Interstitium: The next diagnostic and therapeutic platform in

critical illness
Bala Venkatesh, MD, FCICM; Thomas J. Morgan, MBBS, FCICM; Jeremy Cohen, MBBS, FCICM

Background: For decades we have been testing blood either ex
vivo or else placing monitors directly in the bloodstream to “see”
what might be going on in tissues. In the last 20 yrs, conceptual
and practical advances in interstitial monitoring have begun to
challenge traditional approaches. In this review we explore how
interstitial monitoring might be used as a platform for future
diagnostics and therapy in critical illness.
Results: From a diagnostic perspective, interstitial analysis has
been instructive about the pathophysiology of critical illness. Valu-
able insights have been gained into the pathophysiology of critical
illness. To this end, examples from the areas of interstitial oxygen-
ation and acid base, endocrine pathophysiology, and head injury
monitoring have been used. From a therapeutic perspective, the main
focus has been on antibiotic therapy and an improved understanding
of pharmacokinetics and pharmacodynamics in critical illness.
Conclusions: Monitoring of the interstitium is feasible and can
be achieved through minimally invasive techniques. It has im-
proved the understanding of the pathophysiology of critical ill-
ness, holds potential in the diagnosis and management of sepsis,
may allow early prediction of organ deterioration, and finally
offers the possibility of reduction of blood testing and minimizing
blood loss. While all of these hold promise, randomized trials will
need to be conducted based on interstitial end points rather than
plasma end points. This will pave the way for a more rational
approach to the therapy of critically ill patients. (Crit Care Med
2010; 38[Suppl.]:S630 –S636)
KEY WORDS: interstitium; monitoring; pathophysiology; critical
care; plasma

F or decades we have been either
testing blood ex vivo or else
placing monitors directly in
the bloodstream to “see” what
might be going on in tissues. Strategies
have ranged from the simple tracking of
plasma lactate concentrations to more in-
vasive monitoring of complex end points
such as oxygen delivery, oxygen con-
sumption and their relationships (1),
mixed venous oxygen saturation (2), and
the venoarterial PO2 gradient (3). How-
ever, these monitored end points have
one major drawback in common. They
are all “global” indices. In each case their
values are integrations derived from mul-
tiple inputs, so that their sensitivity to
isolated regional insults is poor.
From the Intensive Care (BV), Princess Alexandra
and Wesley Hospital, University of Queensland,
Queensland, Australia; Intensive Care (TJM), Mater
Misericordiae Hospital, South Brisbane, Australia; In-
tensive Care (JC), Royal Brisbane Hospital, Queens-
land, Australia.
The authors have not disclosed any potential con-
flict of interests.
For information regarding this article, E-mail:
bala_venkatesh@health.qld.gov.au
Copyright © 2010 by the Society of Critical Care
Medicine and Lippincott Williams & Wilkins
DOI: 10.1097/CCM.0b013e3181f24406
The classic example is monitoring tis-
sue dysoxia (oxygen-limited cytochrome
turnover) by tracking mixed venous oxy-
gen tension (PvO2). PvO2 is a function of
mixed venous oxygen content, which it-
self is a flow-weighted average of postcap-
illary oxygen contents from all organs
contributing to venous return. At a PvO2
of 40 mm Hg, the average intracellular
PO2 is 11 mm Hg, whereas at a PvO2 of 26
mm Hg, average intracellular PO2 has
fallen below the “Pasteur point” to 0.8
mm Hg (4). Consequently a PvO2 that is
⬍26 mm Hg is a specific marker of tissue
dysoxia. However, the problem is that a
normal PvO2 does not rule out scattered
pockets of significant dysoxia. To take an
extreme example, a normal PvO2 can per-
sist despite absolute ischemia in a major
organ, as in brain death. Furthermore an
elevated PvO2 is far from a reassurance. It
may even be of more concern than a
reduced PvO2, since it might signal tissue
shunting (5), cytopathic hypoxia (6), or
some combination of both (7). There are
many examples of situations in which cli-
nicians obliged to monitor tissue activity
by remote means are faced with similar
dilemmas, including: 1) titration of anti-
biotic therapy to plasma drug minimum
inhibitory concentrations (MICs); 2)
gleaning tissue and intracellular acidbase
status from plasma measurements; and
3) inferring functional adrenal status or
determining the need for steroid therapy
from plasma cortisol profiles.
In the last 20 yrs, conceptual and prac-
tical advances in interstitial monitoring
have begun to challenge traditional ap-
proaches. This has been largely due to
miniaturization of technology (8, 9) and
the development of techniques such as
microdialysis (10). In this monograph, we
describe the anatomy and physiology of
the interstitium, review some advances in
our knowledge of interstitial pathophysi-
ology in critical illness, and explore how
they might be used as a platform for
future diagnostics and therapy in critical
illness.
Anatomy and Physiology of the
Interstitium
The interstitium is traditionally de-
fined as the space between the capillary
walls and the cells. Its structure and com-
position are relatively uniform in most
tissues. Typically, it consists of fluid with
a characteristic protein and electrolyte
profile, suspended in a gelatinous matrix
of glycosaminoglycans and invested with
a complex weave of collagen fibers. The
matrix performs several functions, in-
cluding provision of mechanical support

S630 Crit Care Med 2010 Vol. 38, No. 10 (Suppl.)

Table 1. Normal electrolyte and protein composition of the interstitium
Plasma Interstitial Fluid Intracellular Fluid
Total volume (L) 3 13.5 23
关Na⫹兴 143 137 10
关K⫹兴 4 3 155
关Mg2⫹兴 2 2 10
关Ca2⫹兴 1 1 35
关Cl⫺兴 107 111 10
pH 7.4 7.4 7.0
关ATot兴 20 — 200
The ionic values are quoted as mEq/L. The protein concentrations are represented by ATot, which
represents the total concentration of nonvolatile weak acids and the main contributor to ATot in plasma
is the protein concentration. Reprinted with permission from Magder (75).
to the cells, participation in wound heal- Pathophysiologic Alterations in
ing and in cell growth and differentiation,
the ISF Associated with
storage of growth factors, and mainte- Critical Illness
nance of a stable biochemical and immu-
nologic microenvironment. The electro- In critical illness, it is well recognized
lyte composition of interstitial fluid (ISF) that major alterations in the volume and
is similar to that of plasma, although composition of the ISF can occur. In sep-
exact concentrations vary from tissue to sis there are well-documented increases
tissue; however, in health, protein con- in the extracellular body water during the
centrations are always considerably lower acute phase of the inflammatory re-
than plasma (Table 1). As the ISF bathes sponse. Elderly patients with sepsis dem-
the cells, its composition will reflect the onstrate increases in extracellular water
local metabolic status of the cells. Conse- compared with younger patients, and in-
quently, the composition of ISF sampled creases in extracellular water are associ-
from different sites across the body will ated with worse outcome (12). Patients
vary owing to the local metabolic activity with major blunt trauma display similar
of the tissues. An example of this is the pathophysiologic changes (13, 14). A
variability in interstitial PO2 and PCO2, study of changes in body composition has
which are indicators of local metabolic also provided insights into the under-
activity and blood flow (Table 2). standing of mechanisms of proteolysis
and cellular dehydration in sepsis (15).
The potential consequences of these
Quantification of ISF changes are several-fold: 1) From a phar-
macologic perspective, large increases in
Extracellular water can be measured drug volumes of distribution occurs; and
by using bromide dilution or bioimped- 2) several diseases share similar patho-
ance techniques (11). The former often physiologic processes. A mere study of
used as a reference standard involves the plasma end points does not reveal the
ingestion of sodium bromide. Bromide is changes in the milieu of the cell.
distributed predominantly in the extra-
cellular space (plasma and interstitium), The Interstitial Focus in Critical
although a small fraction enters the red
Illness: A Brief History
cells. From knowledge of the ingested
dose and the concentration in the The most commonly used body fluid
plasma, the extracellular fluid volume for diagnostic assessment in critical ill-
can be calculated. Bioimpedance utilizes ness is the blood. To a lesser extent,
the principle of change in the body reac- urine, pleural fluid, ascites, and cerebro-
tance and resistance of the tissues with spinal fluid are tested predominantly for
alterations in the water content to deter- diagnosis of sepsis. Although blood sam-
mine the extracellular fluid volume. Bio- pling is easy and convenient in the criti-
impedance has been validated against the cally ill patient, it is associated with a
bromide space measurements and is in- number of disadvantages (Table 3).
creasingly utilized in clinical practice by A key element driving greater interest
physicians, nutritionists, and sports med- in regional monitoring techniques was
icine to determine alterations in body the idea that covert tissue dysoxia is a
composition. major driver in the genesis of multiple
Crit Care Med 2010 Vol. 38, No. 10 (Suppl.)
Table 2. Normal gas tensions in the various
tissues in humans
Tissue Gas Tensions
Site (Torr)
Gastric (76)
PCO2 42
Intestinal mucosal (77)
PCO2 10
Liver (78)
PO2 30–33
Subcutaneous (79)
PCO2 45–55a
PO 2 70
Muscle (80)
PCO2 35
PO2 30–35
Brain (27)
PCO2 40–60
PO2 35–40b
a
Data obtained from normal skin of burn pa-
tients following resuscitation from burn shock;
b
corresponding arterial PO2 was 175 torr.
organ dysfunction syndrome (16). There
was also a realization that global indices
of tissue well-being are insensitive to re-
gional dysoxia, plus a demonstration that
therapies directed at supranormal whole-
body oxygen delivery in critical illness
can increase mortality. One of the earliest
regional methods to be explored was gas-
tric tonometry (17). This was initially a
hybrid approach in which plasma bicar-
bonate (a global index) derived from ar-
terial blood gas analysis was combined
with regional intragastric PCO2 measure-
ments to calculate gastric intramucosal
pH, considered to be a surrogate measure
of covert splanchic dysoxia. Gutierrez et
al (18) seemed to validate this approach
by demonstrating superiority of intramu-
cosal pH-based therapy. Attempts to im-
prove the specificity of the tonometric
measurement by eliminating the sys-
temic acid-base influence of plasma bi-
carbonate with the use of the “CO2 gap,”
defined as regional PCO2 minus arterial
PCO2, were met with limited success (19,
20). It was later realized that the CO2 gap
is more an index of regional blood flow
rather than of tissue oxygenation, since it
has poor sensitivity to dysoxia if flow is
maintained (21).
In the early 1990s, three sentinel ad-
vances maintained the impetus toward
the interstitial approach. The first was
the development of miniaturized optodes
and electrodes, which allowed continu-
ous real time measurements of tissue
PO2, PCO2, and pH, and thus opened a
dynamic window into regional microcir-
culatory and acid-base behavior in shock
S631
Table 3. Potential limitations of plasma-based measurement cluded that tissue PCO2 is primarily a
measure of flow, since it is not elevated in
1) Provides only a global index, and sensitivity to regional isolated insults is poor.
hypoxic dysoxia where there is flow pres-
2) Insults often arise in the tissue. As plasma is an integration of multiple tissue inputs, there might
be a delay in the appearance of the abnormality in the blood. ervation. There is thus no particular CO2
3) The time window of abnormality in blood is small (for example, duration of bacteremia or gap value that can be taken to signal the
viremia), and therefore the potential yield from a blood sample may be limited. anaerobic threshold.
4) The associated blood loss with serial blood testing. Clinical outcome studies based on mon-
itoring interstitial gas tensions have been
disappointing. Titrating oxygen therapy to
tissue oxygen tensions has only been shown
states (22). Microdialysis was simulta- ation incorporates many technological to be useful in patients with impaired
neously evolving as a clinical technique, advances in electrode miniaturization, fi- wound healing (38). Although a number of
allowing more direct sampling of ISF beroptics, and spectrophotometry. trials have demonstrated evidence of a low
(23). Finally, the advent of microchip Site-specific measurements can now intramucosal pH in a variety of disease
technology radically transformed our be performed depending on the clinical states, no convincing data exist to demon-
ability to measure tissue analytes of in- scenario; for example, brain PO2 and PCO2 strate that titrating therapy to intramuco-
terest, ranging from simple electrolytes in neurotrauma (26) and in neurosurgi- sal pH (or the CO2 gap) improves outcome
and glucose to the application of sophis- cal patients during anesthesia and in in- (39). Similarly, although trials in neurosur-
ticated methodologies such as proteom- tensive care (26, 27). The ideal situation gical patients have shown a correlation be-
ics (23, 24). during global threats on organ function tween impaired brain gas tensions and poor
However, despite the diversity of ap- would be an ability to measure tissue gas neurologic outcome, there are no convinc-
proaches available in 2010 for ISF analy- tensions at one specific site possessing ing data to support the hypothesis that in-
sis as part of both diagnosis and therapy, “canary” properties; in other words, at a terventions titrated to brain gas tensions
direct application in critical care medi- site that if adequately oxygenated guaran- translate into clinical benefit.
cine has been limited. From a diagnostic tees acceptable whole body oxygenation. Interstitial Lactate. Lactic acidosis is
perspective, interstitial analysis has been In the quest for such a region, many regarded as a signal of tissue distress, and
instructive about the pathophysiology of tissues have been investigated. These in- is associated with altered tissue perfu-
critical illness. From a therapeutic per- clude the gastric mucosa (17, 28), intes- sion, cell metabolism, and dysoxia (40).
spective, the main focus has been on an- tinal mucosa (29, 30), subcutaneous tis- Persistent hyperlactemia in critical ill-
tibiotic therapy and an improved under- sue (20, 31), sublingual tissue (32), ness portends a poor prognosis (41). Not
standing of pharmacokinetics and skeletal muscle (33), and urinary bladder surprisingly, arterial plasma lactate mea-
pharmacodynamics in critical illness. (34). Other organs such as kidney, liver, surements have therefore become funda-
and myocardial tissue have also been mental to the practice of intensive care.
Improved Understanding studied (35). For the clinician the most However, a number of caveats apply
of the Pathophysiology of promising of all is the gut, which is also when interpreting plasma lactate concen-
Critical Illness one of the least accessible for direct in- trations. Many clinical situations reduce
strumentation. It seems that monitoring the sensitivity of plasma lactate concentra-
We have chosen three areas to outline inputs from multiple regions remains the tions to dysoxia (16). For example, in-
how interstitial rather than plasma mea- way forward. creased lactate export from ischemic tis-
surements have shed new light on the Lessons Learned From Monitoring In- sues may be diluted by venous effluent
pathophysiology of disease processes. terstitial Gas Tensions. Gastrointestinal from better perfused tissues. Liver, kidney,
These are tissue oxygenation and acid- mucosa and subcutaneous tissue have and possibly muscle can act as lactate
base balance, adrenal function, and head demonstrated parallel PO2 perturbations “sinks,” damping significant elevations in
injury. during shock states and perfusion defects plasma. Furthermore hyperlactemia can
(20, 31). Alterations to cerebrospinal fluid arise from aerobic glycolysis in a number of
Interstitial tissue oxygenation and brain tissue gas tensions in a variety of nondysoxic states, including sepsis, liver
and acid base pathophysiologic states are now better un- failure, altered pyruvate dehydrogenase ac-
derstood (36). Paradoxic elevations of ileal tivity, hyperventilation, elevated catechol-
For most of the previous century, bed- and urinary bladder PO2 following endo- amine concentrations, and from the pres-
side assessment of tissue perfusion and toxin infusions have shed light on one of ence of certain drugs and toxins (42, 43).
oxygenation was largely a clinical exer- the important pathophysiologic mecha- It follows that monitoring the lactate
cise. Measurement of arterial blood gas nisms of tissue dysoxia during sepsis (34). production of individual organs may rep-
tensions and pH became a clinical reality Work by Schlichtig and Bowles (37) resent a potentially more reliable index of
in the 1950s (25). This provided valuable and Vallet et al (21) progressed our un- regional anaerobic metabolism than arte-
information concerning gas exchange derstanding of tissue CO2 responses dur- rial lactate concentrations (44). Lactate
and acid-base homeostasis. Measurement ing hypoperfusion. Using Rahn and concentrations are frequently measured
of oxygen tensions further down the ox- Fenn’s modification of the Dill nomo- by using the lactate oxidase technique.
ygen cascade was required, but this did gram, Schlichtig and Bowles sought to Continuous intravascular and tissue lac-
not evolve for a further 40 yrs, and tissue determine the mucosal PCO2 at the anaer- tate-measuring technologies have now
carbon dioxide measurement came into obic threshold during progressive been described, incorporating either an
prominence only in the 1980s. Present- splanchnic ischemia. Many of these con- electrochemical (45) or a fiberoptic sys-
day direct monitoring of tissue oxygen- cepts were overturned by Vallet, who con- tem (46), and their performance charac-

S632 Crit Care Med 2010 Vol. 38, No. 10 (Suppl.)

teristics are encouraging. They include
a broad range of measurement (0 –20
mmol) and a rapid response time (60 –
120 sec). Potential applications of di-
rect tissue lactate monitoring (apart
from those mentioned previously) in-
clude determination of the lactate gap
(tissue lactate minus arterial lactate).
In health, the lactate gap should be
negligible. Persistent regional ischemia
might result in elevated tissue lactate
concentrations but with relatively nor-
mal arterial lactate concentrations,
thus increasing the lactate gap. One
potential application of this approach is
the ability to assess the viability of or-
gans pre- and posttransplant, thus fa-
cilitating precise determination of opti-
mal cold and warm ischemia times (47).
Interstitial Base Excess (BE). If inter-
stitial lactate measurements are not
available, tissue BE may provide an alter-
native (48). The usual definition of BE is
the concentration of strong acid or base
required to return the pH of an in vitro
specimen of whole blood to 7.4 while
maintaining PCO2 at 40 mm Hg by equil-
ibration at 37°C (49). However, there are
two further important pieces of informa-
tion. First, the BE concept can be applied
to any body fluid, not just whole blood.
Second, the BE of any fluid can also be
defined in physical chemical terms as the
offset from normal of the buffer base con-
centration (which is the inverse of strong
ion difference) (50). In other words, BE in
any fluid compartment can be calculated
as (⌬[A⫺] ⫹ ⌬[HCO3⫺]), where A⫺ is the
anion of the nonvolatile weak acid AH,
the total concentration being ATOT (i.e.,
ATOT ⫽ [A⫺] ⫹ [AH]).
Healthy ISF has negligible ATOT, since
there are just small concentrations of inor-
ganic phosphate and a very small amount
of albumin (see Table 1). The A⫺ compo-
nent of normal interstitial buffer base is
thus close to zero. Therefore, interstitial
buffer base concentration (or strong ion
difference) is numerically nearly identical
to interstitial [HCO3⫺], so that interstitial
[HCO3⫺] represents almost the entire in-
terstitial buffer base concentration. Inter-
stitial BE then simply becomes the offset in
interstitial [HCO3⫺].
Importantly, because of the lack of ATOT,
changes in PCO2 can be expected to have a
minimal effect on interstitial [HCO3⫺]. For
example, at a tissue PCO2 of 160 mm Hg,
the expected increase in interstitial
[HCO3⫺] above normal is a mere 1.26
mmol/L. By contrast, the equivalent
change in plasma [HCO3⫺] would exceed 6
Crit Care Med 2010 Vol. 38, No. 10 (Suppl.)
mmol/L. Hence, with a perfectly inserted
interstitial probe (zero insertion trauma),
primary CO2 effects on interstitial [HCO3⫺]
are likely to be small enough to be ignored.
Tissue BE determinations should, there-
fore, be possible in solid organs by using
multiparameter probes. Tissues of interest
need to be examined first to determine the
normal [HCO3⫺] for each tissue and to con-
firm that this does not vary significantly
with primary alterations in PCO2. Based on
this kind of information, BE algorithms
can be constructed for individual tissues by
using the very simple formula:
Tissue BE ⫽ actual tissue 关HCO3⫺兴 ⫺
expected tissue 关HCO3⫺兴.
As with the lactate gap, it then be-
comes possible to monitor the BE gap,
which is tissue BE minus arterial BE. An
increase in the regional BE gap would
have a significance similar to an in-
creased lactate gap.
Endocrine critical illness:
adrenal pathophysiology
Investigating the endocrine status of pa-
tients with critical illness has proved to be
a difficult process. While the sufficiency of
the hypothalamopituitary-adrenal axis re-
sponse is agreed to be vital in the response
to stress (51), measuring it is problematic.
Estimation of total plasma cortisol concen-
trations have formed the cornerstone of
adrenal function testing in intensive care
patients, but suffer from the problems of
significant hourly variability (52), the ef-
fects of protein binding, changes of the
course of illness, gender differences (53),
and significant variations between the
available assays (54). As a result, whereas
patterns of change in plasma cortisol esti-
mations can be recognized in critically ill
patients, their clinical relevance remains
unclear, and they do not appear to be a
useful guide to therapy.
Advances in our understanding of glu-
cocorticoid physiology indicate that tis-
sue cortisol concentrations are not solely
dependent upon the concentrations cir-
culating in plasma. Intracellular cortisol
generation occurs as a result of the activ-
ity of the 11 ß-hydroxysteroid dehydroge-
nase enzyme system (11-ßHSD) and is
tissue dependent (55). In an analogous
fashion to body oxygenation, plasma cor-
tisol measurements may not reveal the
adequacy of the glucocorticoid response
in individual tissues.
Relevance of Interstitial Cortisol Mea-
surements. Cortisol exerts its physiologic
effects by binding to the glucocorticoid
receptor. Free cortisol diffuses from the
capillary into the interstitium, and from
there it passes into the cell. Due to their
lipophilic nature, glucocorticoids pas-
sively diffuse through plasma membrane,
and thus it is the free cortisol concentra-
tion in the ISF that is one of the principal
determinants of the available glucocorti-
coid pool for receptor binding (Fig. 1).
There are a number of reasons to suspect
that cortisol concentrations in plasma
and ISF may not necessarily run in par-
allel. Cortisol can be cleaved from corti-
sol-binding globulin by the actions of
neutrophil elastase, an enzyme released
from polymorphonuclear leukocytes at
the site of inflammation (56). Thus, the
inflammatory response seen in septic
states may engender a local increase in
interstitial cortisol concentrations. An in-
crease in intracellular cortisol generation
secondary to up-regulation of 11-ßHSD-1
may also lead to cortisol diffusion out of
the cell (57). Other factors that may be
relevant include increased capillary per-
meability, microcirculatory disturbances,
and local changes in tissue perfusion.
At present, the role of cortisol mea-
surements of this nature remains specu-
lative. We have recently published a study
examining cortisol concentrations as
measured by microdialysis in patients
with burns (58). This demonstrated that
interstitial cortisol concentrations were
elevated in this population and that they
correlated poorly with the plasma free
cortisol concentrations. More research is
needed into this intriguing field.
Head injury
Monitoring of the cerebral intersti-
tium through microdialysis has been
practiced in the setting of traumatic
brain injury for more than 20 yrs (59).
The use of microdialysis has provided sig-
nificant insight into the pathophysiology
of traumatic brain injury. Using a combi-
nation of various analytes through the
microdialysate, information can be
gleaned about the metabolic status of the
brain (glucose, lactate, and pyruvate, and
lactate/pyruvate ratio), cell membrane in-
tegrity (glycerol), and neurotrasmitter
release (glutamate). These have been in-
strumental in defining secondary insults
at a tissue level. For example, localized
ischemia, nonconvulsive status, or corti-
cal spreading depolarizations may not
S633

Figure 1. A representation of the relationship between plasma and interstitial and intracellular cortisol.
manifest clinically. The presence of mi-
crodialysis catheters has been critical to
the earlier detection of these processes by
the recognition of increasing lactate/
pyruvate ratio and elevated glycerol con-
centrations (60). This methodology can
now be used to determine the efficacy of
therapies. For example, the institution of
hypothermia for raised intracranial pres-
sure, if effective, should be manifest by an
improvement in lactate/pyruvate ratios
and lactate/glucose and a reduction in
glycerol concentrations (61). This was
demonstrated by Wang et al (61) both in
the normal brain and pericontusional
brain. The proliferation in literature on
brain interstitial monitoring is such that
an entire congress was convened to reach
consensus on the clinical indications for
and applications of cerebral microdialysis
(62). It remains to be seen whether ther-
apies directed based on interstitial mon-
itoring will result in improved outcome.
Interstitial Measurements:
Therapeutic Applications
Of all interstitial-based interventions,
antibiotic therapy has led the field. The
driver for this has been the paradigm that
most infections originate in the extracellu-
lar space before translocation into the
bloodstream. Consequently assessing tar-
get antibiotic concentrations in the tissues
carries far more clinical relevance than as-
sessing plasma parameters.
To this end, interstitial antibiotic distri-
butions have been explored in critically ill
S634
patients with sepsis to investigate whether
traditional plasma indices such as mini-
mum inhibitory concentration and maxi-
mal concentration predict tissue concen-
trations reliably. A number of antibiotics
have been examined: Piperacillin, imi-
penem, fosfomycin, cephalothin, and levo-
floxacin. Valuable information regarding
pathophysiology and pharmacokinetics and
dynamics has been gathered. Thallinger et
al (63) examined whether differences in the
severity of sepsis translate to differences in
the pharmacokinetic profile of linezolid in
plasma and the interstitium of target tis-
sues after a single intravenous dose of 600
mg. Twenty-four patients (16 with septic
shock and eight with severe sepsis) were
studied. They concluded that severity of
sepsis has no substantial effect on the phar-
macokinetic profile of linezolid in plasma
and in the interstitium of soft tissues (63).
The work of Zeitlinger et al (64) (n ⫽ 7)
was significant in that they showed that
despite similar plasma minimum inhibi-
tory concentrations, tissue penetration of
antibiotics was variable, raising questions
about the validity of plasma pharmacoki-
netic end points (64). Our group extended
that concept by demonstrating that ceph-
alothin can accumulate in the tissues in
burns, a phenomenon not predicted by
plasma pharmacokinetic data (65). These
are also consistent with the data of Joukha-
dar et al (66). Interstital antibiotic concen-
trations have also provided guidance on the
optimum method of administering antibi-
otics. Roberts et al (67, 68) have shown that
continuous infusions of ß-lactam antibiot-
ics using piperacillin (n ⫽ 13) and mero-
penem (n ⫽ 10) maintains minimum in-
hibitory concentration levels in the tissues
better than intermittent dosing. Tissue an-
tibiotic concentration data provide an op-
portunity for personalized medicine. In
vitro pharmacokinetcs-pharmacodynamics
studies by Zeitlinger et al (64) have shown
that while plasma concentrations of levo-
floxacin did not reveal any significant
kill profile differences for Pseudomonas
between patients, significant interindi-
vidual differences were demonstrable
for bacterial killing rates based on mus-
cle antibiotic concentrations. This ob-
servation provides another mechanism
for antibiotic therapeutic failures and
raises the prospect of individualized
therapy based on tissue concentrations.
Limitations of the Interstitial
Approach
To obtain access to the interstitial space,
any technology by necessity will confer a
degree of invasiveness with its attendant
risks of bleeding. Insertion of probes into
the interstitium may create local tissue he-
matoma and necrosis that may distort the
signal. More fundamentally, while the basic
composition of the interstitium is similar
across the various tissues, heterogeneity
exists between the tissues (69). Therefore,
to derive a signal from a single site mea-
surement (for example, the skin), which is
globally representative, is a challenging
task. This point is exemplified by the study
of Zeitlinger et al (70) in which they exam-
ined whether soft tissue antibiotic concen-
trations would serve as a surrogate for pre-
dicting lung concentrations and concluded
that significant differences were evident.
Host response to the sensor in the form of
macrophage deposition on the external sur-
face and thrombogenicity are additional
problems with in vivo catheter placement.
The signal fidelity is also of importance,
particularly the sensitivity and specificity,
and trend accuracy. Finally, the effects of
the severity of inflammation and sepsis
have an impact on tissue concentrations of
the various analytes of interest (63).
Opportunities for the Future
Novel diagnostic and therapeutic ap-
proaches can be developed based on an
improved understanding of pathophysiol-
ogy and response to therapy. Diagnostic
chips can be developed by using microar-
ray technology where ISF can be accessed
Crit Care Med 2010 Vol. 38, No. 10 (Suppl.)
by using microdialytic techniques. In this
regard, continuous subcutaneous glucose
sensors have already been tested, and in-
sulin therapy titrated to continuous data
has been reported to result in improved
diabetic control (71).
Microdialysis monitoring of liver
grafts has been shown to provide earlier
warnings of graft rejection compared
with conventional blood-based indices
(72). Interstitial proteomics is an evolv-
ing field and has found application in the
neurosciences (24). Using mass spec-
trometry, two protein species related to
glyceraldehyde-3-phosphate dehydroge-
nase and heat-shock protein 70 cognate
have been identified as early warning sig-
nals of cerebral vasospasm in subarachnoid
hemorrhage (73). If these findings are con-
firmed in large-scale studies, then thera-
peutic strategies can be developed based on
the presence of these parameters. Body
fluid proteomics have found a wide appli-
cation in the early detection of cancers.
The ability to pass a probe into the in-
terstitium also offers a therapeutic oppor-
tunity to instill drugs in situations where
flow might be compromised, for example in
the setting of a cerebral infarct. This tech-
nique is already being used in anesthetic
practice where Silastic catheters placed in
the vicinity of the wound are used to infuse
local anesthetic agents during the periop-
erative period for relief of pain.
The advent of nanotechnology provides
the ability for rapid bedside assessment of
interstitial biochemistry, interstitial anti-
biotic concentrations, and early diagnosis
of infection. Nanoprobes can be utilized
that allow both diagnosis and therapy based
on appropriate rational end points (74). The
ability to precisely measure tissue antibi-
otic pharmacokinetics may provide the op-
portunity to titrate antibiotic therapy tai-
lored to the individual.
In conclusion, monitoring of the inter-
stitium is feasible and can be achieved
through minimally invasive techniques. It
has improved the understanding of the
pathophysiology of critical illness, holds po-
tential in the diagnosis and management of
sepsis, may allow early prediction of organ
deterioration, and finally offers the possibil-
ity of reduction of blood testing and mini-
mal blood loss. While all of the above hold
promise, randomized trials will need to be
conducted, based on interstitial end points
rather than plasma end points. This will
pave the way for a more rational approach
to the therapy of critically ill patients.
Crit Care Med 2010 Vol. 38, No. 10 (Suppl.)
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