"Sepsis"--clarity of existing terminology ... or more confusion?
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Bacterial Infections↗
Biomedical subjects
W J Sibbald
Publications and source records attributed to W J Sibbald.
Abnormalities of vascular reactivity in the sepsis syndrome.
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Animals↗
Anti-inflammatory therapy for acute lung injury. A review of animal and clinical studies.
The adult respiratory distress syndrome (ARDS) continues to demonstrate high mortality. This syndrome is frequently observed as a remote complication of another disease process and is characterized by a significant inflammatory component. The purpose of this review is to compare and contrast published research on the use of anti-inflammatory agents, steroidal and nonsteroidal, in animal models of acute lung injury. Emphasis is given to the nature of the experimental pulmonary injury, infusion (ie, oleic acid and zymosan-activated plasma) or bacteriologically (ie, endotoxin and live bacteria) induced and the timing of drug administration relative to induction of the insult. The clinical data available on the use of these drugs in ARDS are discussed, and a rationale is presented for future clinical trials in these patients.
Animals↗
Effect of PGE1 on altered distribution of regional blood flows in hyperdynamic sepsis.
Since the sepsis syndrome is associated with depressed vascular reactivity, it may be incorrect to assume that pharmacologically mediated changes in cardiac output will be proportionately distributed at the regional level of the circulation. We examined the effect of hyperdynamic sepsis and the concurrent administration of the vasodilatory prostaglandin (PGE1) on the regional distribution of blood flows (Q) in unanesthetized sheep rendered septic by cecal ligation and perforation. Systemic Q progressively increased throughout a 48-h study period after cecal ligation and perforation. Simultaneously, organ Q, measured by the radioactive microsphere technique, was depressed to the pancreas, but increased to the heart, gallbladder, brain, and colon; the increased Q to both heart and gallbladder was greater than the simultaneous increase in systemic Q in this septic study. With the infusion of PGE1 (1 microgram/kg/min), mean arterial perfusing pressures fell, while the cardiac index increased further over that recorded during the 48-h septic study. Despite this depression in arterial pressures, the only significant effect of PGE1 on the interorgan distribution of Q was in the renal circulation, where it was demonstrated that kidney Q fell. We conclude that (1) hyperdynamic and normotensive sepsis exerted nonhomogeneous effects on the distribution of organ Q, and (2) an increased systemic Q during PGE1 infusion was proportionately distributed to all organs, except the kidneys, where Q paradoxically fell. The latter finding suggests that the regulation of kidney Q may be depressed across the normal range of arterial perfusing pressures in the sepsis syndrome. Further investigation is essential to understand the effect of clinical interventions on the control of tissue O2 flux at both the regional and microregional levels of the circulation.
Alprostadil↗
Peripheral nerve function in sepsis and multiple organ failure.
Forty-three patients who had sepsis and multiple organ failure (critical illness) were studied prospectively to determine the incidence and severity of peripheral nerve function and to correlate such function with a number of variables. Electrophysiologic studies indicated a primary axonal degeneration of motor and sensory fibers in 30 (70 percent). Fifteen (30 percent) had the clinical signs of difficulty in weaning from assisted ventilation, weakness of limb muscles, and reduced or absent deep tendon reflexes. Full recovery from the polyneuropathy occurred among the 23 (53 percent) who survived, except three who had a very severe polyneuropathy. A peripheral nerve function index, computed from electrophysiologic measurements, showed statistically significant (p less than 0.01) negative correlations with the time in the critical care unit, and the serum glucose value; the serum albumin level showed a positive correlation. Multiple regression analyses indicated all three factors accounted for 47 percent (r2 = 0.4678) of all potential variables. In a separate analysis, the nerve function index correlated with the amplitude of the diaphragm compound muscle action potential (p less than 0.01). The results were consistent with the polyneuropathy being due to the same mechanisms that are currently postulated to cause dysfunction in this syndrome of other organ systems (including the neuromuscular respiratory system).
Bacterial Infections↗
[Dilemmas of the ethical order in critical care units].
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Conflict of Interest↗
Failure of therapy with 2,3-dihydroxybenzoic acid to modify the course of sepsis-induced lung injury.
Oxidant-induced injury of the pulmonary microvasculature reportedly contributes to an increase in microvascular permeability and pulmonary hypertension, both of which are principal features of acute lung injury (ALI). We tested the hypothesis that antioxidant therapy with 2,3-dihydroxybenzoic acid (DHB), initiated in awake sheep after the development of sepsis-induced ALI, would ameliorate the progression of these lesions. DHB has many actions that suggested to us the potential for demonstrating benefit in ALI complicating sepsis; it is a nontoxic hydroxyl-radical scavenger that also inhibits the cyclooxygenase pathway and acts as a weak iron chelator. In preliminary experiments, we demonstrated that pretreatment with DHB prevented an increase in mean pulmonary arterial pressure, plasma thromboxane A2, measured as its metabolite thromboxane B2, and lymph total protein clearance that otherwise followed an infusion of zymosan-activated plasma (ZAP) in sheep. In subsequent experiments, 12 additional sheep were rendered septic by cecal ligation and perforation. Twenty-four to 36 h after cecal ligation and perforation, an increase in lung microvascular permeability was confirmed, because pulmonary lymph flow had increased by 82% while the mean lymph-to-plasma total protein ratio was unchanged from baseline. At this point, six sheep were then treated with parenteral DHB and six with DHB vehicle for the subsequent 24 h. In contrast to the demonstrated benefit of DHB pretreatment in preventing ALI secondary to an infusion of ZAP, the progressive increase in lymph total protein clearance that complicated septic lung injury in the DHB vehicle group throughout this 24-h study period was not ameliorated in the DHB treatment group. However, DHB did prevent a modest increase in mean pulmonary arterial pressures that was demonstrated in the DHB vehicle group throughout this 24-h treatment period. Although pretreatment prevented ALI after a ZAP infusion, we conclude that DHB only incompletely modified disease progression when administered after the onset of sepsis-induced ALI because it ameliorated the pulmonary hypertensive response without concurrently modifying an increase in lung microvascular fluid flux.
Animals↗
Lung microvascular transport properties measured by multiple indicator dilution methods in patients with adult respiratory distress syndrome. A comparison between patients reversing respiratory failure and those failing to reverse.
We conducted indicator dilution studies on the lungs of patients in the early phases of adult respiratory distress syndrome (ARDS) to test the hypothesis that capillary permeability was increased in patients with respiratory failure. Indicator dilution studies were performed using 51Cr-erythrocytes, 125I-albumin, 14C-urea, and 3H-water as tracers. The injectate was infused as a bolus into a central venous line. Peripheral arterial blood was collected and counted for radioactivity. Mathematical analysis of the indicator curves yielded cardiac output, measures of the product of capillary permeability and surface area for urea (PS and D1/2S), the intravascular lung volume (Vv), and the extravascular lung water volume (Ve). Permeability was separated from surface area by normalizing PS and D1/2S to Vv. Patients could be divided into 16 in whom blood gas determinations and radiologic criteria for ARDS were reversed and 23 in whom they were not. We examined indicator dilution and other measures of lung function in the two groups to determine whether significant differences in microvascular function existed. PS and PS/Vv were significantly higher in the nonreversal patients. Ve was above normal, but not different between groups. Linear regression analysis showed significant correlations for all of the following in the nonreversal group: Ve and all measures of permeability, pulmonary vascular resistance (PVR), and the inverse of permeability-surface area measures and AaDO2 and PVR. Only measures of Ve and PS correlated in the reversal group. These results support the hypothesis that capillary permeability is increased in patients with early ARDS and continuing respiratory failure.(ABSTRACT TRUNCATED AT 250 WORDS)
Biological Transport↗
Hyperdynamic sepsis modifies a PEEP-mediated redistribution in organ blood flows.
Changes in organ blood flow (Q) produced by 20 cm H2O positive end-expiratory pressure (PEEP) were measured before and after the induction of hyperdynamic sepsis in nine unanesthetized sheep. During the baseline nonseptic study, PEEP was associated with a 9% fall in thermodilution-measured systemic Q, although arterial perfusing pressures were unaffected. Concurrently, microsphere-derived Q was maintained to the brain and heart, but fell to liver, spleen, pancreas, kidney, large intestine, and gastrocnemius. Twenty-four to 36 h after cecal ligation and perforation, a pre-PEEP septic study demonstrated an increase in all of the cardiac index (CI) (+43%) and systemic O2 delivery (+54%) when compared with the nonseptic study, whereas whole-body O2 extraction (-30%) was depressed. Although PEEP depressed systemic Q (-17%) during the septic study to a greater extent than during the nonseptic study (p less than 0.02), absolute organ Q fell only to pancreas, liver, and spleen. Relative to the simultaneous fall in the CI, Q to some splanchnic organs was not depressed by PEEP to the same magnitude in the septic as in the nonseptic study. When an infusion of Ringer's lactate (993 +/- 295 ml) subsequently restored systemic Q to pre-PEEP septic levels, individual flows that had been depressed by PEEP were not restored. Furthermore, Q-kidney continued to fall, such that the postfluid Q-kidney (-19%) was significantly less than was demonstrated in the pre-PEEP septic study. We postulate that differences noted in the distribution of organ Q between the nonseptic and hyperdynamic septic studies after the application of PEEP were secondary to the vasculopathy of sepsis and/or an alteration in the function of specific organ microcirculations. However, these data do not address whether the changes in organ Q distribution after a PEEP-mediated depression in systemic Q during sepsis significantly restricted tissue DO2. The inability to acutely reverse the PEEP-mediated changes in organ Q after restoring systemic Q by a fluid infusion also suggests the need to evaluate alternative methods of support to organ Q in acute respiratory failure secondary to sepsis when the addition of PEEP acutely depresses systemic DO2.
Animals↗
A role for corticosteroid-binding globulin in delivery of cortisol to activated neutrophils.
In human blood, cortisol is transported by a plasma protein known as corticosteroid-binding globulin (CBG). As anticipated from primary structure comparisons of CBG and alpha 1-proteinase inhibitor (A1-PI), CBG acts as a substrate for neutrophil elastase. However, unlike A1-PI, CBG does not alter the activity of this enzyme, but is cleaved by it at a single location close to its carboxy-terminus, and this reduces its molecular size by 5 kDa with the concomitant release of more than 80% of CBG-bound cortisol. Three small molecular size fragments are detected after elastase cleavage, and carbohydrate analysis of these fragments suggests that they represent the same polypeptide fragment which has been differentially glycosylated. To assess the biological significance of these observations, CBG was incubated with either mononuclear cells or granulocytes obtained from patients with acute inflammation (sepsis) and from a normal volunteer. Only granulocytes from septic patients reduced the mol wt of CBG by about 5 kDa and destroyed its steroid-binding activity. Preincubation with A1-PI prevented this, which demonstrates that neutrophil elastase plays a key role in this event. These results suggest a physiological role for CBG in the delivery of cortisol to sites of inflammation.
Adult↗
Threatened reinfarction. Effective therapy using streptokinase with reversal of cardiogenic shock.
Thrombolytic therapy has an established niche in the treatment of acute myocardial infarction. One view, often rigidly held, is that this therapy should be attempted only if ischemic pain is present for less than four hours. Additionally, treatment is often reserved for those with an anterior infarction, a subgroup that did well in early reports. This case report demonstrates an impressive reversal of cardiogenic shock after streptokinase therapy in a patient who experienced an inferior infarction. His chest pain and ST elevations were present for more than nine hours at the commencement of treatment.
Aged↗
How can new technology be introduced, evaluated, and financed in critical care?
We briefly review issues impacting the introduction, evaluation, and cost of technology in critical care, providing a clinician's perspective. Where appropriate, we note important distinctions between health-care systems in Canada and the United States--primarily the result of significant differences in the methods for funding health care in the two countries. Finally, we discuss what processes might be reasonably considered for evaluating technology in critical care and discuss the probability of various consequences that will significantly affect the care we provide our patients if critical-care practitioners, industry, and health planners fail to jointly undertake this responsibility.
Canada↗
Histologic and ultrastructural changes in nonpulmonary organs during early hyperdynamic sepsis.
Previous studies describing the histologic elements of multi-system organ failure caused by bacterial sepsis may have been complicated by a significant interaction on tissue injury from either a preterminal low-flow state or the effects of therapy immediately before death. Therefore we evaluated the nonpulmonary histologic findings of sepsis during a 3-day period that followed cecal ligation and perforation. In this septic model, mean arterial perfusion pressures remained unchanged from baseline, systemic flows rose by 54%, and laboratory evidence of organ dysfunction including an elevation of the serum bilirubin levels and a depression of the serum total protein values was considered mild. Concurrently, development of the hyperdynamic central circulatory septic state was associated with widespread histologic changes in myocardium, striated muscle, liver, gut, and pancreas. Lesions common to these organs included high-protein interstitial and intracellular edema, mitochondrial destruction, and patchy cell necrosis. Lesions within the pancreas were exaggerated over those noted in other organs. Of all organs examined, only the liver demonstrated microvascular neutrophil accumulation. Unlike models of shock caused by sepsis, fibrin thrombi were not seen in the microvasculature of any organ. We conclude that tissue injury characterized by the accumulation of protein-rich extravascular fluid and the development of reversible and irreversible cell injury antedated significant multiple-system organ failure in this animal model of normotensive sepsis.
Animals↗
An ethical dilemma for the clinician manager.
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Adult↗
The effects of prostaglandin E1 on lung injury complicating hyperdynamic sepsis in sheep.
We examined the hypothesis that PGE1 would reduce the severity of lung injury in sheep rendered septic by cecal ligation and perforation (CLP). Twenty-four to 30 h after CLP, septic lung injury was documented in 37 sheep because pulmonary lymph flow (Qlym) was increased above the baseline, nonseptic study (delta = +7.38 +/- 5.1 ml/h; p less than 0.05), whereas the lymph-to-plasma total protein ratios remained unchanged. During a subsequent 24-h "septic treatment" study period, Qlym continued to increase in an untreated study group (septic treatment minus septic delta = +10.24 +/- 4.9 ml/h; p less than 0.05), but not in sheep treated with PGE1 by continuous infusion at two doses, 1 micrograms/kg/h ("low-dose": delta Qlym = -0.04 +/- 6.1 ml/h; p = NS) and 1 microgram/kg/min ("high-dose": delta Qlym = -0.04 +/- 6.1 ml/h; p = NS. Mean pulmonary artery pressures (Ppa) increased in the untreated group during the septic treatment period (delta = +3.74 +/- 4.8 mm Hg; p less than 0.01), but not during PGE1 infusion in either of the low-dose (delta Ppa = -4.1 +/- 5.7 mm Hg; p less than 0.04) or the high-dose (delta Ppa = -0.1 +/- 6.2 mm Hg; P = NS) groups. Unlike other study groups, the PaO2 fell in the high-dose PGE1 group during the septic treatment study (delta PaO2 = -15.0 +/- 9.6 mm Hg; p less than 0.01). During a study period of drug withdrawal 24 h after the septic-treatment period, Qlym again increased in the low-dose PGE1 group such that the untreated and PGE1 groups were no longer dissimilar.(ABSTRACT TRUNCATED AT 250 WORDS)
Alprostadil↗
PEEP increases non-pulmonary microvascular fluid flux in healthy and septic sheep.
The potential for significant interaction between PEEP and the peripheral microcirculations is not as well appreciated as are its central circulatory effects. Therefore, we studied the effects of PEEP, 15 mm Hg, on microvascular fluid flux in the hindlimb of ten mature sheep. Changes in prefemoral lymph flow (QL) and in lymph to plasma [L/P] total protein (TP) ratios were measured following the application of PEEP for 2 h, before and during hyperdynamic sepsis. Sepsis was induced by cecal ligation and perforation (CLP). Although the onset of sepsis was not associated with an increase in prefemoral QL, the [L/P] ratio of iodinated 125I human serum albumin (125I-HSA) was significantly greater 72 h after CLP than during the nonseptic baseline study. Histologic examination of gastrocnemius muscle also demonstrated an increase in protein-rich interstitial edema during the septic studies. During the 2 h of PEEP, prefemoral QL increased equally (p less than 0.05) in three study periods: (1) baseline nonseptic, delta QL = +1.2 +/- 1.4 ml/h; (2) septic period 1, 24 to 48 h after CLP, delta QL = +1.3 +/- 1.2 ml/h; and, (3) septic period 2, 72 h after CLP, delta QL = 1.0 +/- 0.6 ml/h. Calculated microvascular hydrostatic pressures also rose significantly during PEEP therapy in all three study periods. We conclude that PEEP, 15 mm Hg, increased hindlimb microvascular fluid flux and may thereby increase interstitial fluid content in tissues drained by the prefemoral lymph node. These effects of PEEP were not aggravated by hyperdynamic sepsis, despite a presumed increase in systemic microvascular permeability at this time.
Animals↗
Acute lung injury in septic shock.
Over the past 20 years, substantial information has been gained concerning sepsis-associated ALI. Although the mortality from ARDS remains unchanged, the spectrum of disease has altered. Patients rarely die acutely from the direct sequelae of ALI, including hypoxemia, but most commonly demonstrate a protracted clinical course that eventuates in MSOF. Further, with improved resuscitation of medical and surgical emergencies, the profile of patients who develop ARDS has changed and now reflects an older and more complex patient. While the pathophysiology and mediators of tissue injury in septic ARDS is now better understood, effective therapeutic interventions have not yet resulted from early multicenter trials. It is clear from the recent multicenter trials on the effects of methylprednisolone dose that apparently useful therapies in animal models must undergo this form of investigation before widespread clinical dissemination. Without an effective and singular "golden bullet" for the treatment of the varied presentation of ARDS, it remains our contention that basic management principles of ARDS must continue to emphasize an aggressive approach to the identification and treatment of the septic focus while all efforts are concurrently exploited to reduce the potentially aggravating effects of secondary injury on microvascular function. Currently research into the diagnosis, prevention, and treatment of nosocomial pneumonia is an example of how secondary injury may be minimized in ALI. Further, it is important to recognize the potentially detrimental effects of various therapies on the microvascular membrane in ARDS.
Animals↗
Circulatory disturbances in multiple systems organ failure.
Circulatory disturbances in MSOF disturb normal metabolic autoregulation, the ability to continuously couple tissue oxygen delivery with oxygen need. These may occur at three levels of the circulation: the heart; the regional circulations; and the microcirculation. This article will summarize evidence demonstrating that MSOF is associated with reduced tissue oxygen delivery by virtue of changes in all three circulatory components governing the inadequacy of metabolic autoregulation in sepsis.
Cardiovascular System↗