Rapid Responses to:

RESEARCH: SAFE Study Investigators Effect of baseline serum albumin concentration on outcome of resuscitation with albumin or saline in patients in intensive care units: analysis of data from the saline versus albumin fluid evaluation (SAFE) study BMJ 2006; 333: 1044 [Abstract] [Full text]

Rapid Responses: Submit a response to this article

Rapid Responses published:

Albumin: a marker of inflammation

Venkataswamy Narayana Mahesh   (16 October 2006)

Albumin Versus Albumin

Ahmed N Ghanem   (22 November 2006)

Albumin has its place

Gail SM Masterton, Stewart Campbell   (13 December 2006)

Albumin: a marker of inflammation 16 October 2006
Venkataswamy Narayana Mahesh, SpR Gastroenterology University hospital of North Durham, Durham, DH1 5TU Send response to journal: Re: Albumin: a marker of inflammation	Editor- This study by the SAFE investigators(1) is useful in evaluating the role of albumin replacement, in view of confliction reports(2,3) regarding the clinical effects of resuscitation with albumin. Serum albumin levels are influenced by rate of synthesis, degradation and distribution. Despite being used as a marker of synthetic ability of the liver, its production is suppressed by inflammatory factors like TNF and Interleukin-1.(4,5). Also, given the long half life of upto 20 days and influence of other factors like chronic liver damage, inflammation, dehydration etc, makes albumin an unrelaible marker of nutrition.(6). In this study(1), the cohort with serum albumin concentration of <25g/L, had higher incidence of severe sepsis and ARDS, and also worser outcome with higher 28 day mortality, longer ITU and hospital stay. Hence, it is logical to concur that, albumin in critically ill patients reflect the degree of underlying inflammatory process, and hence correcting the levels i.e. albumin replacement/resuscitation would not change the outcome. REFERENCES: 1. Saline versus Albumin Fluid Evaluation Study Investigators Effect of baseline serum albumin concentration on outcome of resuscitation with albumin or saline in patients in intensive care units: analysis of data from the saline versus albumin fluid evaluation (SAFE) study BMJ 2006; 0: bmj.38985.398704.7Cv1 2. Vincent JL, Navickis RJ, Wilkes MM. Morbidity in hospitalized patients receiving human albumin: a meta-analysis of randomized, controlled trials. Crit Care Med 2004;32:2029-38. 3. Human albumin solution for resuscitation and volume expansion in critically ill patients. Cochrane Database Syst Rev 2004;(4):CD001208.pub2. 4. Perlmutter, DH, Dinarello, CA, Punsal, PI, et al. Cachectin/tumor necrosis factor regulates hepatic acute-phase gene expression. J Clin Invest 1986; 78:1349. 5. Dinarello, C. Interleukin-1 and the pathogenesis of the acute phase response. N Engl J Med 1984; 311:1413. 6. Ackerman, MH, Evans, NJ, Ecklund, MM. Systemic inflammatory response syndrome, sepsis, and nutritional support. Crit Care Nurs Clin North Am 1994; 6:321. Competing interests: None declared
Albumin Versus Albumin 22 November 2006
Ahmed N Ghanem, Urologist EDGH, 70, Glendale Avenue, Eastbourne, BN21 1UN Send response to journal: Re: Albumin Versus Albumin	Sir, I read with interest Professor Fifner’s article on “saline versus albumin fluid evaluation (SAFE) 1, concluding: “saline or albumin produces similar outcome” In 1998 meta-analysis, albumin faired worse2, justifying BMJ slogan “Why albumin may not work”. This is conflicting and perplexing. Professor Vincent3 mentioned in his editorial: “the aim of the analysis was to show that albumin administration is safe.” I wish all luck with the “Save Albumin Campaign”, and confirm that I do not deny albumin safety and usefulness when indicated. The valid painstaking analysis of data and the conclusion of similar or worse outcome, to my mind, re-affirms the fact that albumin oncotic pressure in VIVO is fallacy4-6, explaining BMJ slogan. It is shameful waste to spend so much effort and money on a perfect huge clinical trial, on the wrong basic notion that albumin oncotic pressure exists in VIVO. My aim here, however, is to discuss issues overlooked in all SAFE trials data analysis highlighting a concept that may help to resolve the conflict and more importantly the problems of concerned patients on ICU. Fifner mentioned in discussion: “Patients received the amount of fluid the clinician thought necessary to restore or maintain intravascular volume” I applaud the truthful reality of this statement, and believe it pinpoint precisely where the problems are (highlighted). Thus, if the volume of the given fluid during resuscitation is quantified half the battle is won, and if the scientific basis underlying the thought that mislead physician to infuse such volume is verified and rectified the battle is over. In a letter on the editorial, I mentioned that SAFE trials and analysis are concerned only with the Type of fluid, while missing the important issue of volume, measured in either volumetric or gravimetric method. Volumetric overload (VO) over Time (VO/T) is a concept verifiable by comparing patients’ body weight on ICU to that on hospital admission. This reveals a staggering VO! In 1976, Professor Ashbaugh8 et al documented fluid gain in the first report on the adult respiratory distress syndrome (ARDS) that became later known as the multiple vital organ dysfunction or failure (MVOF) syndrome. Such VO data have not ever since been documented. It is consistently missed in prospective trials. Not a single prospective SAFE or other trial report volumetric data on MVOF patients! Please do correct me if wrong. Fluid Type and Volume, and Time of gain, have vital significance in the pathogenesis and outcome of MVOF patients on ICU. Type of fluid gives characteristic serum solute dilution markers. Volume is directly, while time is inversely, related to the severity. Sadium-free fluids (Type 1) or VO1 dilute all serum contents including albumin, but its best marker is hyponatraemia. The well known transurethral prostatectomy (TUR)9 syndrome is a “clean model” of many such hyponatraemia cases seen in clinical practice. A “Clean model” (TUR) syndrome means it can be, and has been, precisely reproduced in animals in the absence of sepsis, hypothermia and recognized shocks. Hyponatraemia is common hospital complication of fluid therapy that affects men women and children and may be lethal. The TUR syndrome is induced by both the irrigating fluid absorption (1.5% Glycine, 5% Glucose Sorbitol or Mannitol) and the infused intravenous fluids such as 5% Glucose9. A quantity of 3.5l, gained during 1 hour surgery, induces a classical condition while 5-6l may be lethal. The VO of 3.5l may be considered normal daily intake and is tolerated over couple of hours but when gained in one hour it becomes pathological. The condition manifests clinically with paradoxical hypotension shock (Paradoxical means hyper- NOT hypo-volaemic shock) with features unrecognizable from or identical to hypo-volaemic shock except for transient bradycardia and elevation of vascular pressures. It also has paradoxical acute renal failure (ARF) among other features of the MVOF syndrome. This must to be kept in mind in order to recognize VO/T, induced by SAFE fluids, with scarce markers if any. This is important as the TUR procedure is currently performed in saline irrigation (TURIS), so much more VO/T with scarce or no markers will soon appear. The common thought and practice of treating physician in such paradoxical VO/T shock is to infuse further volume of either SAFE isotonic fluid! He aims to elevate pressure by increasing vascular volume in the belief that he is facing hypovolaemic hypotension shock, while data indicate VO/T shock. The action just makes it worse or irreversible shock and establishes MVOF when the patient is shifted to ICU. The insult of both SAFE isotonic fluids may occur in resuscitating the TUR syndrome with definite characteristic serum markers and proven clinical features, or may complicate overzealous resuscitation of any recognized shock, trauma or ICU patient when serum markers are scarce or nil. Nothing to guide physician at all except his thought determined by current basic teaching on vascular volume/pressures relationship on one hand, and the forces regulating the capillary circulation on the other. The latter determine the type and volume of SAFE fluid used in resuscitation of shock, trauma, burns, haemorhage and sepsis. Sodium-based fluids (Type 2): saline induce VO/T shock too. It may complicate the resuscitation of the TUR syndrome when saline erases hyponatraemia while worsening VO. The main serum marker becomes hypoalbuminaemia. It also has the same clinical features of paradoxical hypotension shock and MVOF. It may complicate resuscitation of any recognized shock. The transition from hypo- to hyper-volaemic hypotension shock is hard or impossible to detect. No stop sign to show that such patient is having hyper-volaemic not hypo-volaemic hypotension shock. None to warn when the quantity needed in treating true hypovolaemia is surpassed. Vascular pressures of CVP, PCWP and BP changes of VO/T are identical except for an occasional transient initial rise. Massive plasma and blood infusions have no serum markers or specific vital signs at all except VO increase of body weight and MVOF. It should be realized that hypotension is not always synonymous with hypovolaemia. It is worth mentioning also that, up to this point, sepsis is as innocent as the wolf in Joseph story. A little later sepsis will do its nasty work and further complicate MVOF into its current trendy name associated with sepsis. The scientific basis that underlies physician’s thought while resuscitating a patient take longer to explain. The appendix explains with references4-6,11-13 the evidence on how and why Starling’s law10 is wrong on all accounts while continuing to dictate the type and incorrect volume of fluid in resuscitation while volume is consistently missed in SAFE trials. Yours truly, Ahmed N Ghanem, MBChB, MD (Urology), FRCS. an_ghanem@yahoo.com Conflict of interest: None. Reference: 1. Finfer S. Effect of baseline serum albumin concentration on outcome of resuscitation with albumin or saline in patients in intensive care units: analysis of data from the saline versus albumin fluid evaluation (SAFE) study. BMJ; 333: 1044-6. (18 November 2006) 2. Vincent JL. Editorial. Resuscitation using albumin in critically ill patients: Research in patients at high risk of complications is now needed. BMJ; 333:1029-30. (18 November 2006) 3. Cochrane Injuries Group. Human albumin administration in the critically ill patients: systemic review of randomized controlled trials: Why albumin may not work. BMJ 1998; 317: 235-40. 4. Karnovesky M. J. The ultra structural basis of capillary permeability studied with peroxidase as a tracer. J Cell Biol 1967; 35: 213–236. 5. Hendry E. B. The osmotic pressure and chemical composition of human body fluids. Clinical Chemistry 1962; 8(3): 246–265. 6. Rhodin J. A. The ultra structure of mammalian arterioles and precapillary sphincters. J Ultrastructure Research 1967; 18:181–222. 7. Renkin E. M. Some consequences of capillary permeability to macromolecules: Starling’s hypothesis reconsidered. Am J Physiol (Heart Circ Physiol) 1986; 250, 19: H706–H710. 8. Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratory distress in adults. Lancet 1967; ii: 319-23. 9. Ghanem A. N., Ward J. P. Osmotic and metabolic sequelae of volumetric overload in relation to the TURP syndrome. Br J Urol 1990; 66: 71–78. 10. Starling E. H. Factors involved in the causation of dropsy. Lancet 1886; ii: 1266–1270, 1330–1334 and 1406–1410. 11. Ghanem AN. Hypoalbuminaemic hyponatraemia: a new syndrome? BMJ 1985; 291: 1502 12. Ghanem AN. Magnetic field-like fluid circulation of a porous orifice tube and relevance to the capillary-interstitial fluid circulation: Preliminary report. Medical Hypotheses 2001 Mar; 56 (3): 325- 334. 2001 Mar; 56(3):325-34. 13. Lessels AM, Honan RP, Haboubi NY, Ali HH and Greene MJ. Death during prostatectomy. J Clin Path 1982; 35: 117. 14. Please see the other letter to Editor on the editorial2 Appendix: The scientific basis of fluid resuscitation in shock: Why Starling law is wrong. On the physiological issues; the direct positive relationship of fluid volume and pressure, the work of Poiseuilli on flow and pressure exerted on the wall of strait uniform tubes, as well as the albumin oncotic pressure, were all imported by Starling10 in 1896 direct from physics to medicine at Lancet without any physiological verification or testing what so ever! Modern clinical chemistry allowed verification of albumin oncotic pressure by Hendry5 in 1962. The real ultra structure of the capillary wall revealed by Karnovesky4 and the pre-capillary sphincter revealed by Rhodin6 were reported in 1967. Thus, all physiological research done before 1962 that advocated Starling’s hypothesis and promoted it into law is invalid. Based on the consequences of capillary permeability to macromolecules, Renkin6 advocated reconsideration of Starling’s hypothesis in 1986. What alternative was there then? There was none. Only an idea in mind derived from clinical observation on the use of fluids in resuscitation of shock, trauma and the TUR syndrome was communicated and reported at BMJ11 in 1985. The direct proportional relationship of fluid volume to pressure, works in the vascular system up to a limit only. This is true in physics too, if fluid too much is pushed into a reservoir above its capacity, it will burst and the volume-pressure relationship vanishes. Thus, perhaps volume replacement in shock should not exceed the maximum capacitance of vascular system of 7 litres in adult. Considering that blood loss is fatal when about half the vascular volume is lost, a replacement should not exceed the lost volume after control of bleeding. After any overzealous vascular volume expansion, the excess must leak out into and drown the interstitial space! The most deleterious effect of such internal drowning is on the vital organs. Both vital organ signs8,9 and post-mortem findings13 demonstrate the massive volume of retained fluids. This letter to Editor13 is the only documented evidence in literature that reported the massive retained fluid volume with swollen vital organs at post mortem examination! The only article that reported retained fluid volume was the first report on ARDS by Ashbaugh et al8. Albumen oncotic pressure, no doubt, exists in vitro across membrane impermeable to its molecules. Even, in such physics experiments, oncotic pressure is too weak and too slow a force to be effectively and solely responsible for fluid return into capillary lumen. It has cell building nutritional value. However, the evidence that oncotic pressure works in vivo is non-existing6. The only difference between albumen and saline fluids in SAFE trials is the added albumin presumed to have oncotic pressure, a function of its molecule size in relation to pore size or permeability of membrane. The pores of normal capillary wall became known 7 decades after Starling and shown to allow horse radish, a much larger molecule than albumin, to pass freely4. As the result of this trial1 demonstrated that both SAFE fluids have similar outcome, this further re- affirms that albumen oncotic pressure in clinical medicine1, clinical chemistry5 and modern physiology4 is fallacy (VIVO), simply because albumen molecules pass freely across the large pores of normal capillary membrane4. This may answer the BMJ slogan: Why albumin may not work. So, irrespective whether albumin has equal or worse outcome, the fact that it did not show clear superiority to saline in SAFE trials is affirmative evidence that albumen oncotic pressure is fallacy in VIVO. Such fallacy has also been long proved in biochemical5 and physiological research4,6. Oncotic pressure is the presumed main absorption force in capillary- interstitial fluid transfer, and represents one half of the equation of Starling’s law10. Thus as it has proved wrong, the law must be wrong! This was the reason for repeated calls to reconsider Starling’s hypothesis6,9. However, there was no existing alternative then- only an idea in mind communicated at BMJ11 in 1985. This was later verified and reported, the clinical work9 in 1990 and physics work12 in 2001. Verifying the other half of Starling law equation concerning capillary arterial pressure as the filtration force was my objective. Does the capillary have positive pressure on its wall pushing fluid out? Does the flow pressure akin toi arterial pressure cause filtration? Does the capillary tube act like Poiseuille’ strait uniform tube and have positive pressure on its wall that pushes fluid out through pores? The ultra structure of capillary wall4 and pre-capillary sphincter5 were discovered 70 years after Starling reported his hypothesis. The capillary proved a porous orifice tube. I made several porous tubes fitted with narrow orifice mimicking the capillary with a pre=capillary sphincter on a larger scale to verify this. These porous orifice tubes were used to study hydrodynamic flow and pressure and compared to Poiseuille’s tube, particularly in relation to the pressure exerted on its wall. The porous orifice tube dynamics proves totally different to Poiseuille’s tube. There was no positive pressure exerted on the wall and no fluid filtered out over the proximal half of the porous orifice tube. The flow pressure representing arterial pressure is not responsible for filtration! It caused mainly suction at the proximal half of the tube. Thus the main force in the equation on Starling’s law concerning arterial capillary pressure filtration is also wrong. How does it work? What pushes the fluid out and what returns it in? Does it offer a complete hypothesis to explain the capillary- interstitial fluid exchange? How does it relate to physiology and medicine? To know the answer to the questions on a most fascinating phenomenon, please read the article12. So, the law dictating the scientific basis that underlies physician’s thought on vascular volume expansion at resuscitation of shock, trauma and acutely ill patients is wrong on all accounts. The most harmful part of this erroneous law, is in fact, that concerning arterial pressure, presumed to be the main filtration force in the capillary. This is the part that Starling thought acted like Poiseuille’s strait uniform tube, exerting positive pressure on the wall that filters fluid out. This, I believe, underlies physician thought when embarking on overzealous fluid infusion during the resuscitation of shock. He was taught that volume expansion has direct positive unlimited relationship with pressure. It is the only way he knows off to improve capillary circulation. Well, it does not. Volume replacement is effective when an actual blood volume loss is restored to normal that is less than maximum capacity of the vascular system. After that the relation of volume to pressure is reversed. Any excess volume, vascular expansion or hypervolaemia of VO/T induces hypotension shock just like hypovolaemia does! Considering the concept of VO/T by reporting volume of fluids in future SAFE trials and verifying the scientific basis of fluid resuscitation in shock are needed for resolving the puzzle of MOVD/F and improving outcome of patients on ICU. (References are the same on the above letter) Competing interests: None declared
Albumin has its place 13 December 2006
Gail SM Masterton, SHO 3 Gastroenterology Hairmyres Hospital, Stewart Campbell Send response to journal: Re: Albumin has its place	Dear Editor, We read with interest the recent article by the SAFE investigators (1). This article and the “banner headline” on the cover of the BMJ, when taken together with the Cochrane review published in the BMJ in 1998 (2), with its accompanying wave of publicity both in the medical and lay press, will no doubt increase the difficulties for clinicians attempting to justify the use of albumin based products in UK hospitals. The accompanying editorial (3) stressed that the findings may not be applicable to certain subgroups. Neither the Cochrane review nor the SAFE study have addressed the role of albumin in patients with chronic liver disease, in whom there is an increasing body of evidence to support the efficacy of intravenous albumin, particularly in the treatment of spontaneous bacterial peritonitis (4) where it has been incorporated into consensus guidelines (5). We feel it is important to stress that the findings of the SAFE study do not justify the removal of the availability of intravenous albumin for liver disease patients. Clinicians should remember that “the devil is in the detail” rather than just considering the banner headline. Gail SM Masterton SHO III in Gastroenterology Stewart Campbell, Consultant Gastroenterologist Hairmyres Hospital, Eaglesham Road, East Kilbride, Scotland No conflicting interests References: 1. SAFE Study Investigators. Effect of baseline serum albumin concentration on outcome of resuscitation with albumin or saline in patients in intensive care units: analysis of data from the saline versus albumin fluid evaluation (SAFE) study. BMJ 2006;333:1044 2. Cochrane Injuries Group. Human albumin administration in the critically ill patients: systemic review of randomized controlled trials: Why albumin may not work. BMJ 1998; 317: 235-40. 3. Vincent JL. Editorial. Resuscitation using albumin in critically ill patients: Research in patients at high risk of complications is now needed. BMJ; 333:1029-30. 4. Sort P, Navasa M, Arroyo V, et al. Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. N Engl J Med 1999; 341: 403–9 5. Runyon B. AASLD Practice Guideline. Management of adult patients with ascites due to cirrhosis. http://www.aasld.org/eweb/docs/practiceguidelines/ascites.pdf Competing interests: None declared