Volumetric Overload Shocks Cause the Acute Respiratory Distress Syndrome: Building the Bridge Between Physics, Physiology, Biochemistry, and Medicine

Overload Shocks Cause the Acute Respiratory Distress Syndrome: Building Between Physics, Physiology, culprit in These the first 48 h of a stay

Both types of ARDS present with the multiple organ dysfunction syndrome (MODS) [13][14][15][16][17]. Cerebral features of coma, convulsions and paralysis predominate in VOS 1 or secondary ARDS. Primary VOS 2 causes ARDS in which acute lung injury and acute kidney injury (AKI) predominate. Trunk oedema, coagulopathy and excessive bleeding also occur [12][13][14][15][16]. Many errors on fluid therapy [18] mislead physicians into giving too much fluid during the resuscitation of shock causing ARDS [24]. The faulty Starling's law dictates the faulty rules on fluid therapy [25][26][27] using both liberal and conservative fluid regimen [3][4][5][6]28]. Here I demonstrate how this culprit has been identified in causing ARDS.  [17,[25][26][27], prospective study on 100 TURP patients [21], a case series of 23 patients who had the TURP syndrome [16] and physiologic study on the hind limb of sheep [27]. This was accompanied by critical analytical literature review of all the related issues. These have resulted in many new discoveries in physics, medicine and physiology [29]. The analytical literature review is reported here. The G tube study is highlighted to show how the BRIDGE between physics, physiology, biochemistry, and medicine was constructed. Further updated critical analytical review of the selected landmark articles on ARDS showed that authors have, indeed, suspected "Liberal fluid therapy" regime of resuscitation but never incriminated VO in causing ARDS.
Rangel-Frausto [9] conducted a prospective study on The Natural History of the Systemic Inflammatory Response Syndrome (SIRS) in 1995, wrote: "Equal numbers of patients who appeared to have sepsis, severe sepsis, and septic shock but who had negative cultures. They had been prescribed empirical antibiotics for a median of 3 days. The cause of SIRS in these culture-negative populations is unknown, but they had similar morbidity and mortality rates as the respective culture-positive populations". This is true. So, sepsis is either not there at all in half the ARDS patients or put under control by the appropriate and adequate antibiotics in the other half. This indeed, suggest that sepsis and septic shock in the path-aetiology of ARDS are as innocent as the wolf in Josef' story! We know for sure that the wolf did not eat Josef. It is true that sepsis may attack ARDS patient later doing its nasty work inducing the markers of SIRS. We need to look and search harder in order to recognize the hidden culprit not only responsible for causing ARDS in the negative culture group but also among the positive culture group. Is there alibi for the absence of sepsis in causing ARDS?
Indeed, there is.
Who is better to testify than Angus and van der Poll10 (2013)?
They wrote in the introduction paragraph to the comprehensive article on severe sepsis and septic shock in support of the absence alibi for sepsis as in Josef and wolf theory: "However, with the advent of modern antibiotics, germ theory did not fully explain the pathogenesis of sepsis: many patients with sepsis died despite successful eradication of the inciting pathogen.
Thus, researchers suggested that it was the host, not the germ that drove the pathogenesis of sepsis." With that in mind, particularly as we trust modern antibiotics eradicating sepsis, we continue our search for the real culprit underlying the cause of ARDS. Wioedemann et al. [4] in the FACCT Trial stated in conclusion: "Although there was no significant difference in the primary outcome of 60-day mortality, the conservative strategy of fluid management improved lung function and shortened the duration of mechanical ventilation and intensive care without increasing non-pulmonary organ failures. These results support the use of conservative strategy of fluid management in patients with acute lung injury." This is indeed a sound advice in support of the conservative strategy of FT, but we need to identify and recognize the culprit causing ARDS that is deeply rooted. Showing no significant difference in the primary outcome of 60-day mortality between the 2 fluids regimes, where there should be one, suggest that the correct Time for detecting the significant difference in mortality is important. Certainly, it is not at 60 or 90 days. It is much earlier than that as shall be explained later.
The role of Starling's forces played in this situation is merely hinted at by Sibbald et al. [30] and Rodney 2010 [31]. These authors are getting closer to solving the puzzle of ARDS, but they only need to know about my work demonstrating Starling's law has proved wrong [17]. Other authors have reported discontent with Starling's law criticizing it from different angles such as Alphonsus and Rodseth's in 2014 [32] and Woodcock and Woodcock [28] excellent reviews on endothelial glycocalyx. They highlight important issues which are of relevance here: the relation to Starling's forces, the importance of a smooth endothelial surface for the capillary and vascular bed normal function and the role of hypervolaemic state in the pathogenesis of ARDS. Robert Hahn reported an article on adverse effects of crystalloid and colloid fluids in 2017 [33], and on understanding volume kinetics in 2020 [34]. I observed 38-years ago the adverse effect of irregular internal surface of the of the G tube on the negative side pressure and chamber pressure of the G-C circulatory phenomenon particularly when connected to a circulatory system, as well as the effects of volumetrically overloading the system (. I shall return to discuss Starling's forces later but, by now what appeared to be heterogeneous and disjointed evidence at first look, the BRIDGE is shaping up and making sense. Montegomery et al. [2] concluded: "Most deaths in the first 3 days after entry into the study could be attributed to the underlying illness or injury. The majority of late deaths were related to sepsis syndrome. Of the 22 patients with ARDS who died after 3 days, 16 (73%) met our criteria for sepsis syndrome. There was a six-fold increase in sepsis syndrome after ARDS compared with that in the control group (p < 0.001). When sepsis syndrome preceded the ARDS, the abdomen was the predominant source, but when sepsis syndrome occurred after the onset of ARDS there was usually a pulmonary source" Based on this sound research we should segregate those patients who die within 3 days starting at hospital admission from those who die afterwards in order to show the significance in mortality on comparing further subgroups of the studied patients, as shown later. This is important for revealing the culprit causing ARDS. All the action and most of the mortalities of ARDS occur at the time of resuscitation with fluids (the 6-hours period of EGDT) and perhaps up to 3 days, maximum one week, when significant difference in morbidity and mortality may be detected. This is the time period to look for the cause of ARDS and its significant effect on mortality endpoint not the 60 or 90-days' time endpoint. I shall further discuss the significance and importance of Time a little later. Sepsis becomes responsible for the mortality of ARDS after 3 days from onset or hospital admission.

Schuller et al asked an important and excellent question in the
title of their report in 1991 [3]: "Is fluid balance during pulmonary oedema a marker or a cause of poor outcome? The answer is in their conclusion: "These data support the concept that positive fluid balance per se is at least partially responsible for poor outcome in patients with pulmonary oedema and defend the strategy of attempting to achieve a negative fluid balance if tolerated hemodynamically." That is correct and most useful advice, but what is causing ARDS? Dr Schuller is saying that positive fluid balance per se that is VO or hypervolaemia is at least partially responsible. I agree and go further perhaps it may be even totally responsible.
Please, follow his advice of "attempting to achieve a negative fluid balance" and trust the haemodynamic of the cardiovascular system (CVS) will sort itself out spontaneously and return to normal.
The prevalence of "liberal" fluid infusion in resuscitation of all types of shocks not only septic shock in clinical practice all over the world is attributed to an impactful article by Rivers et al, reported at The N Engl J Med 2001 [11]. Dr Rivers' investigation reported the Early Goal-Directed Therapy (EGDT) in the treatment of severe sepsis and septic shock. In this single-centre study published more than 19 years ago involving patients presenting to the emergency department with severe sepsis and septic shock, the conclusion was: "mortality was markedly lower among those who were treated according to a 6-hour protocol of EGDT, in which intravenous fluids, vasopressors, inotropes, and blood transfusions were adjusted to reach central hemodynamic targets, than among those receiving usual care" Usual care means conservative fluid regime. There is something grossly wrong with this conclusion, but I cannot tell what is it? Not yet. Let us see what other author investigators have said first. The EGDT of liberal fluid infusion has been termed "aggressive" by some authors. However, it has been adopted all over the world not only for the therapy of septic shock but also whenever fluid therapy is required.
In another article by Dr Rivers 10 years later in 2012 [12] he The traumatized bleeding patient, for example, dies before reaching the hospital if half the blood volume quickly lost. In sepsis, severe sepsis and septic shock, there is no fluid loss at all. In the "liberal" approach of EGDT there seem to be no limit on how much fluid should be infused. This VO induce hypervolaemic state that internally drowns the swollen patient on ICU. To resolve this most elusive puzzle of ARDS, there is a need to define this maximum volume of infused fluids not only for the liberal but also for the conservative approach. I know there are a few situations when this maximum must be exceeded such as in burned and the continuously bleeding patients that cannot be stopped and perhaps heat stroke.
In these situations, the advice is: stop the bleeding, replace the loss but do not overdo it.
The PRISM Investigators reported its Trial by Rowan et al at NEJM 20177 concluded: "In this meta-analysis of individual patient data, EGDT did not result in better outcomes than usual care and was associated with higher hospitalization costs across a broad range of patient and hospital characteristics." Thank you, Dr Rowan and colleagues for the excellent research and report. This is good evidence-based medicine, but more is needed, from you, and you have the data to provide it. Based on this conclusion that agrees with other multi-centre trials I wonder is time to say goodbye Dr, Rivers? The aggressive and deleterious liberal approach of EGDT is no longer wanted. It should be abandoned immediately. Even when the nasty liberal approach goes away, hopefully soon, it remains bad enough with the conservative regime as it is now that must be sorted out! I wonder what Dr Rivers has to say about this, particularly as authors of 3 other huge prospective multi-centre trials of The ProCESS/ARISE/ProMISe reported similar conclusion by Huang et al. [8].
What is the gain from doing such long expensive trials if its conclusion and recommendation are not implemented, immediately? What is most interesting, relevant, and important in the reported data in the results section of the article by Rowan et al.
2017 [7] on fluid balance in ARDS patients who wrote the following: "Each study day the liberal-strategy group received more fluid than the conservative-strategy group and on days 1 through 4 had a lower urinary output, resulting in a higher cumulative fluid balance (Table   1). During the study, the seven-day cumulative fluid balance was -136±491 ml in the conservative-strategy group, as compared with The gained fluids were Glycine absorbed (Gly abs), intravenously infused 5% Dextrose (IVI Dext) Total IVI fluids, Total Sodiumfree fluid gained (Na Free Gain) and total fluid gain in Liters. A mean of 3.5 (p=0.0001) liters VO occurred in symptomatic patients presenting with hypotensive shock, recognized as VOS1.

Figure 2:
Volumetric overload (VO) quantity (in liters and as percent of body weight) and types of fluids. Group 1 was the 3 patients who died in the case series as they were misdiagnosed as one of the previously known shocks and treated with further volume expansion based on the conservative approach. They had the clinical picture of VOS 2 and ARDS. Group 2 were 10 patients from the series who were correctly diagnosed as volumetric overload shock (VOS 1) and treated with hypertonic sodium therapy (HST). Group 3 were 10 patients who were seen in the prospective study and subdivided into 2 subgroups; Group 3.1 of 5 patients treated with HST and Group 3.2 of 5 patients who were treated with "guarded" volume expansion using isotonic crystalloids/plasma/blood of the standard conservative approach but much less volume-being "Guarded". One patient from the conservatively treated group 3.2 developed ARDS with coma, convulsions, and bizarre paralysis on the second postoperative day. He was seen by a Neurologist and diagnosed as cerebrovascular accident. He fully and immediately recovered from ARDS, coma and paralysis after belated treatment with HST using 5% NaCl and 8.4% NaCo3. After HST the patient recovered fully from AKI, ARDS, Coma and paralysis. Recovery from AKI that was unresponsive to loop diuretics occurred with the infusion of HST after passing 4.5L of urine. Groups 2 and 3.1 responded similarly to HST. (Reproduced with the permission of author from open access journal). For patients who were not in shock at baseline, the cumulative VO was −1576±519 ml in the conservative-strategy group and THE VO and fluid type of the 10 symptomatic patients among the 100 patients of the prospective trial is reported [21]. There were no mortalities in our prospective study but there was morbidity affecting 10 (10%) patients, one of whom among the conservatively treated group developed the criteria of secondary ARDS who suffered coma, next day, with convulsions and paralysis diagnosed by a neurologist as cerebrovascular accident. He was crossed over and belatedly treated with HST with complete cure. Table 1. Data for the 23 cases series is shown in (Table 2). In our study, a mean total VO of ±3.  Table 2). The VO of 5 L (7% BW) was that of patients presented with severe morbidity of VOS 1 or secondary ARDS. Table 2: The data of the 23-patients of the case series study [11]; the second clinical study on which this article is based. The significant changes of serum solute contents are shown in bald font with the corresponding p-value. Most of the patients showed manifestation of ARDS (Table 1) of which the cerebral manifestation predominated, being on initial presentation (Regional Anaesthesia) and representation of VOS 1 (General Anaesthesia). However, most patients were given large volume of saline that elevated serum sodium to near normal while clinical picture became worse. They suffered VOS2 that caused ARDS. The VO of patients to whom these data belongs are shown. Please note the elevation of urea and unurea of Group 1 who died indicated AKI. Elevations oh Bilirubin and AST indicated hepatic dysfunctions. White cell count (WCC) elevation indicated inflammatory response of VOS 2 in ARDS or SIRS in the absence of sepsis. with shock in theatre, were mistaken for a haemorrhagic or septic shock and were wrongly treated with further volume expansion then developed ARDS and died. Their post-mortem was attended.

Morbidities of Secondary ARDS is shown in
The vital organs of lung, heart, brain and liver were oedematous, and the patient's trunk was grossly swollen and there was accumulation On final revision of this article I added more figures on the G tube in circulatory system Extended data figure) for more clarity and understanding of the G tube hydrodynamic. The toxic theory of glycine, sepsis with septic shock, and hemorrhage were excluded in the patho-aetiology of TURP syndrome back in 1988 in MD Thesis and in 1990 prospective study article [21] that remains as good today in 2020. The type of fluid used in resuscitation during ARDS trials is sodium-based fluid of crystalloids and colloids and/ or hydroxyethyl starch (HES) as well as blood. This is VO type 2 that also induces shock (VOS 2) causing primary ARDS and AKI36 as features of MODS. Primary VOS 2 is induced with fluids of both crystalloids and colloids such as saline, Hartmann, plasma, plasma substitutes and blood, in any combination. Primary VOS 2 has no clear serum marker like HN but hypo-albuminemia is there for VO of crystalloids but not with colloids or blood. Primary VOS 2 is much harder to detect and nearly impossible to recognize.
The hyper-volumetric state affects not only the ISF volume of subcutaneous oedema and swollen vital organs such as the heart, lung, brain and liver but also the cardiovascular system was in a state of hypervolaemia37-39. The occurrence of hypotension with hypervolaemia justifies calling this volumetric overload shock type 2 (VOS 2) as induced by saline-based fluids such as crystalloids and colloids. This further means that acute volume kinetics either by decrease such as severe bleeding and dehydration as well as excessive vascular volume increase by VO induces primary VOS 2 and causes primary ARDS. Surely, this VOS 2 should not be treated by further volume expansion. The endpoint of therapy here in optimizing the CVS volume in VOS 2 of ARDS in order to restore normal arterial pressure. Thus, the aim of therapy should be to lower the CVS volume down to its normal state, or even slightly below as the (-) negative sign reported by Rowan in results [7] and discussed here indicate. Thus, Starling's law is wrong on both forces. The available evidence makes the argument on albumin versus saline obsolete [35][36][37][38][39][40][41][42] and will no longer be entertained here.
What is more interesting is the result and conclusion of the study on the hind limb of sheep, representing the physiological proof reported above. It demonstrates that both albumin and saline  now damaged beyond repair as it is wrong on both of its forces for the reasons presented above in this BRIDGE report. I believe Starling's law is the hidden culprit that dictates the faulty rules responsible for many errors and misconceptions on fluid therapy [18] using both the conservative approach as well as liberal approach [28]. This misleads physicians into giving too much fluid [24] during the resuscitation of all types of shocks, trauma, the acutely ill patients and during prolonged major surgery. We hope NBCI will soon rectify that. Later search for "Ghanem AN" on Google Scholar returned all my articles with citations. I also searched for fluid therapy and ARDS. Indeed, there is a growing body of evidence on "fluid overload" in relation to ARDS that demonstrate the importance of VO/Time concept inducing VOS causing ARDS. authors mentioned below also found a significant effect of crystalloids overload on mortality as they did the research during the first 24-48 hours from hospital admission. I have found only one study on adults' trauma patients by Jones et al. [45], and one paediatrics study by Coons et al. [46] and a remarkable review article by Schrier reported in 2010 [47,48]

Conflict of Interest
None declared by the author.
Funds received for the investigations and reporting: None declared by the author.

Acknowledgements
Many thanks go to Designer Engineer Peter Holder of Urologists, District General Hospital, Eastbourne, UK for teaching me the Urology I know, and for offering me the post of research fellow without an interview in order to do the prospective study [19]. I also like to thank the Internet people, Google for its magic Chrome® and Google Scholar® programs, and the people behind the wonderful PubMed, NLM & NCBI for being most helpful over the years; putting such huge amount of information at the researcher's finger's tip. I like to thank Apple® Computers for inventing the Macintosh® before 1985 and Stat View® 512+ Statistical package; both made analyzing the data of the prospective study absolute fun 1984-1988.