Here we present a plausible pathophysiological cascade initiating the transition of laminar to turbulent flow as a cause for, but not limiting other unknown clinical variable for an increased mortality rate in NCT01663701‐SSSP‐2. Based on the correlation between Perfused Boundary Region (PBR) and number of rolling leukocytes in post‐capillary venules in sepsis cohort, the PBR has been suggested as an index of glycocalyx shedding enhancing the leukocyte–endothelium interaction. NCT00793442 observed that average number of rolling leukocytes was 26 in the sepsis group and 9.8 in the non‐infected control group per field. The sepsis cohort, had an increased number of adhered leukocytes in non‐survivors compared to non‐sepsis cohort. Correlation of aforesaid hemodynamic parameters implicating the LPE impacting the damaged endothelial surface, tissue perfusion and organ dysfunction due to septic shock not withstanding “DIC”. After the LPE start forming in the arterial end of the capillary bed, rolling up and formation of vortex. Amplification of LPE involves the formation of a single vortex of greater strength through the pairing of vortices. As the vortices progress deregulating starling forces from the arterial region in the capillary bed towards the venous end, vortices to become heavily distorted and less distinct. Due to presence of damaged endothelial surface with adhered LPE, flow breaks down, generating a large number of small‐scale eddies, and the flow undergoes rapid transition to the fully turbulent regime. Mixing layers and wakes behind bluff bodies exhibit a sequence of events, leading to transition and turbulent flow. It has known that initial linear instability occurs around Rex, crit = 91 000 forming an unstable two‐dimensional disturbances are called TSW waves. Increased LPE adhesion, endothelial damage, possible scar tissue formation and/or necrotic lesions in the capillary bed are likely to be large enough a secondary, non‐linear, instability mechanism causes the TSW to become three‐dimensional and finally evolve into hairpin Λ‐vortices. In the most common mechanism of transition, would be K‐type transition, where the hairpin vortices are aligned. The hairpin vortices with a high shear region is induced which intensifies, elongates and rolls up. Regions of intense and highly localized changes occur at random times and locations near the damaged endothelial wall. These turbulent spots are carried along with the flow and grow by spreading across the capillary bed, which causes increasing amounts of laminar fluid to take part in the turbulent motion. Under progressive hypotensive state induced endothelial damage and abrupt collapse of interstitial space would result CCP ensuing hypoxia. Such scenario may have been the cause for mortality in NCT01663701‐SSSP‐2. Support or Funding Information Supported by professional development funds and in part CME activities of Subburaj KannanMD PhD for www.aaets.org
A retrospective analysis of EGDT trials from 2000 to 2018 registered in national clinical trials is presented here: (PRISM‐U) Study group attributed that the sepsis cohort with Mycobacterium tuberculosis (MTB) bacteremia for higher rate of in‐hospital mortality. FEAST (ISRCTN69856593) trial observed that fluid resuscitation in children with sepsis significantly increased mortality (48‐hour) possibly due to impaired perfusion. SSSP trail (NCT01449916) showed that though hypoxemic respiratory failure as contributing factor for mortality in addition to tissue hypoperfusion as inclusion criteria of patients with hypovolemia but excluding the patients with severe respiratory distress when ventilator support is not readily available could have potentially improved the survival rate. ARISE (NCT00975793) presented their report on the effectiveness of EGDT compare to that of usual sepsis care had similar (~18%) mortality rate concluding that EGDT did not reduce all‐cause mortality at 90 days. PRISM (NCT02030158) reported that, EGDT miss the mark to relieve mortality rate compare to that of usual care cohort. ProCESS (NCT00510835) reported that among 1341 patients, of whom 439 were randomly assigned to protocol‐based EGDT, 446 to protocol‐based standard therapy, and 456 to usual care in which protocol‐based resuscitation of patients in whom septic shock was diagnosed in the ER did not improve outcomes. ProMISe (ISRCTN36307479) concluded that septic shock cohort identified early and treated with intravenous antibiotics and adequate fluid resuscitation, hemodynamic management according to a strict EGDT protocol showed that no difference in mortality rate by 90 days. The IMPreSS study group found that compliance with “all of the evidence‐based bundle metrics” had a 40 % reduction in the odds of dying in hospital with the 3‐h bundle and 36 % for the 6‐h bundle. ProCESS Investigators (NCT00793442, NCT00510835 ) showed that increase in leucocyte rolling and adhering to dysfunctional endothelial surface in the cohort of septic shock compare to that of control, attributed to an increase in endothelial permeability‐hemostasis as cause for mortality. SSSP‐2 (NCT01663701) reported that cohort with sepsis and hypotension, most of whom were positive for HIV, in a resource‐limited setting, a protocol for early resuscitation with administration of intravenous fluids and vasopressors increased in‐hospital mortality compared with usual care. MOSAICS Study Group attributed the high mortality rate in severe sepsis treatment for the variation in adhering to the “all of the evidence‐based bundle metrics” for sepsis treatment. GENESIS project comparing 6‐hour resuscitation bundle (RB) for severe sepsis cohort showed decreased mortality rate compare to that of no RB bundle. Taken together it is suggested that lack coherent antibiotic stewardship practices across the globe warrant immediate review during EGDT and implementation of such guidelines would likely improve the survival rate in both low and high resource setting. Support or Funding In...
NCT01663701 noted that the median volume of iv fluid administered within 6 hours of presenting to ER in the sepsis intervention group was 3.5 L. The mean volume administered during the similar time interval in prior sepsis resuscitation trials were 5.0 L (EGDT); 5.1 L (ProCESS); and 4.5 L (ARISE). Criticisms of NCT01663701 such as a. the suggested vs administered median volume of fluid administered during the initial phase of resuscitation in the sepsis protocol group (3.5L) may have been higher than the 30 mL/kg recommended by SSC guidelines; b.”Each 1‐hour delay in antibiotic administration was associated with an absolute increase in mortality in the range of 5% to 10%”; and c. the median volume of iv fluid administered between ER presentation and 6 hours for BMI 18.5 kg/m2 ~ 70 mL/kg, here we present a plausible pathophysiological sequel as a contributing factor for mortality rate. Within the six hrs. of fluid resuscitation, a surge of fluid bolus mounted an adverse pressure gradient on the sphincters in metarterioles deregulating the pulsatile blood flow into the capillary bed. Based on the “Whole Brain Fluid and Osmolyte Network Model or” or “The whole brain network” approach a mechanistic model inclusive of major cranial compartments simulated the effect of osmotic therapy predicted that critical intracranial pressure (ICP) increased to >30 mmHg, with insufficient cerebral perfusion, and ventriculomegaly. The ventricular enlargement, in turn, reduces extracellular milieu for fluid exchange lead to a chronic increase in ventricular size shifts attributed to osmolyte administered. It is our hypothesis that after fluid resuscitation blood flows against an adverse pressure gradient in the capillary bed. The fluid particles such as activated and/or aggregating Cellular Aggregates near to the endothelial layer due to their low kinetic energy, “Cellular Aggregates” flows in the opposite direction. Such Cellular Aggregates cannot surmount the adverse pressure, lead to the formation of eddies. Such eddies in the arterial end are likely to cause local flow reversal zone and which retard the velocity concurrently the pressure of the blood flow. Under the low velocity and pressure gradient, the cellular eddies start separating from the endothelium referred to as boundary layer separation causing the blood flow to decelerate against an adverse pressure gradient. Then in the upstream part which is the venous end of the capillary bed, where the cellular eddies achieve boundary layer separation, causing blood pressure to drop from that of the arterial end creating the eddies to drag. At this stage, the pressure distribution in the capillary bed is at the stagnation point, where the velocity becomes zero at which cellular eddies form DIC. Sustained fluid bolus with vasopressor likely to form a non‐pulsatile flow pattern forming turbulent eddies in the venous end and disseminate the coagulated eddies leading to an aberration in the “MKD”. Dysregulated ICP, in turn, alter the ARGR leading to hypoperfusion subsequently coma....
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