Fluid Therapy in Septic Shock

Sepsis and Myocardial Depression in a Young Woman

Independent Clinical Criteria in Medicine: The Unusual Case of Septic Shock

The purpose of this study was to examine the effects of prostaglandin E1 (PGE1) on venous capacitance during controlled hypotension. Trinitroglycerin (TNG) was used as a control agent. In rats anesthetized with ketamine, mean arterial pressure was lowered to 70 mmHg and subsequently 50 mmHg by intravenous infusion of PGE1 or TNG. Venous capacitance was assessed before and during induced hypotension by measuring the mean circulatory filling pressure (MCFP). MCFP was measured after briefly arresting the circulation by inflating an indwelling balloon in the right atrium. MCFP was significantly decreased by PGE1 from 7.9 +/- 0.3 to 6.9 +/- 0.3 mmHg at mean arterial pressure of 70 mmHg and to 6.9 +/- 0.2 mmHg at mean arterial pressure of 50 mmHg. The decrease in MCFP by PGE1 at mean arterial pressure of 70 mmHg was not significantly different from TNG. However, the decrease in MCFP by PGE1 at mean arterial pressure of 50 mmHg was significantly less than that by TNG. The results suggest that the venous capacitance may be increased by PGE1 to a similar degree with TNG at doses to produce a comparable level of moderate hypotension, but the increase in venous capacitance may be less in PGE1 than TNG at doses to produce deep hypotension.

During septic shock, fluid therapy is aimed at increasing cardiac output and improving tissue oxygenation, but it poses two problems: it has inconsistent and transient efficacy, and it has many well-documented deleterious effects. We suggest that there is a place for its personalization according to the patient characteristics and the clinical situation, at all stages of circulatory failure. Regarding the choice of fluid for volume expansion, isotonic saline induces hyperchloremic acidosis, but only for very large volumes administered. We suggest that balanced solutions should be reserved for patients who have already received large volumes and in whom the chloremia is rising. The initial volume expansion, intended to compensate for the constant hypovolaemia in the initial phase of septic shock, cannot be adapted to the patient’s weight only, as suggested by the Surviving Sepsis Campaign, but should also consider potential absolute hypovolemia induced by fluid losses. After the initial fluid infusion, preload responsiveness may rapidly disappear, and it should be assessed. The choice between tests used for this purpose depends on the presence or absence of mechanical ventilation, the monitoring in place and the risk of fluid accumulation. In non-intubated patients, the passive leg raising test and the mini-fluid challenge are suitable. In patients without cardiac output monitoring, tests like the tidal volume challenge, the passive leg raising test and the mini-fluid challenge can be used as they can be performed by measuring changes in pulse pressure variation, assessed through an arterial line. The mini-fluid challenge should not be repeated in patients who already received large volumes of fluids. The variables to assess fluid accumulation depend on the clinical condition. In acute respiratory distress syndrome, pulmonary arterial occlusion pressure, extravascular lung water and pulmonary vascular permeability index assess the risk of worsening alveolar oedema better than arterial oxygenation. In case of abdominal problems, the intra-abdominal pressure should be taken into account. Finally, fluid depletion in the de-escalation phase is considered in patients with significant fluid accumulation. Fluid removal can be guided by preload responsiveness testing, since haemodynamic deterioration is likely to occur in patients with a preload dependent state.

How "Squeezing t H e VeinS" May Help?In the absence of evident loss of fluid, systemic pathological vasodilation results in a decrease in venous return and thus cardiac output.This brings back the argument that how likely fluid resuscitation is going to reverse vasodilation and hypotension.Vasopressors by changing venous capacitance increase mean systemic filling pressure.This mobilizes nonstressed blood volume back to circulation, increasing preload and cardiac output.Secondly, early initiation of vasopressors decreases both the duration and severity of hypotension and improve clinical outcome. 2 Third, vasopressors may additionally increase cardiac output by increasing cardiac contractility through improving ventriculoarterial coupling.Fourthly, coronary artery perfusion is improved due to improved diastolic blood pressure leading to improvement in cardiac function in SS.Fifthly, norepinephrine might increase microcirculatory perfusion in SS, especially when initial microcirculatory blood flow is abnormal.Sixthly, the use of norepinephrine in SS has been shown to be associated with improved MAP, sustained mesenteric blood flow, and better tissue oxygenation when compared with fluid resuscitation alone.

Severe meningococcal disease in childhood

Another Look at Steroid Therapy for Septic Shock

Sepsis and Septic Shock: Selection of Empiric Antimicrobial Therapy

We thank van Eijk et al. for their interest in our work and appreciate their congratulation for the first investigation of vascular reactivity in septic patients [1]. Despite some evidence in favour of endothelial dysfunction during experimental sepsis, we showed that in septic shock, acetylcholine-induced vasodilation in the forearm vasculature is well preserved, albeit in a small number of patients [1]. Van Eijk et al. remark that prior studies demonstrate that in septic animals or during experimental endotoxaemia, endothelial function is impaired as indicated by decreased vasodilation in response to acetylcholine in several organ systems [2-4] and feel that this contrasts with our observations in septic patients [1]. We would like to suggest that observations made in animal models of ‘sepsis’ or during experimental endotoxaemia in human volunteers, may not reflect the complex changes seen in patients with sepsis. In fact, this was the very reason why we decided to study vascular reactivity in septic patients so as to overcome the deficiencies of several sepsis models. By studying patients with similar cardiovascular instability we thought to be able to minimize inter-individual variability in vascular function as much as possible. In fact, in patients with sepsis, acetylcholine induced endothelium-dependent relaxation was found to be intact in the skin compared to ICU patients without sepsis as well as to healthy volunteers [5]. Accordingly, preserved endothelium-dependent vasodilation in the forearm vasculature of our patients with septic shock parallels previous findings in skin microcirculation during sepsis. Of note, however, we did not study endothelial dysfunction during an early stage of sepsis. Van Eijk also suggests that lower vascular resistance in sepsis may be the reason for the decreased response to acetylcholine observed. If this were the case, one would expect impaired vasodilation to acetylcholine due to a decreased vasodilator reserve. In contrast, at least in the forearm vasculature, we observed increased blood flow in patients with septic shock but at the same time a similar response to the exogenous nitric oxide-donator nitroprusside [1]. Thus, vasodilator reserve appears to be maintained in forearm vasculature during human septic shock. Finally, van Eijk comments that a full dose-response relationship of acetylcholine cannot be characterized by the two doses administered (a point we have already addressed in our publication) and that the dose of L-N monomethylarginine given is rather low. We fully agree, but can report that blood flow measurements were indeed performed in the contralateral arm concurrently. These indicated that higher doses of acetylcholine or L-N monomethylarginine resulted in systemic effects in both patients and volunteers. Since we did not want to confuse measurements of regional effects in the forearm by systemic baroreflex mediated effects we limited interpretation and data to the lower dosages reported. Van Eijk speculates that endothelial dysfunction may have been demonstrated following administration of other endothelium-dependent vasodilators, like substance P or bradykinin. Since we studied endothelium-dependent and endothelium-independent vasodilation as well as vasoconstriction using three different vasoconstrictors in the same subjects/patients we had to limit the duration of the study to maintain stable baseline conditions and dispensed the evaluation of additional vasoactive drugs. Obviously, what effect other agents might have had is an area for speculation. In summary, we challenge prior work in animal models of sepsis and in human volunteers following lipopolysaccharide administration by demonstrating in ‘real sepsis’ that endothelial function is preserved in the forearm vasculature of septic patients. While endothelial dysfunction may still occur during earlier stages of sepsis and further studies are needed to address the issue there is nothing that beats data in real, septic humans.

During experimental sepsis, excessive generation of the anaphylatoxin C5a results in reduction of the C5a receptor (C5aR) on neutrophils. These events have been shown to result in impaired innate immunity. However, the regulation and fate of C5aR on neutrophils during sepsis are largely unknown. In contrast to 30 healthy volunteers, 60 patients in septic shock presented evidence of complement activation with significantly increased serum levels of C3a, C5a, and C5b-9. In the septic shock group, the corresponding decrease in complement hemolytic activity distinguished survivors from nonsurvivors. Neutrophils from patients in septic shock exhibited decreased C5aR expression, which inversely correlated with serum concentrations of C-reactive protein (CRP) and clinical outcome. In vitro exposure of normal neutrophils to native pentameric CRP led to a dose- and time-dependent loss of C5aR expression on neutrophils, whereas the monomeric form of CRP, as well as various other inflammatory mediators, failed to significantly alter C5aR levels on neutrophils. A circulating form of C5aR (cC5aR) was detected in serum by immunoblotting and a flow-based capture assay, suggestive of an intact C5aR molecule. Levels of cC5aR were significantly enhanced during septic shock, with serum levels directly correlating with lethality. The data suggest that septic shock in humans is associated with extensive complement activation, CRP-dependent loss of C5aR on neutrophils, and appearance of cC5aR in serum, which correlated with a poor outcome. Therefore, cC5aR may represent a new sepsis marker to be considered in tailoring individualized immune-modulating therapy.

The changes of hemodynamic and oxygen transport variables in human septic shock are well documented [1]. They are essentially characterized by a hyperdynamic circulatory state associated with an increased cardiac output (CO), a decreased systemic vascular resistance (SVR) and a narrowed arterial-mixed venous oxygen difference (a-vO2) together with elevated arterial blood lactate levels. Therefore, when arterial oxygenation is maintained, oxygen delivery (DO2) is as a consequence usually supranormal. This implies a defective tissue oxygen extraction as the most important mechanism that limits oxygen consumption (\( \dot{V}{{O}_{2}} \)) in septic shock. Throughout a septic episode the basic pathophysiologic problem seems to be a disparity between the uptake of oxygen and the demand of oxygen in the tissues as manifested by increased blood lactate levels. Limitation of oxygen uptake may significantly contribute to morbidity and mortality by predisposing to multiple organ failure. Several observations suggest that inadequate tissue oxygenation is a central mechanism mediating the widespread and irreversible tissue damage that is associated with multiple organ failure and a fatal outcome [2, 3].

Haemodynamic effects of the lateral decubitus position and the kidney rest lateral decubitus position during anaesthesia

IntroductionThe aim of this study was to assess the efficacy of arginine-vasopressin (AVP) as a rescue therapy in catecholamine-refractory septic and non-septic shock in extremely low birth weight (ELBW) infants with acute renal injury.MethodsProspective assessment of AVP therapy in three ELBW infants with catecholamine-refractory septic shock and acute renal injury (mean birth weight 600 ± 30 g) and three ELBW infants with non-septic shock and acute renal injury (mean birth weight 770 ± 110 g) at a University hospital. The main outcome measures were restoration of blood pressure with adequate organ perfusion and survival at discharge.ResultsIn all three ELBW infants with catecholamine-resistant septic shock, systemic arterial blood pressure increased substantively with restoration of urine output after AVP administration (dosage, 0.035 to 0.36 U/kg/h; length, 70 ± 21 hours). In the three ELBW infants with non-septic shock, only a transient stabilization in mean arterial pressure with restoration of urine output was observed after AVP therapy (dosage, 0.01 to 0.36 U/kg/h; length, 30 ± 16 hours). The mortality rate was 1/3 in the sepsis group versus 3/3 in the non-septic group.ConclusionAVP may be a promising rescue therapy in catecholamine-resistant shock in ELBW infants with acute renal injury. Larger prospective clinical trials are warranted to assess the efficacy and safety of AVP as a pressor adjunct in septic versus non-septic shock in ELBW infants.

Barbiturate therapy has been employed for reduction of increased intracranial pressure (ICP) after acute brain injury and also for cerebral resuscitation. However, this treatment may be complicated by hypotension with an adverse impact on survival. We, therefore, investigated the acute hemodynamic effects of pentobarbital (PB) when administered in loading doses of 4-7 mg/kg and maintenance doses of 1-4 mg/kg. After pentobarbital therapy, HR, mean arterial pressure (MAP), and rectal temperature were significantly reduced. Four episodes of hypotension and 6 episodes of oliguria were observed during the initial 12 h of therapy in close relationship to reduced cardiac output, stroke volume, and MAP. These abnormalities were corrected by infusion of colloid-containing fluids. We postulate that increases in venous capacitance, hypovolemia, and decreased barostatic reflexes, rather than depression of myocardial function, accounted for the hemodynamic abnormalities.

Despite significant efforts toward improving therapy for septic shock, mortality remains high. Applying veno-arterial (V-A) extracorporeal membrane oxygenation (ECMO) in this context remains controversial. Since the cannulation of the femoral artery for V-A ECMO return leads to lower body hyperoxia, this study investigated the impact of V-A ECMO therapy on the intestinal and hepatic microcirculation during septic shock in a rodent model. Thirty male Lewis rats were randomly assigned to receive V-A ECMO therapy with low (60 mL/kg/min) or high (90 mL/kg/min) blood flow or a sham procedure. Hemodynamic data were collected through a pressure-volume catheter in the left ventricle and a catheter in the lateral tail artery. Septic shock was induced by intravenous administration of lipopolysaccharide (1 mg/kg). The rats received lung-protective ventilation during V-A ECMO therapy. The hepatic and intestinal microcirculation was measured by micro-lightguide spectrophotometry after median laparotomy for two hours. Systemic and pulmonary inflammation was detected via enzyme-linked immunosorbent assays (ELISA) of the plasma and bronchoalveolar lavage (BAL), respectively, measuring tumor necrosis factor-alpha (TNF-α), interleukins 6 (IL-6) and 10 (IL-10), and C-X-C motif ligands 2 (CXCL2) and 5 (CXCL5). Oxygen saturation and relative hemoglobin concentration were reduced in the hepatic and intestinal microcirculation during V-A ECMO therapy, independent of the blood flow rate. Further, rats treated with V-A ECMO therapy also presented elevated systolic, diastolic, and mean arterial blood pressure and increased stroke volume, cardiac output, and left ventricular end-diastolic volume. However, left ventricular end-diastolic pressure was only elevated during high-flow V-A ECMO therapy. Blood gas analysis revealed a dilutional anemia during V-A ECMO therapy. ELISA analysis showed an elevated plasma CXCL2 concentration only during high-flow V-A ECMO therapy and elevated BAL CXCL2 and CXCL5 concentrations only during low-flow V-A ECMO therapy. Rats undergoing V-A ECMO therapy exhibited impaired microcirculation of the intestine and liver during septic shock despite increased blood pressure and cardiac output. Increased pulmonary inflammation was detected only during low-flow V-A ECMO therapy in septic shock.