Experimental studies
The sublingual microcirculation (Tongue
microcirculation,lingua
microcirculation,Side stream dark
field imaging (SDF))and its changes have been
studied during various experimental settings, mostly in animal mod¬els of sepsis and shock (7). Verdant deter¬mined the
relationship between sublingual and intestinal mucosal
microcirculatory(sublingual
microcirculation,Tongue
microcirculation,lingua
microcirculation,Side stream dark
field imaging (SDF)) per¬fusion and his findings support the
sublin¬gual region as an appropriate region to mon¬itor the
microcirculation in sepsis (45). On the model of endotoxemia in
sheep, sublin¬gual microvascular flow indexes were re¬duced,
fluid resuscitation corrected both serosal intestinal and
sublingual microcirculation(Tongue
microcirculation,lingua
microcirculation,Side stream dark
field imaging (SDF)) but was unable to restore
intestinal mucosal perfusion (46). Effects of the selec¬tive
iNOS inhibitor with those of norepi¬nephrine (NE) on
sublingual microcirculation was studied in a sheep model of septic shock,
selective iNOS inhibition had more beneficial effects than NE on
microcircula¬tion assessed by SDF imaging sublingually(sublingual
microcirculation,Tongue
microcirculation,lingua
microcirculation,Side stream dark
field imaging (SDF)) (47). The
use of enalaprilat prevented the worsening of sublingual
microcirculatory variables in fluid-resuscitated, hyperdynamic
model of septic shock (48). Alterations of sublingual
microcirculation are present also during experimental haemorrhagic shock
and these alterations arise from the first step of the bleeding
(49), restoration of microcir¬culatory flow may be achieved by
gelatine and hydroxyethyl starch (50). During cardiac arrest in
pigs, sublingual microcirculatory blood flow was highly
correlated with macrocirculatory hemodynamics. Adminis¬tration
of epinephrine dramatically de¬creased microcirculatory blood
flow (51). Microvascular blood flow in the sublingual mucosa is
also closely related to coronary perfusion pressure during
cardiopulmonary resuscitation and predictive of outcome (52).
During hypodynamic state of experimental sepsis after infusion
of E. coli time-depend¬ent strong correlation exists between
sublin¬gual and other microvascular beds, neverthe¬less, the
sublingual mucosa exhibited the most pronounced alterations of
microcircula¬tory flow in comparison with conjunctival, jejunal,
and rectal microvasculature (53). Al¬teration of sublingual
microvascular re¬sponse was also detected during experimen¬tal
mild hypothermia in an ovine model, where there was a
significant decrease in the proportion and density of small
perfused ves¬sels, all microcirculatory variables returned to
baseline levels during the re-warming phase (54).
Clinical studies
Not surprisingly, probably due to the fact that technology of
OPS-SDF imaging (sublingual
microcirculation,Tongue
microcirculation,lingua
microcirculation,Side stream dark
field imaging (SDF)) has been in¬corporated into a small hand-held
video-mi¬croscope, which can be used in clinical set¬ting, much
more studies on sublingual microcirculation are in humans,
particularly in area of critically ill patients. A growing body
of ev¬idence exists on disturbed sublingual micro¬circulatory
functions in relation to increased morbidity and mortality in a
wide array of clinical scenarios (12, 13). Changes of
sublin¬gual microcirculatory parameters (total and perfused
small vessel density) have been re¬cently proposed as an early
predictor for crit¬ically ill patients (55, 56) and there are
sever¬al areas in human medicine, where observa¬ tion of
sublingual microcirculatory bed has been carried out ¨C sepsis,
shock, cardiac ar¬rest, effect of various treatments and extreme
physiological conditions.
Sepsis and septic shock
In the last few years, an important body of knowledge has been
developed showing the pathophysiological relevance of the
sublin¬gual microcirculation in the development of multi organ
failure associated with sepsis. In addition to the compelling
experimental evi¬dence, the development of new videomicro¬scopic
techniques allows now the evaluation of the microcirculation in
critically ill pa¬tients. Consequently, the
sublingual microcirculation (Tongue
microcirculation,lingua
microcirculation,Side stream dark
field imaging (SDF))can be easily monitored at bed¬side.
Therefore, studies performed in the sublingual area show that
severe microcircu¬latory sublingual alterations are present in
septic patients (5). Sepsis results in derange¬ments of
microvascular flow, which can be identified in the early stages
of this disease. These abnormalities are more marked in the most
severely ill patients (57), those changes are present during
early course of infection even in preterm infants (3). Sepsis
mortality is closely linked to multi-organ failure; im¬paired
microcirculatory blood flow is thought to be a key point in the
pathogene¬sis of sepsis-induced organ failure (58). Im¬ages of
the sublingual microcirculation (Tongue
microcirculation,lingua
microcirculation,Side stream dark
field imaging (SDF))dur¬ing septic shock and
resuscitation have re¬vealed that the distributive defect of
blood flow occurs at the capillary level. Boerma validated
intra-observer and inter-observer reproducibility of OPS images
analysis for sublingual bed and concluded that semi¬quantitative
analysis of sublingual microcir¬culatory flow provides a
reproducible and transparent tool in clinical research to
moni¬tor and evaluate the microcirculation during sepsis (4). De
Backer and coworkers investi¬gated sublingual microcirculation
(Tongue
microcirculation,lingua
microcirculation,Side stream dark
field imaging (SDF))
in 50 pa¬tients with sepsis by using OPS technique; the density
of all vessels was significantly re¬duced in patients with
severe sepsis (4.5 [4.2-5.2] versus 5.4 [5.4-6.3]/mm in
volun¬teers, p < 0.01). The proportion of perfused small (< 20
um) vessels was reduced in pa¬tients with sepsis (48 [33-61]
versus 90 [89¬92]% in volunteers, p < 0.001), these alter¬ations
were more severe in nonsurvivors and they concluded that
microvascular blood flow alterations are frequent in patients
with sepsis and are more severe even in patients with a worse
outcome (44). The sublingual microcirculation
(Tongue
microcirculation,lingua
microcirculation,Side stream dark
field imaging (SDF))was investigated
by using OPS in patients with sepsis and organ failure in order
to characterize the time course of microcirculatory dysfunction
and relation to clinical outcome. Small vessel perfusion im¬proved over time in survivors (p<0.05 be¬tween survivors and
nonsurvivors) but not in nonsurvivors. Despite similar
hemodynamic and oxygenation profiles and use of vaso¬pressors at
the end of shock, patients dying after the resolution of shock
in multiple or¬gan failure had a lower percentage of per¬fused
small vessels than survivors (57.4 [46.6-64.9] vs. 79.3
[67.2-83.2]%; p =. 02) (59). Changes in microcirculation
occurred at an early stage in all patients with severe
sepsis/septic shock treated with early goal-di¬rected therapy,
sublingual perfusion indices were more markedly impaired in
nonsur¬vivors compared with survivors (57, 60). In¬terestingly,
sublingual microvascular de¬rangements in septic shock did not
differ be¬tween noncytopenic and cytopenic patients (61).
Haemodynamic monitoring of septic patients is often impeded by
the discrepancy between the macrocirculation and
microcir¬culations parameters, however some correla¬tion between
systemic hemodynamic param¬eters and microcirculation may exist,
as shown in a study comparing pulse contour analysis (PiCCO)
variables and sublingual microcirculation
(Tongue
microcirculation,lingua
microcirculation,Side stream dark
field imaging (SDF))perfusion indices,
where significant correlations were found for cur¬rent velocity
in small venules with systemic vascular resistance (r(2) =
0.252, p < 0.05) and mean arterial blood pressure (r(2) = 0.259,
p < 0.05), in addition, a significant correlation was also found
between the oxy¬gen transport index and the density of small
vessels in sublingual area (r(2) = 0.355; p < 0.05) (62). Recent
papers also reveal correla¬tion between lactate level and degree
of sub¬lingual microcirculation impairment. In 31 surgical
patients significant correlation be¬tween the total small vessel
density at 1 h and the blood lactate level at 24 h was found
(55). During septic shock, increased lactate may play an
important role in terms of wors¬ening microcirculatory
abnormalities, pa¬tients without hyperlactatemia presented
higher proportion of perfused vessel and mi¬crovascular flow
index (63). Changes in sub¬lingual microcirculation during
sepsis were identified also in children and infants (3, 64). To
summarize, the main characteristics of sublingual
microcirculation(Tongue
microcirculation,lingua
microcirculation,Side stream dark
field imaging (SDF))in patients with septic shock are hypoperfusion
and in¬creased flow heterogeneity and nonsurvivors showed more
severe alterations than sur¬vivors (65).
Effect of various interventions
Fluids, vasopressors/inotropes during sepsis and organ support
techniques are (together with the control of infection source)
key ele¬ments of treatment in all patients with severe sepsis
and septic shock. Each of these com¬ponents were extensively
studied with re¬gard to their effect on microcirculation dur¬ing
past years, however mainly in experi¬mental setting and
unfortunately only few human studies have been published so far.
Early protocol directed resuscitation (includ¬ing fluid
administration) was associated with reduced organ failure at 24
h and results sup¬port the hypothesis that targeting the
micro¬circulation distinct from the macrocircula¬tion could
potentially improve organ failure in sepsis (60). There is
ongoing discussion re¬garding target blood pressure in patients
with septic shock (66), increasing MAP above 65 mmHg with
norepineprhrine was associated with improved microvascular
function, on the other side, the microvascular response may vary
among patients suggesting that in¬dividualization of blood
pressure targets may be warranted (67). Effect of fluid
administra¬tion on microcirculatory alterations was eval¬uated
in 60 patients with severe sepsis, where fluid administration
increased signifi¬cantly perfused small vessel density,
impor¬tantly, microvascular perfusion increased in the early but
not in the late phase of sepsis and microvascular effects of
fluids were not related to changes in cardiac index or mean
arterial pressure (68). Dubin compared 6% hydroxyethyl starch (HES)
130/0.4 with nor¬mal saline for resuscitation during early
goal¬directed therapy (EGDT) in 20 septic patients by using SDF(sublingual
microcirculation,Tongue
microcirculation,lingua
microcirculation,Side stream dark
field imaging (SDF)),
sublingual capillary density was similar in both groups, but
capillary mi¬crovascular flow index, percent of perfused
capillaries, and perfused capillary density were higher in 6%
HES (69). The use of hy¬pertonic fluids in patients with septic
shock did not improve sublingual microcirculatory blood flow in
comparison to isotonic fluid (70). Improvement of
microcirculation in pa¬tients with severe sepsis may be
achieved, however, even by passive leg rising aiming to increase
intravascular volume (71). Using vasopressors to maintain blood
pressure has been an important part of septic shock, ac¬cording
to experimental results, their use may compromise
microcirculatory flow in different areas. To investigate the
effect of norepinephrine (NE) on sublingual microvas¬cular flow
(SDF)(sublingual
microcirculation,Tongue
microcirculation,lingua
microcirculation,Side stream dark
field imaging (SDF)) in patients with septic shock, increasing dose of NE was adminis¬tered to achieve MAP from 60 to 70-90 mm Hg. No changes
in sublingual microvascular flow index, vessel density, the
proportion of perfused vessels, perfused vessel density, or
heterogeneity index were identified during NE infusion (72).
Similar study was carried out in 20 septic shock patients where
at a MAP of 65 mmHg, norepinephrine was titrated to reach a MAP
of 75 mmHg, and then to 85 mmHg, sublingual microcirculation
was assessed by SDF imaging(sublingual
microcirculation,Tongue
microcirculation,lingua
microcirculation,Side stream dark
field imaging (SDF)). All pa¬tients showed severe
sublingual microcircu¬latory alterations failed to improve with
the increases in MAP with norepinephrine (69). Adding
terlipressin or arginine vasopressin to norepineprhrine (NE) in
patients with NE de¬pendent septic shock does not affect
sublin¬gual microcirculatory flow (73). Dobutamin is recommended
as an inotropic agent ac¬cording to Surviving Sepsis Campaign
Guidelines. De Backer evaluated effect of dobutamine on
microcirculatory alterations in 22 patients with septic shock,
dosage of 5 mug/kg.min dobutamine can improve but not restore
capillary perfusion in patients with septic shock and these
changes are in¬dependent of changes in systemic hemody¬namic
variables (74). Compared to dobuta¬mine, levosimendan improved
sublingual microcirculatory blood flow in patients with septic
shock, as reflected by changes in mi¬crocirculatory flow indices
of small and medium vessels (75) Dobutamine, however prevented
postoperative decrease of sublin¬gual microvascular blood flow
in patients af¬ter esophagectomy (76). The administration of
hydrocortisone in septic shock results in a modest but
consistent improvement in sub¬lingual capillary perfusion (77).
Transfusion as a part of EGDT protocols and Surviving Sepsis
Campaign Guidelines was also evaluated in terms of its effect on
mi¬crocirculation in patients with sepsis and sep¬tic shock. An
effect of red blood cell transfu¬sion on sublingual
microvascular perfusion was studied in 35 patients with sepsis
before and 1 hour after transfusion by using OPS im¬aging.
Microvascular perfusion was not sig¬nificantly altered by
transfusion, but there was considerable interindividual
variation. The change in capillary perfusion after trans¬fusion
correlated with baseline capillary per¬fusion and red blood cell
storage time had no influence on the microvascular response to
red blood cell transfusion (78-81). Effect of transfusion on
microcirculation probably also depends on baseline
microcirculatory status, patients with relatively altered
baseline vari¬ables (proportion of perfused vessel) tend to
demonstrate improvement in perfusion fol¬lowing transfusion,
whereas those with rela¬tively normal perfusion at baseline tend
to demonstrate either no change or, in fact, a decline in this
parameter (82). Mechanical ventilation and PEEP have no general
delete¬rious effects on microvascular perfusion of the
sublingual mucosa (83).
Heart failure and cardiogenic shock
Microcirculatory alterations are present in patients with severe
heart failure. De Backer evaluated sublingual microcirculation(Tongue
microcirculation,lingua
microcirculation,Side stream dark
field imaging (SDF))
in in 40 patients with acute severe heart failure, including 31
patients with cardiogenic shock, by using OPS and found the
propor¬tion of perfused small (<20 um) vessels was lower in
patients with cardiac failure and car¬diogenic shock than in
control patients (63% [46%-65%] and 49% [38%-64%] vs. 92%
[90%-93%], P <.001). The proportion of perfused vessels was
higher in patients who survived than in patients who did not
survive in all vessels (90% [84%-93%] vs. 81% [74%-87%], P <.05)
and in small vessels (64% [49%-68%] vs. 43% [37%-62%], P <.05)
(84). Similar results were found in Jung¡¯s study evaluating 24
critically ill pa¬tients admitted to ICU. Seven patients with
cardiogenic shock had lower microflow compared with patients
without cardiogenic shock (small p<0.001, medium p<0.001, large
p=0.003). Several other diseases, in¬cluding diabetes and
arterial hypertension, age, gender, had no influence on
microcircu¬latory parameters (85). Recent paper by El¬bers
revealed also microcirculatory abnor¬malities during atrial
fibrillation and succes¬full electrical cardioversion improved
in¬dices of sublingual microvascular perfusion (86), similarly
as with cardiac resynchroniza¬tion (87). To summarize the key
findings of sublingual microcirculation
(Tongue
microcirculation,lingua
microcirculation,Side stream dark
field imaging (SDF))during severe heart
failure and cardiogenic shock ¨C there is reduced vascular
density and impaired mi¬croflow, especially in the smallest
vessels (88). Vasopressors, inotropes and intra-aortic balloon
pump represent most often thera¬peutic approaches in patients
with severe heart failure and cardiogenic shock. Several studies
examined effect of those common in¬terventions with regard to
sublingual micro¬circulation. The first paper evaluating effects
of vasopressor therapy on sublingual microcirculation
(Tongue
microcirculation,lingua
microcirculation,Side stream dark
field imaging (SDF))by using
OPS was a case report in patients with severe distributive and cardio¬genic shock following cardiac surgery, where vasopressin
was used, however de¬spite its strong vasopressor effects
vaso¬pressin infusion did not worsen microcircu¬latory
alterations in this patient (89). Effect of nitroglycerine was
tested in 17 patients with cardiogenic shock and chronic heart
failure. Nitro-glycerine dose-dependently increases tissue
perfusion in patients with severe heart failure, as observed by
an increase in sublin¬gual perfused capillary density (90).
Similar findings were found during intravenous infu¬sion at a
fixed dose of nitroglycerine (NTG) 33 microg/min in 20 acute
heart failure pa¬tients, where even low-dose NTG significant¬ly
improved sublingual microvascular perfu¬sion (91). Effect of
intra-aortic balloon pump support (IABP) on macrocirculation and
sublingual microcirculation (SDF) (Tongue
microcirculation,lingua
microcirculation,Side stream dark
field imaging (SDF))in patients with cardiogenic
shock was studied by Uil, 13 patients were treated with IABP at
differ¬ent assist ratios. Discontinuation of IABP de¬creased the
mean arterial pressure and car¬diac index; however, these
changes in macrohemodynamics did not significantly influence
sublingual perfused capillary den¬sity and capillary red blood
cell velocity (92). Improved sublingual microcirculatory flow
after IABP was described by Jung in 13 pa¬tients with
cardiogenic shock (93), combin¬ing IABP with extracorporeal
membrane oxy¬genation has led in patient with severe re¬fractory
cardiogenic shock to further im¬provement of sublingual
microcirculatory flow assessed by SDF imaging(sublingual
microcirculation,Tongue
microcirculation,lingua
microcirculation,Side stream dark
field imaging (SDF)) (94). Interest¬ingly recent paper by Munsterman describes
discontinuing IABP support showed (SDF)(sublingual
microcirculation,Tongue
microcirculation,lingua
microcirculation,Side stream dark
field imaging (SDF)) an increase of
microcirculatory flow of small vessels after ceasing IABP
therapy and his observation may indicate that IABP impairs
microvascular perfusion in recovered pa¬tients (95).
Sublingual
microcirculation was assessed also during CPR, first report of
using SDF imaging(sublingual
microcirculation,Tongue
microcirculation,lingua
microcirculation,Side stream dark
field imaging (SDF)) during chest compressions re¬vealed persisting
capillary flow even during CPR interruption. Indices of
microvascular perfusion were low and were relatively
inde¬pendent from blood pressure (96). In cardio¬surgery, the
use of pulsatile cardiopulmonary bypass (CPB) preserves
microcirculatory per¬fusion throughout the early postoperative
pe¬riod, irrespective of systemic hemodynamics (97), also
changes in CPB flow rate within 20% did not alter the
sublingual microcirculation (98) on the other side, the use of the
miniaturized extracorporeal circulation sys¬tem is associated
with a statistically signifi¬cant reduction in sublingual
microcirculato¬ry hypoperfusion compared with the use of the
conventional extracorporeal circulation system (99). In off-pump
coronary artery by¬pass, cardiac displacement was accompa¬nied
by significant decrease of red blood cell velocity (100). During
cardiopulmonary by¬pass, different effect of various
inhalational anesthetic agents on indices of
sublingual
microcirculation (Tongue
microcirculation,lingua
microcirculation,Side stream dark
field imaging (SDF))was shown, sevoflurane had a negative effect on
the microcircula¬tion, isoflurane decreased vascular density and
increased flow, desflurane produced sta¬ble effects on the
microcirculation (101).
Interesting physiological study was pub¬lished just recently,
effect of high altitude on sublingual microcirculation
(Tongue
microcirculation,lingua
microcirculation,Side stream dark
field imaging (SDF))was
evaluated in 24 subjects using side stream dark field imag¬ing,
as they ascended to 5300 m.; one cohort remained at this
altitude, while another as¬cended higher (maximum 8848 m). Among
other variables, the Microvascular flow index (MFI) and vessel
density were calculated. To¬tal study length was 71 days, images
were recorded at sea level (SL), Namche Bazaar (3500 m), Everest
base camp (5300 m), the Western Cwm (6400 m), South Col (7950 m)
and departure from Everest base camp (5300 m; 5300 m-b).
Compared with SL, altitude resulted in reduced sublingual MFI in
small (<25 microm; P < 0.0001) and medium vessels (26-50 microm;
P = 0.006). The greatest reduction in MFI from SL was seen at
5300 m-b; from 2.8 to 2.5 in small vessels and from 2.9 to 2.4
in medium-sized vessels. The reduction in MFI was greater in
climbers than in those who remained at 5300 m ¨C in small and
medium-sized vessels (P = 0.017 and P = 0.002, respectively). At
7950 m, ad¬ministration of supplemental oxygen resulted in a
further reduction of MFI and increase in vessel density (102).
Summary
In humans, and especially in critically ill pa¬tients, the
evaluation of the microcirculation has long been difficult.
Recent years have witnessed the development of new tech¬niques
that can either directly visualize or in¬directly evaluate
microvascular perfusion. Currently, monitoring
sublingual microcirculation by OPS/SDF imaging
(sublingual
microcirculation,Tongue
microcirculation,lingua
microcirculation,Side stream dark
field imaging (SDF))remains the only one
possibility how to evaluate patient¡¯s mi¬crocirculation at the
bedside. In humans, fur¬ther improvement, particularly in area
of de¬veloping rapid, simple and fully automated analyzing tool
allowing quantitative assess¬ment during imaging or immediately
may help to identify the patients at risk for devel¬oping
multiple organ failure linked to insults of various kind. Early
detection of microvas¬cular abnormality is a key factor to start
early therapeutic intervention to reverse microvas¬cular
dysfunction and to achieve better clini¬cal outcome. In
experimental setting, observ¬ing sublingual microcirculation(Tongue
microcirculation,lingua
microcirculation,Side stream dark
field imaging (SDF)) is
an impor¬tant part of any research focused on the role of
microcirculation during various diseases models and to assess
effect of different treat¬ment modalities on microcirculation.
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