Clinical relevance of early sublingual microcirculation monitoring in septic shock patients

Abstract

INTRODUCTION:

Although microcirculation dysfunction plays unique role in septic shock, translation of microcirculation to clinical practices is limited by current semi-quantities analysis and unclear clinical relevance of microcirculation monitoring. Our aim was to critically evaluate the characteristic nature and relevant clinical important of microcirculation.

EVIDENCE ACQUISITION:

Pubmed (2000 to August 2015) were searched to identify observation, case-control, intervention and randomized clinical studies evaluating the relationship between microcirculation alterations and mortality, morbidity and drug responses. The STROBE and CONSORT Statement for assessment of the quality of included studies.

EVIDENCE SYNTHESIS:

We examined results from 17 observations, 4 randomized controlled trials and one case report published studies. This data set comprised of 637 patients. Early septic shock is associated with hypoperfusion and heterogeneous microcirculation that is associated with hyperlactemia and metabolic acidosis. The evidence on clinical relevance of microcirculation is less striking, mainly due to the limited number of studies and problems related to the methodological protocol of the studies and currently semi-quantitative analysis technique. In particular the baseline and time course of microcirculation alteration appears to be controversial.

CONCLUSION:

There is lack of evidences of clinical importance of early microcirculation monitoring and mechanism of microcirculation dysfunction in septic shock patients. This could be due to the methodological protocol of the studies and currently semi-quantitative analysis technique.

Keywords

Septic shock tissue perfusion organ dysfunction drug response hemodynamic

1 Introduction

Microcirculation plays a key role in the pathophysiology of various disease states. Microcirculation could behave differ from that of systemic circulation, especially in shock states. Sublingual microcirculatory derangements consist of a decreased microvascular density, perfusion, along with increased flow heterogeneity in septic shock patients [1 –3]. The correction of those abnormalities has been suggested as a valid therapeutic goal [4, 5].

Recently, technological advances have enhanced the image quality of the microcirculation. Orthogonal polarization spectral (OPS) imaging and side-stream dark field (SDF) imaging have been extensively employed in the field of clinical microcirculatory research. However, they still present some drawbacks such as suboptimal imaging induced by excessive probe pressure and movements of devices [6].

Cytocam- Incident dark field imaging (IDF) automated technique is the third generation novel tool that has been validated by previous studies [7 –9].

Although evolution in non-invasive microcirculation monitor, the relevant clinical important of microcirculation monitoring during septic shock remains unclear. The objectives of our systematic review were to: 1. critically evaluate the characteristic nature and relevant clinical important of microcirculation monitoring, mainly as the risk screening and therapeutic monitoring tool during early septic shock, and whether the scientific findings of previous studies are consistent and can be generalised to different populations and 2. Use of current best evidences in making suggestions about future trials of predictive power of septic shock microcirculation monitoring.

2 Material and methods

2.1 Identification of studies

Investigators conducted searches of studies from January 2000 to August 2015 using Pubmed electronic databases. To capture the broadest possible sample of relevant articles, we used multiple search terms, including: terms related to critically illness (intensive care, ICU, critically ill, intensive care unit, critical care, severely ill and emergency), terms related to perfusion and vasculature (microcirculation, tissue perfusion, microvasculature, vasoplegia, endothelium, capillary), terms related to septic shock (sepsis, shock, hypovolemia, hypotension, acidosis), and terms related to drug therapy (resuscitation, vasopressor, inotropic, fluid, crystalloid, colloid). Next, we manually examined the reference sections of relevant reviews for studies that meeting our inclusion criteria to locate articles not identified in the database. Studies that were published in Germany were translated to English and further reviewed (See Supportive file 1 PubMed searching protocol; for more details).

2.2 Inclusion criteria

In order to be included in the systematic review and comparison, the clinical studies (observational and experimental) had to meet the following inclusion criteria: 1. Published in English or German; 2. Included a group of patients (>18 years old) diagnosed with septic shock according to the international criteria for septic shock [10 –13]; 3. Microcirculatory assessment, concomitantly to evaluation of systemic hemodynamic and perfusion parameters, were performed during septic shock.

2.3 Quality assessment of included studies

Both STROBE and CONSORT Statement for observation and randomized clinical trials were employed to assess the reporting quality of included studies. These statements comprise items evaluating the quality of observational and interventional studies in terms of selection, randomization, comparability, outcome, bias and confound variables controlling (See Supportive file 2 STROBE and CONSORT checklist; for more details).

2.4 Data abstraction

A standardised form was made for data abstraction. To increase the accuracy of coding and data entry, each article was coded by two raters. Coders extracted several characteristics of each study. We collected information on author, year of publication, country where the study was conducted, study design, criteria of included patients, number of patients, protocol of microcirculation assessment, outcomes measures used and duration of studies (See Supportive file 3 data extraction sheet; for more details).

3 Results

3.1 Description of studies

Our query on August 2015 produced 3149 results. We excluded 3101 studies and identified a total number of 48 studies of which 26 not considered after reviewing (See Supportive file 4 List of primary included articles that were excluded after reviewing; for more details).

From 99 reviews, an additional 28 candidates, not covered in the database search, were added for consideration, of which only one were obtained and included Fig. 1.

Fig.1

Flowchart of searching protocol.

In this paper, we examined results from 17 observations, 4 randomized controlled trial and one case report published studies. 1–3, 14–32 This data set comprised of 637 patients. The studies have been conducted in the Argentina (4), Chile (4), Brazil (1), Italy (4), Belgium (4), United Kingdom (1), Netherlands (4), China (1) and Czech Republic (1) Table 1.

Table 1

Microcirculation characterization and its clinical importance in septic shock patients

study	type	Frequency of microcirculation assessment	Baseline microcirculation character*	Microcirculation time course character^$	Tissue oxygenation status	Tissue metabolic status	Measured outcomes	Main findings
[1]	PO	Once (24 hrs)#	Hypoperfusion: mild-severe Heterogeneous: mild-severe	N/A	Normal DO₂; VO₂; O₂ER	Metabolic acidosis and hyperlactemia	-HM -SOFA	Baseline microcirculation derangements and hyperlactemia were more severe in non-survivors
[2]	PO	24 hours after septic shock development and 24 hrs after shock resolution	Hypoperfusion: severe Heterogeneous: severe	Significant increase in perfusion and decrease in heterogeneous after shock resolution	N/A	Significant reduction of lactate level after shock resolution	-Leukocyte and platelet alterations -Tissue perfusion alteration	Chemotherapy-induced cytopenia did not modify the pattern of sepsis-induced microvascular dysfunction.
[3]	PO	Once (6 hrs) #	Hypoperfusion: severe Heterogeneous: Mild-severe	N/A	N/A	Hyperlactemia	-ICUM -HM -SOFA	Baseline microcirculation derangements and hyperlactemia were more severe among organ dysfunction and non survivor
[14]	RCT	Before (21–52 hrs) # and 6 hours after different treatments (TP, AVP, NE)	Hypoperfusion: mild-severe Heterogeneous: mild-severe	Significant increase in perfusion and decrease in heterogeneous after TP, AVP and NE with no significant differences between all treatments	No difference in DO₂, VO₂ and O₂ER	Persistent hyperlactemia after TP, AVP and NE	Tissue perfusion alteration	Persistent hyperlactemia, in spite of improved microcirculatory perfusion TP, AVP and NE had similar effects on the microcirculation.
[15]	PO	4 different MBPs [65(48 hrs)#, 75, 85, 65]	Hypoperfusion: mild-severe Heterogeneous: mild-severe	Non significant tendency to increase microcirculation perfusion and decrease heterogeneous	Significant increase DO₂; O₂ER	Significant decrease in lactate level	Tissue perfusion alteration	Individual variable microvascular responses.
[16]	RCT	Before (24 hrs)# after Levosimendan (24 hrs)	Hypoperfusion: mild-severe Heterogeneous: mild-severe	Significant increase in perfusion and decrease in heterogeneous	No difference in DO₂, VO₂ and O₂ER	persistent hyperlactemia	Tissue perfusion alteration	Persistent hyperlactemia in spite of improved microcirculatory perfusion
[17]	PO	Before (24 hrs)#, 12 hrs HVHF and 6 hrs after HVHF	Hypoperfusion: mild-severe Heterogeneous: mild-severe	Non significant reduction tendency of microcirculation heterogeneous alterations Only MFI significantly increased	No differences in DO₂, VO₂ and O₂ER	Significant reduction in lactate level	Tissue perfusion alteration	Microcirculatory flow index and hyperlactemia significantly improved.
[18]	PO	Daily for 7 days after septic shock development	Hypoperfusion: severe Heterogeneous: severe	Significant improvement of microcirculatory perfusion observed among survivor in comparison to non survivor	No differences in DO2,VO2 and O₂ER between survivor and non survivor	Significant difference in lactate level between survivor and non survivor	-Organ dysfunction -ICU length stay -7 day survival rate	Time course of microcirculation derangement and not baseline alterations can characterize outcome during septic shock.
[19]	PO	Before (12 hrs)# and 4 times after hydrocortisone [1 , 24 hrs]	Hypoperfusion: severe Heterogeneous: severe	Early (1–4 hrs) significant changes in perfusion and heterogeneous alterations that persist with no significant differences after 24 hrs	N/A	Persistent hyperlactemia	Tissue perfusion alteration	Discrete effects of hydrocortisone on microcirculation
[20]	PO	3 different MBPs [65(24 hrs)#, 75, 85]	Hypoperfusion: mild-moderate Heterogeneous: severe	No significant changes in perfusion and heterogeneous alterations	No differences in DO₂ and VO₂	Persistent metabolic acidosis and hyperlactemia	Tissue perfusion alteration	Individual variable microvascular responses
[21]	RCT	Before (24 hrs)# and after dobutamine	Hypoperfusion: severe Heterogeneous: mild-severe	No changes in perfusion and heterogeneous alterations	Significant increase in DO₂ but no significant changes in VO₂	Persistent hyperlactemia	Tissue perfusion alteration	Persistent microcirculatory derangement and hyperlactemia
[22]	PO	Before (24 hrs)# and after dobutamine	Hypoperfusion: mild-severe Heterogeneous: mild-severe	No differences in perfusion and heterogeneous alterations	Significant increase DO2 and decrease in O₂ER but no significant effects on VO2	Persistent hyperlactemia	Tissue perfusion alteration	Individual variable microvascular responses
[23]	PO	Before (48 hrs)# and twice after Terlipressin (6 hrs)	Hypoperfusion: mild-severe Heterogeneous: mild-severe	Significant improve in microcirculatory perfusion and reduction in heterogeneous	N/A	Persistent hyperlactemia	Tissue perfusion alteration	Terlipressin effectively improved microcirculatory parameters
[24]	PO	Before (24 hrs#) and after Dobutamine treatment	Heterogeneous: severe	Significant decrease of microcirculation heterogeneous	Only significant increase VO₂	Significant decrease in lactate level	Tissue perfusion alteration	Significant relation between microcirculation and tissue metabolic status
[25]	PO	4 different MBPs 60(24 hrs)#, 70, 80, 90]	Hypoperfusion: severe Heterogeneous: mild-severe	No changes in perfusion and heterogeneous alterations	No changes in DO₂ and VO₂	Persistent hyperlactemia	Tissue perfusion alteration	Persistent microcirculatory derangement and hyperlactemia in spite of global improved tissue oxygenation
[26]	PO	Before (24 hrs)# and twice after esmolol treatment (24 hrs)	Hypoperfusion: mild Heterogeneous: mild	Except for MFI, No differences in microcirculatory perfusion and heterogeneous parameters	Significant decrease in DO2,VO2 and O₂ER	Persistent hyperlactemia	Tissue perfusion alteration	Except for microvascular blood flow and stroke volume, esmolol had no effect on other microvascular or tissue metabolic status
[27]	CO	Once (24 hrs)#	Hypoperfusion: mild-severe Heterogeneous: mild-severe	N/A	N/A	Hyperlactemia	- Tissue perfusion alteration -HM -SOFA	Only baseline microcirculation derangements and hyperlactemia were more severe in non-survivors
[28]	PO	First and third day after septic shock development	Reduced sublingual and stoma MFI	Significant increase of both sublingual and stoma MFI	N/A	N/A	Tissue perfusion alteration	Lack of early correlation between sublingual and stoma microcirculation that restored later
[29]	PO	Before (24 hrs)# 3 times after papaverine treatment [15, 30, 60 min]	Hypoperfusion: mild Heterogeneous: mild	Significant improve in microcirculatory perfusion	N/A	Persistent hyperlactemia	Tissue perfusion alteration	Microcirculation improvement after short term papaverine treatment
[30]	PO Cross over	Once (48 hrs)#	Hypoperfusion: severe	N/A	Significant increase DO₂ and decrease EO₂ after dobutamine in comparison to placebo treatment	Significant decrease in lactate level	Tissue perfusion alteration	Dobutamine improved microvascular perfusion, an effect that is independent of its global hemodynamic effects.
[31]	RCT	Before (24 hrs#) and after isotonic or hypertonic fluid	Hypoperfusion: mild-moderate Heterogeneous: mild-moderate	No changes in perfusion and heterogeneous alterations	N/A	Persistent Hyperlactemia	Tissue perfusion alteration	Persistent microcirculatory derangement and hyperlactemia in spite of hemodynamic improvement
[32]	CR	One hour after septic shock development and 3 times after telipressin infusion(20, 40, 60 min)	No evidence of heterogeneity	Dramatic decrease in PPV and eventually a complete stand-still of flow	N/A	N/A	–	Telipressin could be deleterious to microcirculatory perfusion

^*Baseline microcirculation is classified in to hypoperfusion: mild-moderate; PVD >12 n/mm or severe; PVD ≤ 12 n/mm and heterogeneous: mild-moderate; PPV>86%, HI≤1 or severe; PPV≤86%, HI>1; # after ICU admission and stabilization; $ spontaneous dynamic changes of microcirculation were reported in references [4 , 21], interventional dynamic changes of microcirculation were reported in references [6 , 12–20] and blood pressure related dynamic changes of microcirculation were reported in references [3 , 7]. PO; Prospective, observational, CO; Cross section observational, RCT; randomized controlled trial, CR; case report HVHF; high-volume hemofiltration, TP; terlipressin, AVP; arginine vasopressin, NE; norepinepheribne, MFI; microvascular flow index; n/mm, number of vessels per millimetre, PPV; proportion of perfused vessels, PVD; perfused vascular density, HI; heterogeneous index, SmvO2, mixed venous oxygen saturation, N/A; non applicable, DO2; oxygen delivery index, VO₂; oxygen consumption index, O₂ER; oxygen extraction ratio, SOFA; Sepsis-related Organ Failure Assessment score, HM; Hospital Mortality(%), ICUM; ICU mortality(%), MAP, mean arterial pressure.

3.2 Risk of bias in included studies

In general, the included studies did not show major problems of selection bias; the majority use the same population. However, Losses to follow-up might represent a problem for mortality and morbidity studies, in some studies the amount of losses to follow-up is not reported and the possible risk of bias is not predictable. Blinding was not well reported in almost all studies. The quality of allocation was unclear in RCT. Since many factors can influence microcirculation, such as sedation [33] and vascular diseases (mainly hypertension [34] and diabetes mellitus [35]), adjustment for confounding factors was a relevant quality problem in almost all studies.

3.3 Sublingual microcirculation assessment as risk screening tool

Three observation studies reported the predictive value of early baseline alteration of microcirculation 1, 3, 27. Clinical significance of time course of microcirculation was reported in 3 observation studies 2, 18, 28 Table 1.

3.4 Sublingual microcirculation assessment as drug response monitoring tool

Therapeutic responses of microcirculation to different treatment strategies were reported in 13 observation interventional studies (5 vasopressors 15, 20, 23, 25, 32, 4 HR modulating treatments 22, 24, 26, 30, 3 other interventional 17, 19, 29) and 4 randomized control studies 14, 16, 21, 31 Table 1.

4 Discussion

This systematic review synthesises the evidence from observations and RCTs studies that were designed to investigate the clinical relevance of microcirculation monitoring in early septic shock patients across a wide variety of conditions. Risk and therapeutic screening were chosen in this systematic review because they are clinically relevant in the efficacy of early microcirculation monitoring in septic shock patients.

The evaluation of microcirculation takes into account the assessment of density, perfusion, and flow heterogeneity. Total vessel density (TVD) and perfused vessel density (PVD) are used to quantify density. Microvascular flow index (MFI) is used to describe tissue perfusion, and difference in MFI between different investigated areas is used to calculate heterogeneity index. We found that evidences support decreased perfusion and heterogeneous circulation during septic shock. Furthermore, no direct relation between macrocirculation and microcirculation changes was observed during septic shock. However, we observed lack of consistency in evidences for clinical importance of microcirculation monitoring during septic shock.

Hernandez et al. [27] previously suggested cut-offs of 86% for proportion perfused vessel (PPV) and 12 n/mm for perfused vessel density (PVD) as critical determinant values for outcomes. In one time point cohort study, Edul et al. [1] reported that mainly PVD and PPV, were more severe altered in non-survivors. Non-survivors had significantly lower PVD (n/mm); 11.3 [7.4–13.8] and PPV; 79.8% [70.1% – 93.5%] values in comparison to survivors [27]. However, Sakr et al. [18] could not find significant differences in vascular density (5.6 [4.7–7.0] vs. 6.2 [5.4–7.0]/mL) and the percentage of perfused small vessels (65.0 [53.1–68.9] vs. 58.4 [47.5–69.1] between survivors and non-survivors at onset of septic shock. Furthermore, they demonstrated that small vessel perfusion increased over time in survivors but not in non-survivors, whether they died during the septic shock episode or later due to persistent organs dysfunctions. Change in small vessel perfusion less than 7.8% was associated with 71% mortality rate. The areas under the receiver operating characteristic curve (ROC) for changes in small vessel perfusion between the first and second day of shock as well as between the first and last day of shock were higher than for changes in any of the other hemodynamic and biological observed variables [18]. Meanwhile, Boerma et al. reported that all observed patients with persistent reduction in microcirculatory flow survived to hospital discharge, whereas 22% of patients with a normal flow died [28].

Individualization of microcirculation responses was suggested with different observation interventional studies. Both Thooft et al. [15] and Dubin et al. [20] found considerable inter-individual variations in the microcirculation responses to the increases in mean pressure with norepinephrine that seem to depend on the basal condition of the microcirculation. Perfused capillary density improved in patients with severe altered sublingual perfusion at baseline, and decreased in patients with preserved basal microvascular perfusion [20]. Enrico et al. 22 reported individual variable response of microcirculation to dobutamine infusion that is not related to the cardiac index or the mean arterial pressure modifications rather to the basal PVD. They also reported that patients with PVD of 12 mm/mm2 or less at baseline showed an improved microcirculation in response to dobutamine. These findings further supported by Hernandez et al. 21, randomized, double-blind, crossover study that failed to find significant effect of dobutamine on perfused microvascular density or in any of the other assessed microcirculatory variables. Debaker et al. 30 also reported the quite variable alterations in capillary perfusion among patients with septic shock, who were treated with dobutamine. The observed changes were larger when microvascular perfusion was more severely altered at baseline, and they were not related to observed changes in cardiac index, arterial pressure, or in systemic vascular resistance. Administration of hydrocortisone was demonstrated to result in a discrete (only PVD), but significant, improvement in microcirculatory variables, independent of changes in global hemodynamic variables in septic shock patients. Significant negative relationship between microvascular response to hydrocortisone and baseline microvascular perfusion was also observed, and this response was not related to the improvement of vascular tone [19]. Moreover, only patients with the worst PVD and PPV had the largest improvements during the 12-hour high volume hemofiltration (HVHF) [17].

Patients who had similar microcirculation baseline, failed to show significant differences in microcirculation responses to different vasopressor treatments (terlipressin (TP) and arginine vasopressin (AVP)) [14] or even to different types of fluid therapy [31].

It remains unclear whether the observed significant improvement of microcirculation after levosimendan [16], dobutamine [24], terlipressin [23] or papaverine [29] is due to specific therapeutic effects of different drugs or due to spontaneous improvement of microcirculation.

Microcirculation plays a unique determinant role on the metabolic status of different tissues early during septic shock. The semi-quantitative descriptive results across 22 independent studies, with a number of different factors, including races and health care quality, found that hyperlactemia and acidosis were associated with a reduction in the microcirculatory flow and increasing of the perfusion heterogeneity.

Loss of parallel relationship between macrocirculation (MBP and CVP) and microcirculation during early septic shock (12–24 hours) found in most of included studies. Only Trzeciak et al. [36] reported a direct relationship between macrocirculation and microcirculation parameters during early sepsis (6 hours). Moreover, they found that parallel relationship was associated with successive fluid resuscitation therapeutic strategy [36, 37].

Microcirculation plays a key role in the pathophysiology of shock states. Microcirculation could behave differ from that of systemic circulation, especially during sepsis [38 –40]. The factors contribute to individualize character of microcirculation and spontaneous responding capability of microcirculation remains unclear. Few studies investigated the role of endothelium functionality and micro-rheological changes on the observed microcirculation alteration during early septic shock [41 –43]. Septic shock vasoplegia was characterized by intact endothelium dependent vasodilatation response, and differential responses of vascular endothelium to vasopressors, with exaggerated vasoconstrictor response to vasopressin and impaired vasoconstrictor response to alpha adrenoceptor and angiotensin II receptor agonists [44, 45]. Debaker et al. [30] previously reported significant increased perfused capillary density and PPV after topical application of acetylcholine, suggesting that early septic shock microcirculation alteration is associated with intact endothelium dependent vasodilatation response. Karvunidis et al. [2] suggested that circulating peripheral leukocytes might not be a dominant prerequisite for microcirculatory distress in sepsis.

Insight of previous OPS and SDF obtained evidences, we suggest that microcirculation has unique character that could not be interpreted by different macrocirculatory parameters and it significantly influences tissue metabolic status and functionality. The factors contribute to this observation remain obscure and need further investigations. From all included trials, we still cannot conclude the predictive value of early microcirculation monitoring because of heterogeneous evidences. This could be due to the methodological protocol of the studies and semi-quantitative analysis technique.

We recognized limitations in our systematic review: First; even though the search strategy was designed in order to be as comprehensive as possible, we cannot exclude that some study has been missed and not included in this systematic comparison. Second; we considered only published studies, which could introduce reporting bias.

5 Conclusion

In spite that microcirculation plays unique determinant role in tissue metabolism and functionality, the evidence on the critical predictive value of microcirculation is not consistent, mainly due to the limited number of studies, problems related to the methodological quality of the studies and the variability in microcirculation assessment protocol. Our systematic review is expected to enhance future investigations to identify detrimental variables that could influence microcirculatory behaviour, improve microcirculatory analysis techniques and to construct measurement protocol (including parameter of interest, onset and frequency of measurement).

Authors’ contributions

NS and CL carried out the study design and performed the analysis. RM, SW and RG carried out studies recruitment and data extraction. NS, RG and CL participated in study qualifications. SW participated also in study coordination. All authors helped to draft the manuscript.

Footnotes

The Supporting Information is available in the electronic version of this article: .

Acknowledgments

This study was funded by the Stars in Global Health program (sponsored by Grand Challenges Canada).

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