepsis was defined by sepsis plus at least one organ failure, except when that organ failure was already present 48 hours before the onset of sepsis. Organ failure was defined as a SOFA score > 2 for the organ in question [86]. ICU acquired sepsis was defined as sepsis identified at least 48 hours after ICU
admission. Non-ICU acquired sepsis was defined as sepsis present on admission or within 48 hours of ICU admission. Daily fluid balance was calculated as the total fluid balance over the ICU stay divided by the ICU length of stay. Cumulative fluid balance within the first 72 hours of onset of sepsis was also calculated.
Statistical methods
Data were analyzed using SPSS 11.0 for windows (SPSS Inc, Chicago, IL).
Descriptive statistics were computed for all study variables. Difference testing between groups was performed using the two-tailed T test, Mann-Whitney U test, chi square test and Fisher’s exact test as appropriate. A forward stepwise logistic regression multivariate analysis with the ICU outcome as the dependent factor in patients with sepsis was conducted. Variables considered for the multivariate modeling included the country of origin, demographic data, co-morbidities, SAPS II score on admission, site of infection, type of microorganism, organ failure as assessed by the SOFA score on the first day of sepsis, the maximum number of concomitant organ failures, and the mean SOFA score during the ICU stay, invasive procedures at the onset of sepsis, onset of infection (in days), type of sepsis (ICU acquired sepsis and sepsis on admission), cumulative fluid balance within the first 72 hrs of the onset of infection, and daily fluid balance. Age, severity scores, and fluid balance were included as continuous variables. Only
variables associated with a higher risk of ICU mortality (p<0.2) on a univariate basis were modeled, i.e., heart failure (p=0.187) and diabetes mellitus (p=0.117) on admission, sepsis on admission (p=0.092) and ICU-acquired sepsis (p=0.091) with reference to sepsis on the first day of admission, and respiratory tract infection (p=0.093). The “country” effect was included in the last step of the model as a categorical variable with reference to the country with the lowest mortality in sepsis patients (Germany was chosen due to the small sample size in Switzerland).
All variables included in the model were tested for colinearity. A strong colinearity was identified between the initial and the mean SOFA score (R2=0.76), the initial SAPS II score, and the maximum number of concomitant organ failures (R2=0.71), and between the cumulative fluid balance within the first 72 hours of the onset of sepsis and the daily fluid balance (R2=0.74). These variables were injected
separately into the model and were all statistically significant. We used the initial SOFA score, the cumulative fluid balance within the first 72 hours and the SAPS II score in the final modeling as we judged them to be more relevant clinically. None of the tested interactions were relevant, and were, therefore, not considered in the final model. The final model correctly classified 76.9% of cases with adequate performance (Nagelkerke pseudo R2=0.27, AUC=0.7 (95% CI= 0.67-0.73)).
Hosmer and Lemeshow test confirmed the goodness of fit (Chi square = 8.8, p=0.362) of the model. Interactions involving combinations between comorbid diseases on admission, between sites of infection, and between major classes of microorganisms were tested. Nagelkerke pseudo R2 classification tables, and odds ratios (OR) (95% confidence interval (CI)) were computed. The probability of ICU mortality was calculated based on the final model and the area (AUC) under the receiver operator curve (ROC) was computed. Linear regression analysis was done to evaluate the correlation between ICU mortality and the frequency of sepsis in all
Table 1. Number of patients, SAPS II score, frequency of sepsis, and ICU and hospital mortality rates according to country (listed alphabetically).
Characteristics of sepsis patients (n=1177) Centers
n
Patients, n (%)
ICU mortality, n (%)
Hospital mortality,
n (%) Frequency (%) SAPS II score, mean ± SD
ICU mortality§
(%)
Hospital mortality
§ (%)
Severe sepsis (%)
Austria 8 68 (2.2) 14 (20.6) 16 (24.2)‡ 26 (38.2) 42.5 ± 17.2 6 (23.1) 8 (30.8) 18 (26.5)
Belgium 19 703 (22.3) 86 (12.2) 120 (17.3)10 188 (26.7) 38.7 ± 15.0 39 (20.7) 57 (30.8)¶ 125 (17.8) Eastern Europe* 15 174 (5.5) 41 (23.6) 53 (30.8)‡ 83 (47.7) 40.2 ± 15.0 24 (28.9) 31 (37.3) 74 (42.5)
France 21 332 (10.5) 63 (19.0) 70 (21.1) 136 (41.0) 43.4 ± 18.0 37 (27.2) 44 (32.4) 99 (29.8)
Germany 21 329 (10.5) 39 (11.9) 51 (15.7)$ 102 (31.0) 41.6 ± 15.8 16 (15.7) 20 (19.6) 78 (23.7)
Greece 10 109 (3.5) 18 (16.5) 23 (21.1) 47 (43.1) 47.1 ± 20.2 14 (29.8) 16 (34.0) 41 (37.6)
Italy 24 237 (7.5) 61 (25.7) 73 (31.3)$ 89 (37.6) 43.4 ± 15.3 31 (34.8) 39 (45.3) ¶ 75 (31.6)
Netherlands 7 144 (4.6) 33 (22.9) 43 (30.7) 56 (38.9) 43.8 ± 16.8 18 (32.1) 25 (47.2) ¶ 49 (34.0)
Portugal 6 69 (2.2) 24 (34.8) 28 (40.6) 50 (72.5) 46.2 ± 14.8 16 (32.0) 19 (38.0) 44 (63.8)
Scandinavia** 16 209 (6.6) 29 (13.9) 51 (24.4) 74 (35.4) 41.1 ± 15.7 14 (18.9) 45 (39.2) 52 (24.9)
Spain 13 202 (6.4) 44 (21.8)† 49 (25.8)$$ 70 (34.7) 38.3 ± 17.0 21 (30.4) 26 (38.2)‡ 57 (28.2)
Switzerland 4 114 (3.6) 9 (7.9) 16 (14.0) 20 (17.5) 38.4 ± 15.4 2 (10.0) 4 (20.0) 11 (9.6)
UK and Ireland 34 457 (14.5) 122 (26.7) 154 (34.2) 236 (51.6) 42.6 ± 17.6 75 (31.8) 95 (40.6) 207 (45.3) Total 198 3147 583 (18.5)† 747 (24.1) 1177 (37.4) 42.3 ± 16.6 313 (26.6) 413 (35.5)¶¶ 930 (29.6)
*Czech Republic, Poland, Romania, Slovenia, Slovakia, Hungary, Serbia and Montenegro, and Israel; **Denmark, Finland, Sweden, and Norway. § valid percentages are presented after exclusion of missing values. † 1 missing, ‡ 2 missing, ¶ 3 missing, $ 4 missing, $$ 12 missing, ¶¶ 13 missing
Table 2. Demographics of the ICU patients and procedures during the ICU stay
All patients*
(n=3147)
No sepsis*
(n=1970)
Sepsis*
(n=1177) Age, years$, median [IQ] 64 [50-74] 64 [49-74] 65 [51-74]
Sex, male/female**, % 62/38 61/39 63/37
Type of admission, % Medical
Surgical Elective Emergency
1759 (55.9) 1388 (44.1) 778 (24.7) 610 (19.4)
1091 (55.4) 879 (44.6) 561 (28.5) 318 (16.1)
668 (56.8)§§
509 (43.2) 217 (18.4) 292 (24.8) ICU admission source†§§, %
ER / ambulance Hospital floor OR / Recovery room Other hospital
913 (32.2) 793 (28.0) 784 (27.7) 345 (12.2)
652 (36.8) 424 (21.5) 508 (28.6) 190 (10.7)
261 (24.6) 369 (34.8) 276 (26.0) 155 (14.6) SAPS II score, mean ±SD 36.5 ± 17.1 33.1 ± 16.5 42.3 ± 16.6 §§
SOFA score, mean ±SD Initial
Mean Max
5.1 ± 3.8 4.5 ± 3.5 6.6 ± 4.4
4.3 ± 3.5 3.9 ± 3.2 5.3 ± 3.9
6.5 ± 4.0 §§
5.6 ± 3.7 §§
6.5 ± 4.0 §§
Sepsis, % 1177 (37.4) NA 1177 (100.0)
Severe sepsis, % 930 (29.6) NA 930 (79.0)
Septic shock, % 462 (14.7) NA 462 (39.3)
Central venous catheter, % 2272 (72.2) 1246 (63.2) 1026 (87.2)§§
Arterial catheter, % 2240 (71.2) 1263 (64.1) 977 (83.0)§§
Mechanical ventilation, % 2025 (64.3) 1087 (55.2) 938 (79.7)§§
Pulmonary artery catheter, % 481 (15.3) 266 (13.5) 215 (18.3)§§
Hemofiltration, % 211 (6.7) 61 (3.1) 150 (12.7)§§
Hemodialysis, % 141 (4.5) 62 (3.1) 79 (6.7)§§
Cumulative fluid balance, Liters++
First 72 hrs $$ 1 ± 4.18 0.51 ± 3.47 1.8 ± 5.04§§
Daily fluid balance 0.15 ± 1.3 0.12 ± 1.22 0.2 ± 1.41+
Total fluid balance 0.19 ± 11.69 0.08 ± 5.3 0.37 ± 17.76§§
Duration of ICU stay, days, median [IQ] 3.0 [1.7-6.9] 2.1 [1.3-4.0] 6.9 [3.1-15.0]§§
Duration of hospital stay, days, median [IQ] 15.0 [7.0-32.0] 9.4 [4.2-18.0] 17.8 [8.0-38.2]§§
ICU mortality‡, % 583 (18.5) 270 (13.7) 313 (26.6)§§
Hospital mortality§, % 747 (24.1) 334 (17.2) 413 (35.5)§§
* valid percentages are presented after exclusion of missing values, ** 35 missing (27 with no sepsis and 8 with sepsis). † 312 missing (196 with no sepsis and 116 with sepsis). ‡ 1 missing. § 44 missing (32 with no sepsis and 13 with sepsis). §§ p<0.001 compared with patients with sepsis. $ 9 missing (5 with no sepsis and 4 with sepsis). $$ first 72 hrs after admission in the no sepsis group and after 72hrs of the onset of sepsis in sepsis patients. + p<0.05 compared with no sepsis. ++ 47 missing (40 with no sepsis and 7 with sepsis)
countries. All statistics were two-tailed and a p <0.05 was considered to be significant.
RESULTS
A total of 3147 patients were enrolled; participating countries are shown in Table 1.
The median patient age was 64 years (mean ± SD: 60.5 ± 17.4), and 62% of
patients were male. Medical admissions accounted for 56% of admissions, elective surgery for 25%, and emergency surgery for 19% (Table 2). Cardiovascular
diagnoses accounted for 32% of admissions, respiratory for 19%, and neurological for 16%. The most frequent source of admission was the emergency room and/or ambulance (32%); only 12% of patients were referred from another hospital. The median length of ICU stay was 3 days (IQ: 2-7 days, mean ± SD: 6.5 ± 9.2 days).
Frequency, Distribution, and Patterns of Sepsis
Overall, 64% of patients received antibiotics at one time or another during the ICU stay. A total of 1177 (37%) of patients had identified infection. Of these, 454 (38.6%) had a documented clinical infection with identification of pathogens, 468 (39.8%) had clinical infection without identification of pathogens, and 255 (21.7%) had isolated pathogen(s) but without evident clinical infection. There was no
difference in ICU mortality between the three groups (29%, 26%, and 25%, respectively). Isolation of microorganisms (n= 196) or clinical suspicion of infection (n= 49), without administration of antibiotics, was not considered as infection (colonization or contamination) (Fig. 1).
The lung was the most common site of infection (68%), followed by the abdomen (22%), blood (20%), and urinary tract (14%). Cultures were positive in 60% of the patients with sepsis. Gram-positive organisms were isolated from 40%
