How to cite this article:Ahmed N G, Salma A G, Khalid A G, Nisha P, Yasmina S E. Illusive Dynamic Nadirs and Masks of Postoperative Hyponatraemia
and the TURP Syndrome: Volumetric overload over time (VO/T) concept for resolving its puzzle. JOJ uro & nephron. 2019; 6(4): 555691.
Introduction and objective: Postoperative hyponatraemia (HN) cause serious morbidity and mortality, of which the transurethral resection of the prostate (TURP) syndrome is a unique model. Clinical presentation is circulatory shock and multiple vital organ dysfunction/ failure (MVOD/F) or death. All severe cases were reported retrospectively and attributed to multiple toxic/ dilution hypotheses interchangeably with recognized clinical conditions. The overlooked VO/T causes dynamic HN nadirs and masks making it a complex clinical and biochemical jigsaw puzzle. The objective here is to resolve this puzzle.
Patients and methods: Investigations based on clinical observations, critical literature analysis, physics-physiological and clinical prospective studies done over the past 32 years. Observations and deductive analysis identified volumetric overload over time (VO/T) insult, HN nadirs, clinical paradoxical masks of shock and MVOD/F. Prospective studies verified and quantified VO/T insult causing secondary, tertiary HN nadirs and osmotic gaps. Severity depends on VO/T and fluid type of sodium-free (VO1) and sodium-based (VO2) fluids.
Results: “VO/T” causes the biochemical and clinical features of HN and the TURP syndrome. Dilution HN “shock” and “VO” concepts were reported but VO insult remained invisible. The puzzle was resolved after unraveling the dynamic role of T in HN nadirs. 3.5L of VO1 infused in 1h causes HN shock and MVOD/F syndrome. The immediate postoperative secondary HN nadir is proportional to VO1 and clinical severity but shock mask is confused with haemorrhage or sepsis shocks. The late tertiary HN nadir is disproportional to both as osmotic fluid shift fluid into cells “Missing VO”. Cell oedema and necrosis confuses VO1 with cerebral or cardiac infarction. Inappropriate therapeutic response with “aggressive vascular expansion” erases HN, makes shock irreversible and establishes MVOD/F.
Conclusion: The concept of “VO/T’ insult explains the aetiology of HN and the TURP syndrome and pathophysiology of HN nadirs unveiling its paradoxical presentation masks and refuting dilutional and toxic hypotheses. It exposes the biochemical, clinical and therapeutic illusions, resolving HN puzzle and has paved the way to identify “VO shocks”, “optimize” fluid therapy and precise life-saving hypertonic sodium therapy. The new capillary-interstitial hypothesis based on G tube dynamic makes resolving MVOD/F and ARDS puzzle neither difficult nor distant.
Keywords: Hyponatraemia; The transurethral resection of the prostate (TURP) syndrome; The adult respiratory distress syndrome (ARDS); The multiple vital organ dysfunction/failure (MVOD/F) syndrome; Volumetric overload shocks (VOS); Hypertonic sodium therapy
Abbreviations: HN: Hyponatraemia; TURP: The Trans-urethral Resection of the Prostate Syndrome; HST: Hypertonic Sodium Therapy; VO: Volumetric Overload; VOS1: VO Shock of Sodium-Free fluids or ‘Type1’; VOS2: VO Shock of sodium-based fluids or ‘Type2’; T: Time; MVOD/F: The Multiple Vital Organ Dysfunction/ Failure syndrome; SSC: Serum Sodium Concentration; IVI: Intravenously Infused Fluids; ARF: Acute Renal Failure; ECF: Extra-Cellular Fluid Compartment; IVF: Intra-Vascular Fluid Compartment; ICF: Intracellular Fluid Compartment; ECF: Extra-Cellular Fluid; BW: Body Weight (BW) Percent BW; H: Hour (h) L: Litre; SC: Symptomatic Cases; NSC: None Symptomatic Cases; A, B, C, D Times Refer to Hospital Admission, Preoperative, immediate 1h and 24h Postoperative, respectively; CVP: Central Venous Pressure
This report concerns hospital-induced hyponatraemia (HN)
particularly the postoperative of which that complicating the
transurethral resection of the prostate (TURP) is well known
syndrome. Of historical interest, in 1913, Rowan tree ,
reported acute water intoxication. In 1946, Danawiski et al. ,
reported HN shock and its hypertonic sodium therapy (HST) in
dogs. In 1948, Creevy  reported post TURP reaction induced
by the absorption of water irrigant causing haemolysis. Since the
introduction of osmotic electrolyte-free irrigant, haemolysis has
no longer been seen in clinical practice. In 1956, Harrison et al.
, first reported the TURP syndrome as dilutional HN shock
and the successful use of HST.
The absorption of 1.5%Glycine irrigant is well known to
induce the TURP syndrome but was not quantified and rarely
reported. All cases of hospital postoperative HN are likewise
induced by a sodium-free fluid such as 5%Glucose but rarely
incriminated. In 1987, Arieff  reported a unique article,
alluding to 8 liters of gained 5% Dextrose. In 1990, Ghanem
and Ward , identified and quantified the precise volumetric
overload (VO), contributed by both irrigant absorption and
intravenously infused (ivi) fluids, as the real insult. The
concept of VO was unimaginable cause of shock previously as it
contradicted received concepts based on faulty physiological law
that dictates the rules on fluid therapy. New reported discovery
of hydrodynamic phenomenon of porous orifice (G) tube
addressed this issue with reference to capillary and circulatory
haemodynamic under physiological and pathological conditions
Hyponatraemia is the most common biochemical
abnormality in clinical practice causing serious morbidity and
mortality among men [4,6,8], women [5,9,10] and children
[11,12]. ‘The incidence of postoperative HN is about 1%, or
250,000 cases among the roughly 25 million inpatient operations
that are performed each year, in USA . It is of great surgical
and medical interest that causes much international concern
and anxiety. It lacks a definition. pathos-physiological etiology
is unknown, therapy is disputed, and prognosis is poor [8-12].
The diagnosis is extremely difficult and differential diagnosis
is enormous. It is huge biochemical and clinical jigsaw puzzle
with false and missing pieces. Resolving such puzzle required
identification of causative insult and factors making it illusive.
It is of note that severe to lethal cases of HN [5,8-12] and
TURP syndrome [4,6,13] were reported retrospectively. Serum
sodium concentration (SSC) measurement introduced into
clinical practice after World War II  coinciding with the
wide clinical use of ivi fluid therapy [15,16]. HN became a
clinical diagnosis soon later . It is <70 years old. During this
period few studies have added key issues, hundreds of authors
contributed most puzzle pieces while thousands of prospective
studies repeatedly added little but fueling the debates.
In order to understand the disease and resolve debates
on patho-physiology and management much more than
analyzing hundreds prospective studies and doing some was
required. Critical literature review, deductive analysis and
drawing analogy kept the main picture in focus while fitting
correct pieces and identifying the stepping-stones. The false
and missing pieces had to be segregated then rejected and
discovered, respectively. Clinical observations identified the
insult and its paradoxes, illusive nadirs and presentation masks,
before precise quantification using prospective clinical  and
scientific physics studies .
The TURP syndrome is generally thought ‘well known, rare,
obscure and limited to urology’ but it was foreseen as unique
model for resolving its own puzzle and that of postoperative
HN. The bottom line for understanding the condition concerns:
how much volume, of what type and during what time a fluid
gained access into vascular system, and what is immediate
haemodynamic effects and delayed clinical masks? The TURP
syndrome is unique because all quantifiable VO occurs during
surgery of less than one hour (1h) [6,13].
The stepping-stones of ‘shock, HST [2,4] and anoxia ’ led
through the difficulties to new understanding of “VO” as the real
causative insult, were reported [4,6] years ago. However, the
puzzle has not been resolved yet. Multiple 21 dilutional and toxic
hypotheses  used interchangeably, and in combinations
with recognized clinical conditions [5,8-12], for pathological
explanation  testify that HN has remained illusive. The concept
of shock [2,4] was affirmed not to be due to any of the unduly
incriminated haemorrhage [18,19] or sepsis  shock. Vascular
shock and acute renal failure (ARF) were observed paradoxical
effects of VO and the analogy with MVOD/F was reported .
MVOD/F was originally reported as adult respiratory distress
syndrome (ARDS) . Other authors  affirmed our data
on incidence, quantity of absorbed irrigant and blood loss in
the absence of sepsis, hypothermia and hypoxaemia. However,
the concept of “VO/T” has remained invisible so has the debateresolving
new advances on the subjects [6,7].
The role of VO and its type of sodium-free (VO1) and sodiumbased
fluid (VO2) in inducing the secondary and tertiary HN
nadirs and illusive clinical masks, taking time (T) into account,
was a scientific challenge that took years to unravel. Presenting
with paradoxical hypotension shock and ARF to surgeons and
encephalopathy coma [5,8-12] to physicians are a few among
many bizarre illusive clinical masks of HN, based on which
analogy to MVOD/F was made . The objective of this report is
resolving the puzzle of HN and TURP syndrome, highlighting the
invisible “VO/T” insult and identifying dynamic HN nadirs and
its illusive clinical paradoxes and presentation masks that may
also help to resolve the puzzle of MVOD/F or ARDS.
Investigations included clinical observations, critical
literature review with deductive analysis plus physics and clinical
prospective studies done over the past 33 years. The majority of
puzzle pieces contributed by many authors and stepping-stones
that led to new understanding were gathered and aptly fitted,
segregating false and missing pieces for rejection and discovery.
Clinical observations, analysis and drawing analogy identified
the real insult and factors causing paradoxes, nadirs and masks
Prospective clinical study quantified the “VO” insult, its
biochemical and clinical effects but it took years to unravel the
dynamic role of T causing HN to be so illusive. Physics studies
discovered a hydrodynamic phenomenon that challenges the
law on capillary-ISF transfer. The studies were continuous
process of going back and forth between mentioned methods,
using appropriate statistics tools and mathematics to achieve the
objective imposed by the scientific challenge. The data is based
on MD Theses accepted at the Institute of Urology, Mansoura
University, Egypt, 1988. Overlapping with previous reports is
minimal unavoidable necessity for clear understanding required
for resolving the puzzle of HN and the TURP syndrome.
The most important clinical observations were: First,
accepting that shock and annuria are real clinical features of VO
though paradoxical to received concepts. Second, despite giving
the standard shock therapy of ‘aggressive vascular expansion’,
using VO2 fluids that elevated SSC and corrected HN, the vascular
shock persisted becoming irreversible with full blown picture
of MVOD/F” or death! Third, the received concept of elevating
central venous (CVP) pressure to a level of 18 cm water or higher
during the management of hypotension shock is inconsistent
with its normal value of around 0 with a range of -7 to +7 cm
water. Fourth, if arterial blood pressure is truly responsible
for capillary-ISF filtration, as the current law indicates, why is
oedema never seen clinically to complicate the most common
arterial hypertension, and why does massive extra-vascular
fluid shift occur during shock therapy despite hypotension? This
is of vital relevance to the observed shock and anuria of “VO/T”
insult, causing cell oedema and MVOD/F.
HN nadir is the lowest drop of SSC induced by a given sodiumfree
VO1. A single bolus of VO1 induces a dynamic dilutional HN
nadir that depends on the diluted body fluid compartment and T,
inducing 3 different values: the primary, secondary and tertiary.
The primary HN nadir refers to a situation when all gained
VO1 dilutes IVF only. VO1 infusion done and SSC measured
within minutes makes it is so rapidly transient and practically
impossible to detect with massive VO to be of any practical
clinical significance. The secondary HN nadir is that occurring in
the immediate postoperative period that defines HN of the TURP
syndrome. It occurs when all gained VO1 pervades extra-cellular
fluid (ECF), causing the lowest SSC, measured within <2h of VO.
The tertiary HN nadir is the most frequently detected drop of SSC
at 24h or later that also reflects ECF dilution. Being T dependent,
it is most dynamic and illusive, revealing only part of the gained
VO1, after osmotic fluid shift into cells or intracellular fluid
(ICF). The interaction of factors inducing and defining dynamic
HN nadirs and illusive clinical masks are presented.
Data of prospectively studied 100 TURP patients showed
direct proportional relationship of VO1 to the immediate
postoperative drop of SSC (Figure 1). VO was the most significant
factor to clinical signs (P=0.0007). Summary of VO according
to fluid type is shown in (Figure 2). Hypo-osmolality was less significant (p=0.0212) and HN was not (p=0.0597), the latter
became significant only after removing VO from the multiple
regression analysis. Mean VO of symptomatic cases was 3.5l,
of which one liter was saline and 2.5l were VO1 fluids, 0.5l was
5% Dextrose and 2l was 1.5% Glycine gained during the TURP
surgery of 1h duration.
Figure 3 demonstrates the diluted serum solute contents
shown as % of normal preoperative value at the immediate
postoperative period (C). It demonstrates diluted serum
contents are common affecting symptomatic cases (SC) of 10%
of patients and none symptomatic (NSC) cases. Secondary HN
nadir is not only proportional to VO1 but also clinical severity
at C time. It is of note that the drop of hemoglobin and albumin
is dilutional, not due to blood loss. Precise blood loss was
measured, and sepsis was excluded by negative urine and blood
cultures in our prospective study. All diluted serum solutes were
unduly incriminated in dilutional hypotheses while VO1 has
remained invisible. The rise of SSC elevating HN nadir at 24h
is either physiological due to urine and insensible water loss
or pathological due to osmotic fluid shift into cells. Hence, the
tertiary HN nadir may be misleading at D time as it does not
reflect the real massive VO1, making HN appear disproportional
to the clinical severity. The real VO1 and clinical severity remain
to match the earlier secondary HN at C.
Figure 4 demonstrate the rise of serum glycine, reflecting
VO1 of the absorbed 1.5% Glycine gained per-operatively. The
rise of serum Glycine at C returned spontaneously to normal
within 24h at D time without any specific therapy. All serum
solute changes whether drop or rise seemed to move towards
normal at 24h but it is difficult to tell whether such dynamic
change is physiological or pathological correction.
The rise of renal and hepatic function tests, and white cell
count, affecting only SC occurred most prominently at D, reversing
the initial dilutional drop affecting all patients at C. The rise of
SSC from secondary to tertiary HN nadir is thus pathological in
the presence of annuria of ARF. Glycine rise (Figure 4) and its
metabolites of ammonia and oxalates were incriminated as toxic
causes of TURP syndrome. Ammonia may be detected only when
hepatic dysfunction becomes failure as part of MVOD/F at D.
Cardiac, cerebral, renal, hepatic and respiratory dysfunction or failure has its own clinical methods of detection. Figure 5 shows
the serum solutes changes at D. Note the rise in renal and liver
function tests and WBC. Figure 6 correlates the drop in SSC and
rise in serum glycine to the volume of Glycine absorbed.
The most important factors affecting dynamic HN nadirs and
its clinical masks are observed. Each litre of VO1 causes a drop of
7 mmol/l in SSC causing HN nadir at C (Figure 1). The secondary
HN nadir at C is based on mean SSC. The tertiary HN nadir at D
and the “Missing VO” that shifted into ICF during the adaptation
period are observed. The matching clinical severity is segregated
into haemodynamic disturbance, MVOD/F of cardiac, cerebral
and respiratory organs, and renal response. Any additional
VO2 fluids may erase HN nadirs but worsen VO and establishes
MVOD/F. A secondary HN nadir that becomes a tertiary one after
24h, neither reflects the real VO1 nor correlates with clinical
severity. The dynamic effect of T is now considered.
Not only VO1 (quantity and type) but also T is important
for defining HN nadirs. VO1 gained in 1h (the induction period)
induces the secondary HN nadir that accurately represents both
the drop of SSC diluting ECF Figures 1,5 and correlates with
clinical severity, However, the precise dynamic relationship of
VO to clinical severity is T dependent, more specifically severity
is dependent on the induction and adaptation periods of VO.
The importance of the induction period of T lies in the fact
that when a given VO1 such as 3.5l (5%BW) is infused to an adult
in 1h it is pathological and may be lethal. However, when given
over a period of 24h it is about normal daily fluid intake. HN is
thus inversely proportional to T of the induction period.
When VO quantity and induction period remain constant,
fluid type affects the severity of VO toxicity. The same VO of
3.5l (5% BW ivi in 1h) of distilled water is probably lethal, of
1.5%Glycine is critical, of 5%Glucose is serious, of 3% Mannitol is
severe and of VO2 is perhaps of moderate severity. The evidence
here is essentially based on common sense clinical observations
as was derived from multiple reported studies on ivi fluids in
animals that match NH nadirs and clinical severity of the TURP
The above data demonstrates that “VO/T” is the insult
causing the biochemical and clinical severity of secondary HN
nadir at the immediate postoperative T. The most illusive effect
of “VO /T” continues to operate invisibly during the tertiary HN
The tertiary HN nadir is the most commonly measured drop
of SSC postoperatively at 24h or later, typically at the morning
after surgery (D). It is so dynamic that it misleadingly leads to
multiple interpretations and conclusions. It may represent a
spontaneous physiological rise of a previous secondary HN nadir
if the renal function is maintained and insensible loss is taken
into account. This is seen with VO1 of <2L when renal function
allows dieresis. However, anuria of ARF is common with large
VO1, during which rise of SSC also occurs due to osmotic fluid
shift into ICF causing cell oedema of MVOD/F. The severity of
MVOD/F is disproportional to the apparently mild HN nadir of
rising SSC. The adaptation period of T is an overlooked factor
causing tertiary HN with diagnosis of illusive clinical masks.
The apparent rise of SSC occurring over 24-48h after massive
VO1 and anuria is pathological due to internal osmotic water
shift from ECF into ICF. The fluid that moves and lodges inside
cells is the “Missing VO”, which is mathematically and clinically
in excess of 2/3 of gained VO1. During the adaptation period
of T, not only the “Missing” part of VO1 goes into cells but also
fluids flooding ECF shift into the potential body cavities of pleura
and peritoneum, evident at postmortem examination, due to the
limited vascular system capacitance.
Furthermore, the elapsed adaptation period of T allows
various interpretation of tertiary HN. Unawareness of a previous
SSC drop confuses the secondary with tertiary HN nadir and
overlooks the “Missing VO”. The spontaneous rises of SSC make
the tertiary HN appears of lesser magnitude or insignificant
as SSC may revert to normal or above normal, particularly
with saline infusion, giving a false sense of improvement. It is
impossible to tell if the rise of SSC is physiological improvement
due to urine excretion and insensible loss or pathological due to
the osmotic water shift into ICF and VO2 fluid infusions. Anuria
is evident clinically, but pitting is not a feature of cellular edema
to reflect osmotic fluid shift into ICF.
The tertiary HN nadir neither represents all gained VO1 nor
reflects the severity of its clinical features. The latter remain to
match the earlier secondary HN nadir and its VO1. The part of
VO1 that remains in ECF causing the tertiary HN is about 1/3
of the real total VO1. The remaining 2/3 is the “Missing VO1”
causing cellular oedema and MVOD/F. A massive VO1 of 3.5l/h
causing secondary HN nadir of 107 mmol/l . It presents with
paradoxical vascular hemodynamic shock and anuria of ARF that
has a tertiary nadir of 126 mmol/l at 24h when MVOD/F is of
critical severity. In the absence of an accurate per-operative fluid
balance chart, only the increase in body weight (BW) can reveal
the real total VO insult, its “Missing VO” part and any excess VO2
fluids in ECF and potential body cavities.
In addition to “VO/T”, there are other factors that affect the
tertiary HN, contributing to biochemical, clinical and therapeutic
conspiracy of confusion and illusion. Saline or any ivi VO2 fluids,
may erase remaining evidence on HN and totally mask the real
There are two osmolality gaps corresponding to the
secondary and tertiary HN: the initial hypo-osmotic and late
hyper-osmotic gaps, respectively (Figure 7). Being dependent on
SSC, the gap of VO1 of metabolizable glucose and glycine is hypoosmolality
but isotonic 3%Mannitol induces iso-osmolality
HN. Likewise, the tertiary HN being dependent on SSC, T and
therapy, late gap is dynamic and elusive. It may be hypo-, iso
or hyper- osmolality gap. The latter gap occurs in established
MVOD/F cases, has poor prognostic value and is shown in Figure
7. The late osmolality gap may rebound to hyper-osmolality with
inappropriate therapy in patients with established MVOD/F.
The presented evidence demonstrates that “VO/T” is the
invisible insult causing all serum solute changes and grades,
nadirs, paradoxes and masks of HN and TURP syndrome.
Biochemical, clinical and therapeutic illusions have caused
misinterpretation of data and the multidimensional puzzle.
Neither bleeding, sepsis, chemical toxins, hypothermia,
vascular obstruction nor hypoxaemia play a primary role in
pathophysiology of HN and the TURP syndrome . The clinical
features from prodromal symptoms to severe signs and sudden
death though it presents with masks of recognized conditions,
have a different patho-aetiology.
The observed analogy with MVOD/F and severity grade
of HN is evident from presented data and analyzed literature
reports. Hypotension shock and combination of MVOD/F is the
main illusive presentation at a surgical setting . Vascular
shock is documented though usually incorrectly attributed to
haemorrhage [18,19] or sepsis  because the paradoxical
shock of “VO/T” was previously inconceivable. Heart failure,
infarction or arrest and sudden death [22-24], and respiratory
distress or pulmonary oedema [25,26] may cause a dilemma of
diagnosis during or immediately after surgery. Those aware of
the TURP syndrome consider dilutional and toxic hypotheses
, while sudden death is attributed to recognized medical
conditions, such as myocardial cerebral infarctions, each of which
is an acceptable cause of death for different pathological causes.
The real cause may be overlooked at postmortem examination
unless the pathologist is fully aware of the condition .
Respiratory distress and pulmonary oedema have also been
Encephalopathy coma of postoperative [4-6,10,27-32] and
medical [8,9,11,12,33-36] HN cases is common presentation
to physicians, which with convulsions and paralysis indicate
cerebral oedema and infarction. The real culprit of VO1 insult,
being invisible, was unmentioned in all but one retrospective 
and prospective  report. Of noteworthy, HN coma complicates
any surgery and is not limited to TURP. The predisposing factors
and route of VO1 gain, through prostate or peripheral vein
or peritoneum is of minor significance to patho-etiology but
relevant to prevention of irrigant absorption. Other electrolyte
changes [33,34], renal  and hepatic dysfunctions [36,37],
coagulopathies [38,39] and gastro-intestinal disorders may
occur. Combinations are common but one or two MVOD/F may
prevail. Figure 4 demonstrates the abnormal renal and hepatic
function tests at D time as part of MVOD/F.
With such bizarre features and wide range of severity, the
masks of clinical presentations of HN and TURP syndrome are
many. The differential diagnosis is enormous and extremely
hard. Prodromal symptoms may be attributed to hypothermia
 or to anesthesia, drugs and glycine toxicity  while severe
cases may be mistaken for known medical conditions of shock or
cerebral and cardiac failure or infarction, respiratory, renal or
hepatic failure [22-37]. This adds to the dilemma of dilutional
and toxic hypotheses of TURP syndrome . Postmortem
examination may show oedema and necrosis of brain or heart
that may be overlooked being mistaken for arterial occlusion but
organ necrosis of VO1 occurs in absence of arterial ischaemia
and hypoxaemia. The cause of death is missed unless VO1 is
proved by low SSC in the vitreous body sample taken from the
eye . Verifying cerebral and coronary arteries for obstructive
atheroma or clots should be done.
Clinically, the condition has the same haemodynamic
disturbance of haemorrhage or septic shock, but hypovolaemia
is not synonymous with hypotension. It mimics MVOD/F of any single vital organ, but the insult is generalized due to shock and
cell oedema or necrosis (infarction) of VO1. The elevated renal
and hepatic function tests and leucocytosis figure 4 occurring
during the adaptation period of T, at 24h or later are effects of
VO. Brain, heart and lungs having special grading and assessment
methods are grouped as MVOD/F. In severe cases of VO1, annuria
of ARF is resistant to loop diuretics of up to the triple normal
dose and VO2 therapy worsens VO. Biochemical and clinical
severity of the tertiary HN nadir being disproportional cause
misdiagnosis and therapeutic illusion.
The fundamental difference between surgical and medical
presentations is the therapeutic response it evokes. Presenting
with profound vascular hypotension shock in theatre or recovery
room at the time of secondary HN nadir contradicts preconceived
concepts on shock and fluid therapy. “Aggressive vascular
expansion” executed frantically and indiscriminately in falsebelief
that haemorrhage, hypovolaemia or sepsis is at operation.
The misguided attempt of massive VO2 infusion erases HN,
makes shock irreversible, worsens VO and establishes MVOD/F.
Other authors affirmed our clinical observations on prodromal
to severe manifestations of HN of VO1 but unfortunately was
attributed to hypothermia  or glycine toxicity [9,41]. The
same manifestations, however, have been reported with glucose
and mannitol fluids in the absence of hypothermia, glycine and
ammonia toxicity .
Capacitance of the cardiovascular system is limited to
7l and CVP is around 0 (+7 to -7) cm water . Aggressive
vascular expansion exceeding these limits, even during genuine
hypovolaemia or sepsis shock therapy, spills over excess fluids to
ISF whether it corrects arterial hypotension or not. The osmotic
pressure of plasma proteins thought to be the force to return
fluid back into IVF does not exist . The capillaries have
pores that allow easy passage of protein molecules. Guyton and
Coleman  elegant subcutaneous chamber demonstrated this
and proved that ISF pressure is -7cm water. Increased venous
pressure is well known common cause of oedema but high
arterial pressure has no such effect. This should evoke thoughts
about Starling’s law and received concepts on fluid therapy.
The newly reported hydrodynamic phenomenon of the narrow
orifice (G) tube  demonstrated its significance to capillary
and vascular haemodynamic under both physiological and
pathological conditions. VO causes hypotension shock indicating
that acute vascular volumetric changes of hyper- or hypovelamina
cause shock at capillary-ISF level, causing cell anoxia
 despite full oxygen saturation of arterial blood.
Presenting to physicians later with encephalopathy coma,
at the time of tertiary HN nadir, is an illusion too. Most gained
VO1 has already gone missing from IVF and ECF into cells, hence
rarely reported. The recommended therapy in such situation
has been conservative with fluid restriction, loop diuretics
and cardio-respiratory supportive measures while HST was
thought contraindicated. For elevating SSC, ether isotonic saline
or plasma VO2 fluids was liberally used , or HST of low
concentration was slowly infused . This is contradictory to
fluid restriction. Despite debating this view when the available
evidence was observations or anecdotal cases and recently
reporting hard evidence [6,7], the general view on therapy of HN
remains unchanged [5,8,10-12], save a welcome recent report by
World authorities on HN .
Irrigant absorption is well known to induced HN of TURP
syndrome, attributed to multiple dilutional HN [4-13,22-41],
hypo-osmolality [6,44-50], low albumin [33,49] and calcium
 or toxic hypotheses (ammonia, glycine, serum K+ and acid
phosphatase). Hemoglobin (Hb) dilution was always thought
due to haemorrhage in treating shock. All serum changes
used, interchangeably and in combinations with mentioned
medical conditions, for explaining the pathophysiology of TURP
syndrome and its bizarre clinical presentation masks.
The long-standing dispute between hypo-osmolality and
HN [43-49] as causes of severe symptoms is based on the
observation that marked hyponatraemia may occur without
severe matching signs. This may be resolved on understanding
of the presented data on tertiary HN nadirs and osmolality gaps.
Figures (1-4) demonstrate the bases of most dilutional and toxic
hypotheses. The “VO/T” insult is so obvious that is invisible.
All previous studies neither quantified irrigant absorption nor
considered ivi fluids.
Correlating data on VO1 induced by both the absorbed irrigant
and ivi fluids to the signs of HN of the TURP syndrome makes its
bizarre features easier to understand, detect and explain. The
above results demonstrate that both hypo-osmolality and HN of
VO1 occur with glycine and dextrose fluids being metabilazable
[6,44-50] but mannitol causes HN without hypo-osmolality .
Hence mannitol appears less toxic than glucose or glycine and HN
may be disproportional to signs . Hypo-osmolality is short
lived and may be undetectable . Both VO2 and/or cellulysis
with liberation of cell osmols may revert serum osmolality to
normal or above normal, causing late osmolality gap reported
in MVOD/F patients with poor prognosis . Patients may
have iso-, hyper- or hypo-osmolality at any time. The late hyperosmolality
gap is a rebound of the initial hypo-osmolality gap. It
has great therapeutic potential in preventing occurrence of late
gap, if HST is timely and rapidly given. Likewise, HN has a longer
T scale. Hence both hypo-osmolality and HN of VO1 play vital
but transient secondary role in pathophysiology, lasting hours
and days, respectively - when remained unclouded by VO2
It has been demonstrated that ivi of one litre of 1.5% Glycine
or 5% Dextrose, gained in 1h, caused a drop-in serum sodium of 7 mmol/l and induced prodromal symptoms in healthy volunteers
. The lowest reported serum sodium level compatible with
life was 98 mmol/l occurring with 3% Mannitol  and 101
mmol/l with 1.5% Glycine [22-30]. The corresponding lethal
dose of pure VO1 is 5.6l. The mean VO1 for HN of <120 mmol/l of
middle severity range was 3.5l (5%BW), including 1l of ivi VO2
fluids . These data are the bases of using HN nadirs and mean
SSC drop, respectively, in relation to subjective clinical severity
Figure 1 shows that 10-14 mmol/l drop of SSC indicates VO1
of <2l that may or may not be self-correctable. A drop of 15-20
mmol/l indicates VO1 of 2.5L. An extra ivi one litre of VO2 fluid
brings the total VO mean to 3.5L (5%BW) causing severe signs.
An adult patient may accommodate an extra 1-2L of VO2 fluids
but recovery from MVOD/F is the exception. A combination of
VO1 and VO2 of up to 10% BW or larger volume of pure VO2 is
common after major surgery and trauma resuscitation [17,35].
Massive VO2 induces critical MVOD/F that may not be lethal but
is rarely reported or incriminated, except in the unique original
report on the adult respiratory distress syndrome (ARDS) .
Saline infusions cause apparent rise of SSC to normal or above
normal but obviously worsens VO. This may explain the delayed
TURP syndrome presentation with features mimicking cerebral
or cardiac infarction, in which HN and hypo-osmolality though
detectable  is easily erasable. A delay of appropriate therapy
causes cell lyses liberating toxic contents into IVF that also erase
hypo-osmolality, rebounding to hyper-osmolality gap. Giving
VO2 erases both HN and hypo-osmolality. Liberated toxic cell
contents into circulation have confused the findings with sepsis
and misguided research on MVOD/F syndrome, particularly in
the presence of leucocytosis demonstrated here as a response
of VO insult (Figure 4). Sepsis is perhaps over-incriminated in
MVOD/F. The fact that one or two litres of normal saline are
better tolerated than that of metabolizable hypotonic 1.5%
Glycine or an isotonic 5% Glucose fluids, does not mean a direct
proportional relationship between VO2 quantity and safety.
The reported haemodynamic evidence on cardiac stress
during TURP surgery [40,41] occurs in the absence of
hypothermia, hypoxaemia and sepsis in all cases of the TURP
syndrome. Also, most severe cases of HN and TURP syndrome
suffer from coma in the absence of ammonia toxicity that is only
rarely detected in established hepatic failure as part of MVOD/F.
The condition also occurs with 3%Mannitol  and Sorbitol in
the absence of elevated serum glycine. All dilutional and toxic
hypotheses are equally incorrect, leaving the real culprit of
“VO/T’ insult invisible.
Severe to lethal HN and TURP syndrome cases occur rarely
during prospective studies and only two Eastbourne studies
documented such cases [6,51], while all HN cases were reported
retrospectively. An incidence of 10% causing moderate to severe
morbidity  with mortality of 0.5-1.5%  is the currently
accepted figures . Other authors affirmed the accuracy of
our data on incidence, per-operative blood loss and fluid balance
. The incidence applies to postoperative, if not all hospitalinduced
HN [33-37] affecting men, women and children of
medical and surgical specialties [4-13], whether reported as HN
or with a specialty label of the TURP syndrome or identical twins
[33,37]. Tertiary HN nadir and the “Missing VO” induce a triple
biochemical, clinical and therapeutic illusions.
“VO/T” insult is not only overlooked but also the contribution
of ivi fluids is usually ignored, being contradictory to received
concepts on fluid therapy of shock and monitoring critically ill
patients. Osmotic shift of the water component of VO1 fluids
from ECF into ICF (Missing VO) causes apparent elevation of SSC
and wide cell oedema with dysfunction of vital and non-vital
organs, explaining the illusion of tertiary HN nadir. Cell oedema,
necrosis and lyses complete the picture of shock and MVOD/F.
Cellular, unlike the interstitial venous or cardiac, oedema is
not pitting. It manifests clinically with the bizarre features of
MVOD/F. VO2 fluids may correct low SSC but masks HN marker,
confuses diagnosis, worsens VO and causes internal drowning,
and above all does not correct cell oedema by mobilizing the
“Missing VO” out of cells and patient’s body. Capillary dysfunction
causes shock and cell anoxia in the absence of hypoxaemia, as
has recently been proved histo-pathologically .
The total fluid balance and net VO with reference to fluid
type at the time of diagnosis, particularly of cases that suffer
from cerebral or cardiac ischaemic episode or infarction and/
or respiratory distress in the postoperative period, should be
carefully analyzed. SSC and osmolality changes on a time scale
reveal valuable evidence . Though not easy, the tertiary HN
nadir or normal SSC postoperatively, must be carefully analyzed
with reference to “VO/T” taking fluid type into account. In
cases of ARF with high urine output, the serious attempt for
spontaneous recovery by the kidneys may be defeated by
the “output-input fluid chase”, in which every urine output is
thoughtlessly replaced by equal quantity of ivi fluids. At many
times, quantifying VO can only be detected by the increase in BW
Understanding the above discussed issues on VO/T has
allowed the discovery of volumetric overload shocks in the
patho-etiology of HN and TURP syndrome [53,54]. It also allowed
the discovery of the hydrodynamics of a porous orifice tube that
provides the correct replacement for the wrong Starling’s law
for the capillary-interstitial fluid transfer . Resolving the
puzzle of MVOD/F syndrome and ARDS is pending.
The concept of “VO/T’ insult explains the aetiology of HN and
TURP syndrome and pathophysiology of HN nadirs unveiling its
paradoxical illusive presentation masks and refuting dilutional
and toxic hypotheses. Irrigant absorption of 1.5% Glycine
induces the TURP syndrome but was neither quantified nor
reported, likewise 5% Dextrose induces all postoperative HN cases though VO1 is rarely reported. Secondary HN nadir of
VO1 is proportional to clinical severity but presentation with
vascular shock contradicts received concepts and initiates
the inappropriate therapy of ‘aggressive vascular expansion’.
Likewise, tertiary HN nadir causes biochemical, clinical and
therapeutic illusions. Osmotic fluid shift into ICF causes apparent
rise of SSC but the “Missing VO” causes cell oedema or necrosis
of vital organs. The bizarre features of MVOD/F cause difficulty
in diagnosis and differential diagnosis of HN when presenting
with masks of cerebral or cardiac ischaemia or infarction. It is
important to differentiate infarction of arterial obstruction from
that due to cell oedema and necrosis as delayed presentation
masks of HN and the TUR syndrome.
The real unique value of understanding the exact pathoetiology
of the ‘rare, obscure and well known’ but unique TURP
syndrome lies not only in resolving its own puzzle but also that
of identical twins and conditions characterized with HN. This
has paved the way to identify new “VO shocks”, correct rules
to “optimize” fluid therapy in shock and report conditions for
successful life-saving HST of severe inadvertent HN cases. In the
light of the new hypothesis for capillary-ISF dynamics, resolving
another most illusive puzzle of MVOD/F syndrome or ARDS
should not be too difficult or distant.
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