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P.Holloway
(1), S .Benham (1) and A St John (2).
- Intensive Therapy Unit, John Radcliffe Hospital, Oxford UK
- Roche Diagnostics, formerly AVL Medical Instruments AG,
Stettemerstrasse 28, CH-8207 Schaffhausen, Switzerland
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Abstract
In response to clinical demand some point-of-care analysers now
provide blood lactate measurements in critical care. Recent
literature has raised concerns about the value and interpretation
of these measurements. Two particular concerns relate to
over-interpretation of lactate rises as equating tissue hypoxia and
also the failure to recognise the contribution from inotropic
support. We undertook this study to evaluate blood lactate
measurements in intensive care unit (ICU) patients in the
assessment of response to, and requirements for, haemofiltration
(HF) with lactate replacement fluid and to evaluate influences from
hepatic failure and from inotropic supportive therapy.
Haemofiltration is a convenient renal replacement therapy widely
used in intensive care management as an alternative to
haemodialysis. Mainly used for the treatment of acute renal failure
the process involves removal by filtration of fluid, electrolytes,
metabolites and other substances and simultaneous replacement of
essential fluid and electrolytes as well as a buffer, usually in
the form of lactate (sodium salt). There is controversy about
whether lactate replacement may be harmful to the patient and, if
so, when it would be appropriate to use a lactate-free fluid at
greater expense.
Serial blood lactate with simultaneous blood gas measurements
were recorded in 27 patients requiring HF for acute renal failure.
At baseline all patients had base deficits of >5mmol/L and 14
(52%) had blood lactates of >3.5mmol/L. Lactate 'tolerance' was
monitored by peak changes in these parameters during the procedure.
There was a worsening of base deficit in only three of the patients
in whom lactate rises exceeded 10 mmol/L at some stage during HF
with one survivor. A further twelve patients with rises of blood
lactate greater than 5 mmol/L improved their base deficit (+1 to
+17) with 8 (67%) survivors. Of the remaining twelve patients with
improved base deficit (+2 to +20), 10(83%) survived. The influence
on 'lactate tolerance' in patients with co-incidental liver disease
and those on inotropic support was studied. In these groups lactate
tolerance was compromised, particularly those on adrenaline
support. Patients with initial blood lactate measurements of
>10mmol/l and large base deficits were also lactate
intolerant.
The data suggest that rises in blood lactate during HF signal
harm if accompanied by inadequate improvement in base deficit.
Blood lactate and simultaneous acid-base response measurements
during HF help to assign correct buffer replacement and should be
performed on all patients.
Introduction
Increased metabolic monitoring in intensive care patients has
been a key development from new technology in point-of-care testing
for critical care and the introduction of parameters to the
'metabolic set' need to match clinical needs and to have a clear
role in patient management. The highest mortality rate in intensive
care is in patients with multi-system failure associated with
severe sepsis, a common complication of which is a degree of lactic
acidosis. In recent years much debate has taken place about the
mechanisms underlying lactic acidosis in patients with severe
sepsis. Traditionally, high blood lactate levels have been regarded
as a reflection of cellular hypoxia and hypoperfusion. However many
recent experimental and clinical studies have shown that lactate
levels do not always correlate with indices such as total oxygen
debt, the degree of hypoperfusion or the severity of shock (1).
This has led to confusion amongst critical care clinicians
concerning the clinical utility of blood lactate measurements.
However the lack of correlation between the degree of lactate
elevation and the other indices does not necessarily negate the
value of lactate determinations but reflects the fact that the
changes which take place in sepsis are complex and variable between
different tissues (2).
The arterial lactate concentration depends upon the rate of its
production and utilisation by various tissues. Net producers of
lactate include muscle, brain, skin, red cells and intestine whilst
organs which consume lactate include the liver, heart and the
kidney. One example of the metabolic complexity is that above a
certain lactate level, skeletal muscle is believed to be a net
consumer of lactate rather than a producer. Another is the
significant reduction in hepatic lactate consumption in hypotensive
and acidotic conditions.
Lactate is produced in the cytosol by the action of lactate
dehydrogenase on pyruvate as follows:
CH3COO + NADH +
H+ �
CH3CH(OH)COO+ +
NAD+
At a cellular level the determinants of the lactate
concentration include: the pyruvate concentration, the cytosolic
redox state or NADH/NAD ratio and the rate of transmembrane
transport of lactate. From the above equation it will be
appreciated that an increased pyruvate concentration will therefore
lead to increased lactate concentration by mass action. As
mentioned previously, there is little evidence to support the view
that increased lactate levels stem from impaired metabolism of
pyruvate due to lack of oxygen. However evidence in septic patients
does exist for increased pyruvate concentrations as a result of
excessive glycolysis, producing more pyruvate than can be
metabolised oxidatively, consequently leading to high blood lactate
levels. Similarly catecholamines that are administered in often
high doses as cardiac inotropes in severe shock can also increase
glycolysis and reduce hepatic gluconeogenesis. The effects of such
drugs on lactate levels has been convincingly demonstrated in
animals (Figure 1) and similar effects are believed to
be the cause of high lactate levels seen in patients receiving
catecholamine infusions and particularly when given to septic
patients (3). There is no convincing evidence of the role of
lactate transporters in determining cellular lactate levels.
Another possible cause for high lactate levels in sepsis is
reduced oxidation of lactate via the TCA cycle as a result of
inhibition of activity of the pyruvate dehydrogenase complex by
endotoxin and cytokines with subsequent unavailability of pyruvate
for mitochondrial oxidation. In addition several studies have
documented hyperlactataemia in patients with sepsis and lung injury
which has been attributed to lactate release predominantly from the
lungs, a sizeable proportion originating from activated lymphocytes
(4,5). Finally, impairment of kidney and liver function are common
abnormalities in septic patients and hyperlactataemia is a common
feature of both and can predict poor outcome.
These recent investigations provide some understanding of the
complex biochemical and cellular events involved in lactate
metabolism. They show that in patients with sepsis, increasing
lactate levels do not necessarily correlate with hypoxia, the
magnitude of the hypoperfusion or the severity of the shock.
However hyperlactatemia during critical illness can serve as a
metabolic marker of cellular stress and in intensive care regular
monitoring of blood lactate levels provides a guide to diagnosis
and treatment in certain patients. It is recognised that
hyperlactataemia occurs relatively late in patients with ischaemic
bowel when the balance of overproduction of lactate is no longer
matched by its utilisation. In patients at risk of this
complication, and when methods of assessment of local ischaemia
such as gastric tonometry are unavailable or unvalidated, regular
monitoring to detect an increasing blood lactate should serve to
alert the clinicians. Most importantly, in this and many other
contexts, units that measure lactate consistently with each blood
gas analysis recognise the value to their patient management of the
'normal lactate'.
An example of the importance of this regular metabolic
monitoring is in-patients undergoing continuous veno-venous
haemofiltration (CVVH or HF) for the treatment of acute renal
failure and metabolic acidosis. Haemofiltration is a convenient
renal replacement therapy widely used in intensive care management
as an alternative to haemodialysis because it can be sustained over
a 24-hour period with better control of the pH and less disturbance
of homeostasis in very sick patients. The process of HF involves
removal by filtration of fluid, electrolytes, metabolites and other
substances and simultaneous replacement of essential fluid and
electrolytes as well as a buffer, usually in the form of lactate
(sodium salt). There is controversy about when lactate replacement
may be harmful to the patient and, if so, when it would be
appropriate to use a lactate-free fluid at greater expense
(6,7,8,9,10,11). Apart from cost other advantages of lactate over
bicarbonate buffer include ease of use and lesser volume
replacement.
Methods
To investigate the metabolic effects of using lactate buffer
in-patients undergoing HF we carried out an observational study of
27 patients undergoing this procedure for treatment of acute renal
failure in the ICU. The 'lactate tolerance' in these patients was
monitored by measuring the peak changes in acid-base parameters
including base excess and blood lactate levels during the HF
procedure. All acid-base and lactate measurements were performed on
a Roche OMNI 9 Critical Care Analyser (Roche Diagnostics, Mannheim,
Germany). Survival, defined as those patients alive five days after
completion of the course of haemofiltration, was used as an
arbitrary endpoint recognising its limititation in these sick
patients
Results
At baseline all the patients had base deficits of >5mmol/L
and 14 (52%) had blood lactates of >3.5mmol/L. During the HF
there was a worsening of base deficit in only three of the
patients, in whom lactate rises exceeded 10 mmol/L at some stage
during the procedure with one survivor. A further twelve patients
with rises of blood lactate greater than 5 mmol/L improved their
base deficit, from +1 to +17: 8 (67%) of these patients were
survivors. Of the remaining twelve patients with improved base
deficit (+2 to +20), 10(83%) survived (Figure 2). The influence on 'lactate tolerance'
in patients with coincidental liver disease was studied. In these
groups lactate tolerance was compromised although the baseline
lactate did not predict either the rate of lactate tolerance or the
outcome. However patients with initial blood lactate measurements
of >10mmol/l and large base deficits were also lactate
intolerant (Figure 3). Patients on inotropic support at
least at the commencement of HF were also less lactate tolerant
with less improvement in base deficit.
Discussion
The data suggest that rises in blood lactate during HF signal
harm if accompanied by inadequate improvement in base deficit.
Blood lactate and simultaneous acid-base response measurements
during HF help to assign correct buffer replacement and should be
performed on all patients. The data from this study suggest good
outcome where peak base excess exceeds 6.0 mmo/l at peak lactate
and worse outcome if the peak lactate exceeds 5.0 mmol/l. This
study is continuing with monitoring of the metabolic effects of
changing replacement buffer to lactate-free in lactate intolerant
patients.
The controversy in this area extends to the actual mechanism of
how acidosis is corrected by haemofiltration with lactate and how
it could be might be exacerbated in certain patients. On the basis
of conventional acid-base theory, the lactate anions are eventually
converted into CO2 which is removed by ventilation, thereby
correcting the acidosis. This relies to a large extent upon the
liver metabolising the lactate as part of the Cory cycle ,carrying
out the appropriate conversion to glucose with simultaneous
consumption of hydrogen ions. In patients with compromised liver
function, this conversion does not take place with development of
an acidosis from free unmetabolised CO2
However an alternative theory is that the removal of lactate
from the plasma by the liver maintains the Strong Ion Difference
(SID), calculated from the equation (Na + K + Ca (i) + Mg - Cl +
lactate), at a normal level (40-42 mmol/l) thereby reducing the
dissociation of water to produce hydrogen ions (12). In cases of
severe liver failure or when the metabolic pathway for lactate
metabolism is compromised for reasons discussed earlier, then
lactate accumulates in plasma, SID is lowered and more water
dissociates to maintain electroneutrality leading to more hydrogen
ions and an acidosis. This theory is not easy to evaluate in
patients entirely on lactate replacement but may be studied in
those where the buffer is changed and in those on lactate-free
replacement from the onset of HF.
The unravelling of this system in intensive care patients with
multi-system failure requiring complex and continuous manipulation
of physiological processes, is critical not only for prognosis but
also management. Point-of-Care testing in the ICU is now able to
help provide more continuous and precise metabolic monitoring of
acid-base disturbances in the critically ill and should allow real
progress in this unravelling process.
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