
==== Front
Intensive Care Med Exp
Intensive Care Med Exp
Intensive Care Medicine Experimental
2197-425X
Springer International Publishing Cham

39222259
662
10.1186/s40635-024-00662-3
Research Articles
Nitroglycerin challenge identifies microcirculatory target for improved resuscitation in patients with circulatory shock
http://orcid.org/0000-0001-5861-4505
Bertacchi Massimiliano 1
http://orcid.org/0000-0001-7775-3279
Wendel-Garcia Pedro D. 1
Hana Anisa 1
Ince Can 2
http://orcid.org/0000-0001-8180-2117
Maggiorini Marco 1
http://orcid.org/0000-0002-2765-881X
Hilty Matthias P. matthias.hilty@usz.ch

1
1 https://ror.org/01462r250 grid.412004.3 0000 0004 0478 9977 Institute of Intensive Care Medicine, University Hospital of Zurich, Zurich, Switzerland
2 https://ror.org/018906e22 grid.5645.2 0000 0004 0459 992X Laboratory of Translational Intensive Care, Department of Intensive Care, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
2 9 2024
2 9 2024
12 2024
12 765 10 2023
21 8 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Background

Circulatory shock and multi-organ failure remain major contributors to morbidity and mortality in critically ill patients and are associated with insufficient oxygen availability in the tissue. Intrinsic mechanisms to improve tissue perfusion, such as up-regulation of functional capillary density (FCD) and red blood cell velocity (RBCv), have been identified as maneuvers to improve oxygen extraction by the tissues; however, their role in circulatory shock and potential use as resuscitation targets remains unknown. To fill this gap, we examined the baseline and maximum recruitable FCD and RBCv in response to a topical nitroglycerin stimulus (FCDNG, RBCvNG) in patients with and without circulatory shock to test whether this may be a method to identify the presence and magnitude of a microcirculatory reserve capacity important for identifying a resuscitation target.

Methods

Sublingual handheld vital microscopy was performed after initial resuscitation in mechanically ventilated patients consecutively admitted to a tertiary medical ICU. FCD and RBCv were quantified using an automated computer vision algorithm (MicroTools). Patients with circulatory shock were retrospectively identified via standardized hemodynamic and clinical criteria and compared to patients without circulatory shock.

Results

54 patients (57 ± 14y, BMI 26.3 ± 4.9 kg/m2, SAPS 56 ± 19, 65% male) were included, 13 of whom presented with circulatory shock. Both groups had similar cardiac index, mean arterial pressure, RBCv, and RBCvNG. Heart rate (p < 0.001), central venous pressure (p = 0.02), lactate (p < 0.001), capillary refill time (p < 0.01), and Mottling score (p < 0.001) were higher in circulatory shock after initial resuscitation, while FCD and FCDNG were 10% lower (16.9 ± 4.2 and 18.9 ± 3.2, p < 0.01; 19.3 ± 3.1 and 21.3 ± 2.9, p = 0.03). Nitroglycerin response was similar in both groups, and circulatory shock patients reached FCDNG similar to baseline FCD found in patients without shock.

Conclusion

Critically ill patients suffering from circulatory shock were found to present with a lower sublingual FCD. The preserved nitroglycerin response suggests a dysfunction of intrinsic regulation mechanisms to increase the microcirculatory oxygen extraction capacity associated with circulatory shock and identifies a potential resuscitation target. These differences in microcirculatory hemodynamic function between patients with and without circulatory shock were not reflected in blood pressure or cardiac index.

Supplementary Information

The online version contains supplementary material available at 10.1186/s40635-024-00662-3.

Keywords

Microcirculation
Critical care
Sublingual microcirculatory assessment
Microcirculatory reserve capacity
Capillary recruitment
Resuscitation
University of Zurich Walter und Gertrud Siegenthaler Foundationissue-copyright-statement© European Society of Intensive Care Medicine and Springer Nature Switzerland AG 2024
==== Body
pmcBackground

Circulatory shock and multi-organ failure remain primary contributors to morbidity and mortality in critically ill patients. Circulatory shock, defined as a life-threatening state of insufficient tissue perfusion and oxygenation, is closely related to hemodynamic impairment on a macro- and microcirculatory level [1], and it is generally accepted that the goal of resuscitation should be the restoration of tissue perfusion and oxygenation. It remains challenging, however, to use the microcirculatory function as a resuscitation target, not only because of a lack of techniques incorporated in resuscitation procedures targeting tissue perfusion, but foremost because of a lack of understanding of the intrinsic regulation mechanisms of the microcirculation in response to reduced oxygen availability in the tissues and their role in circulatory shock, which is elemental in the definition of treatment targets. Previously, a clear association has been shown between the degree of sublingual microcirculatory dysfunction and outcome in adults [2–4] and children [5] presenting with circulatory shock, with a reduced functional capillary density (FCD), capillary red blood cell flow velocity (RBCv), or inter-capillary heterogeneity representing the most frequently observed abnormalities [6–9]. To counteract reduced oxygen availability in the tissue, as examinations in hypoxemic healthy volunteers exposed to high altitude have suggested [10, 11], regulation mechanisms intrinsic to microcirculation, such as the recruitment of FCD, may provide for an increase in oxygen extraction capacity in the tissue by decreasing diffusion distances, independent of cardiac output and arterial blood pressure. Previous observations in patients with circulatory shock have shown that the topical sublingual application of acetylcholine further increased FCD after systemic administration of dobutamine in patients with septic shock [12], and in comparison to native measurements in patients with cardiogenic shock [6], revealing the presence of microcirculatory reserve capacity which can be utilized for improving oxygen extraction and thereby optimizing resuscitation. However, acetylcholine-dependent vasodilation relies on proper endothelial cell function which may be altered in conditions of inflammation, thus not revealing the full reserve capacity. An endothelial cell-independent alternative may be the use of a topical excess of nitroglycerin. Inconsistency between the extent of intrinsic compensation and the nitroglycerin response could also help explain the loss of coherence between the macro- and microcirculation that has previously been described in these patients [7, 9]. To explore the characteristics of the nitroglycerin-elicited microcirculatory reserve capacity in patients being resuscitated from circulatory shock, in the present study we compared the native sublingual microcirculatory FCD and capillary RBCv to the changes in these variables as a result of topical nitroglycerin administration sublingually in patients admitted to the ICU with circulatory shock after the initial resuscitation and those without circulatory shock. Our hypothesis was that (I) patients suffering from circulatory shock have a lower native FCD and RBCv as compared to patients without circulatory shock, and (II) they present with a lower microcirculatory reserve capacity as identified by a nitroglycerin challenge as compared to patients without circulatory shock as a sign of intrinsic compensatory mechanisms of the microcirculation to increase oxygen extraction in the tissue. We propose that sublingual handheld vital microscopy offers a technique to quantitatively measure FCD and RBCv as the determinants of tissue perfusion and that a topical nitroglycerin challenge would allow identification of recruitable microcirculatory fraction still in need of resuscitation.

Methods

In this prospective observational study, mechanically ventilated patients admitted to the ICU of the University Hospital of Zurich from January 1st, 2018, to January 31st, 2019 were consecutively screened for inclusion. Patient inclusion in the study was concluded when the intended number of patients presenting with circulatory shock was reached. The study was approved by the ethics committee of the Canton of Zurich (BASEC 2017-01564, ClinicalTrials.gov Identifier: NCT03651635) and conducted in accordance with the Declaration of Helsinki.

Study design

Inclusion criteria were mechanical ventilation and the availability of research personnel to perform microcirculatory measurements in the first 24 h after admission and after the initial resuscitation according to the clinical standard of practice [13]. Exclusion criteria were age under 18 years and missing explicit consent of the patient or legal representative. Written informed consent for participation from the patient, or in case of death or disability, from the next of kin or legal representative was sought for every included patient. Patients were then retrospectively divided into two groups. Patients with persistent signs of circulatory shock after initial resuscitation, as defined by the presence of more than three of the following criteria: cardiac index < 2.2 l/min/m2 [1], lactate concentration > 2 mmol/l [14], vasopressor dependency index > 3 [15], Mottling score ≥ 2 [16], capillary refill time > 3 s [17], mean arterial pressure < 65 mmHg [14], or the need for veno-arterial extracorporeal membrane oxygenation [18], were assigned to the circulatory shock group. All criteria for circulatory shock were recorded at the time of microcirculatory measurement. The other patients were assigned to the control group. The hypothesis was tested by comparing the sublingual microcirculatory hemodynamics between the two groups, with the difference in FCD serving as the primary end point. As a secondary end point, we analyzed RBCv, the nitroglycerin response, and the correlation between micro- and the macrocirculatory variables. Finally, we analyzed the differences in the microcirculatory variables in survivors and non-survivors at 28 days.

Measurement of the sublingual microcirculation and clinical variables

The sublingual microcirculation was assessed by performing a bedside optical visualization of sublingual capillary bed with incident dark-field imaging [19, 20] by gently placing a handheld vital microscope under the tongue. Sublingual microcirculation was measured within the first 24 h after admission, after the initial volume and catecholamine resuscitation as performed by independent physicians in the ICU according to the clinical standard of practice. Following the current guidelines [21] and a recently described method to assess recruitability using the topical application of nitroglycerin [22], six recordings of sublingual microcirculation were performed for each measurement using a high-resolution incident dark-field handheld vital microscope (Braedius Medical, Huizen, The Netherlands) placed without pressure on the sublingual mucosa. Three initial recordings of 20 s (250 frames) were taken in different sublingual territories, and three additional recordings 60 s after the topical administration of three drops (150 μl) of 1% nitroglycerin (4.4 × 10−2 M, diluted in 1:100 NaCl 0.9%) for a final dose of 0.015 mg per application. This protocol has previously been demonstrated to avoid impact on systemic blood pressure and leave no measurable traces of nitroglycerin metabolites in the systemic circulation [23]. All image sequences of the sublingual microcirculation were recorded and stabilized using the CCTools software [24] (Braedius Medical, Huizen, The Netherlands) and assessed using the Massey score [25]. Recordings with a Massey score ≥ 10 were excluded from further analysis. Acceptable quality in > 50% of all image sequences per patient was required for analysis. Automated image sequence analysis and calculation of FCD and capillary RBCv, considering all vessels with a diameter < 20 µm, was then performed using the MicroTools advanced computer vision software (Active Medical BV, Leiden, The Netherlands) [26]. The mean of the three initial measurements was reported as the native microcirculatory FCD and RBCv, and the mean of the three measurements after application of a topical sublingual nitroglycerin challenge was reported as FCDNG and RBCvNG (Fig. 1B). The difference between the two measurements was reported as ΔFCDNG and ΔRBCvNG. Arterial blood pressure and central venous pressure were measured immediately before each microcirculatory measurement, via a fluid-filled catheter inserted into the radial artery and the internal jugular vein, respectively. Mottling score and capillary refill time were assessed by trained personnel at the same time as described in detail elsewhere [16, 17]. Cardiac output was measured either via transpulmonary thermodilution (PiCCO, Getinge, Gothenburg, Sweden) or continuous cardiac output monitoring via a Swan–Ganz catheter (Edwards Life Sciences, Irvine, USA). Arterial blood gas analysis, SAPS, and SOFA scores were extracted from the patient data monitoring system, and 28-day survival was recorded during follow-up.Fig. 1 Study flowchart, including the number of microcirculatory measurements for each group (A) and representation of the study design with the initial cardio-respiratory resuscitation at admission, followed by the microcirculatory measurements of sublingual capillaries. The left column with the baseline measurement in three territories, with the extraction of FCD and RBCv, and the right column with the measurements of three territories after the nitroglycerin challenge with the extraction of FCDNG and RBCvNG (B). MS Massey score, MAP mean arterial pressure, FCD functional capillary density, RBCv red blood cell velocity, FCDNG maximal recruitable functional capillary density, RBCvNG maximal recruitable red blood cell velocity

Statistical analysis

All variables were tested for normal distribution using QQ plots, confirming normal distribution of all variables except for the total fluid administration. Results are reported as mean ± SD for continuous, normally distributed variables, and median (IQR) for non-normally distributed variables. Comparisons of microcirculatory variables between both groups were made using linear mixed model analysis with circulatory shock status entered as fixed effects and intercepts for subjects and per-subject random slopes representing the effect on the dependent variables entered as random effects. Linear correlation was used to descriptively assess potential associations between microhemodynamic variables measured in the sublingual microcirculation, macrohemodynamic variables, and capillary refill time. Pearson’s product–moment correlation coefficient was calculated, and r ≥ 0.6 or r ≤ − 0.6 in the presence of a positive statistical significance test was considered as relevant. Bonferroni’s correction was applied to the p values resulting from linear correlation analysis of the individual variables (n = 48 tests). The relationship between microcirculatory variables and survival at 28 days was tested via Student’s t test. For sub-group analysis differentiating septic and cardiogenic shock from other forms of shock, microcirculatory variables were compared via one-way analysis of variance. The sample size needed was estimated based on previous data, with critically ill patients suffering from septic and cardiogenic shock presenting with a difference in FCD of − 3.7 ± 3.9 and − 6.7 ± 3.9 mm/mm2 as compared to a general ICU population [27]. Thus, to detect a difference in means of FCD induced by any form of circulatory shock versus in an ICU population, using a two-sample t test with an 80% power and 5% two-sided type I error rate, the inclusion of at least 13 patients in each group was targeted. Data analysis was performed with JMP (SAS Editor, version 15.2.1) and R (version 4.1.2). Figures were created with JMP and with a licensed version of biorender.com. A two-sided p value < 0.05 was considered statistically significant.

Results

Patient characteristics

Data from 71 patients were collected, of which 16 were excluded because of missing informed consent and 1 because of poor image sequence quality. A total of 54 patients were thus included in the study, with 323 recorded image sequences (Fig. 1A). Seven image sequences were excluded from analysis due to insufficient video quality (Massey score ≥ 10). Microcirculatory measurements were performed 10.3 ± 7.1 h after ICU admission. All included patients were mechanically ventilated and severely ill, with a mean admission SAPS score of 57.3 ± 18.2 and a mean SOFA score of 9.4 ± 4.0 (Table 1). 13 patients fulfilled the criteria for persistent signs of circulatory shock, and 41 were assigned to the control group. Among patients with circulatory shock, six patients presented with cardiogenic shock, four with septic shock, and three with other types of shock. In the control group, 22 patients were diagnosed with neurologic or respiratory disease, 8 patients with sepsis, and 11 patients with heart failure. Three patients with circulatory shock and four patients in the control group were treated with veno-arterial extracorporeal membrane oxygenation (see Supplementary Table S3 for microhemodynamic variables). Patients with circulatory shock presented with higher SAPS score (p = 0.03), heart rate (p < 0.001), lactate levels (p < 0.001), vasopressor dependency index (p < 0.001), Mottling score (p < 0.001), capillary refill time (p < 0.01), and central venous pressure (p = 0.02, see Table 1). Total fluid administration during the initial resuscitation phase amounted to 3850 (167–5380) ml in patients with circulatory shock and 1635 (987–2285) ml in the control group. Patients with cardiogenic shock received 1773 (650–2897) ml. Survival at 28 days was 54% in patients presenting with circulatory shock and 73% in the control group. Table 1 Patient characteristics in the circulatory shock group and the control group

	All patients
n = 54	Circulatory shock group
n = 13	Control group
n = 41	Between group
p value	
Patient characteristics	
 Age [a]	56.9 ± 14.0	59.1 ± 13.6	54.2 ± 14.2	0.53	
 Body mass index [kg/m2]	26.1 ± 5.0	24.7 ± 4.5	26.6 ± 4.6	0.18	
 Sex (male)	35 (65%)	9 (69%)	26 (63%)	0.70*	
 SAPS score at ICU admission [1]	57 ± 18	68 ± 18	54 ± 17	0.03	
 SOFA score at ICU admission [1]	9 ± 4	11 ± 4	9 ± 4	0.15	
 Acute kidney injury	30 (6%)	9 (69%)	21 (51%)	0.25*	
 Chronic kidney disease	15 (28%)	4 (31%)	11 (28%)	0.82*	
Extracorporeal support therapy	
 VA-ECMO	7 (13%)	3 (20%)	4 (10%)	0.24*	
Macrohemodynamic function variables	
 Cardiac index [l/min/m2]	2.9 (2.0–4.2)	2.9 (1.9–4.6)	2.9 (2.5–3.7)	0.82	
 Temperature [°C]	36.70 ± 1.1	36.7 ± 1.8	35.8 ± 5.8	0.99	
 Systolic arterial pressure [mmHg]	103.5 (93.7–114)	101 (86–113)	107 (96–114)	0.13	
 Mean arterial pressure [mmHg]	70 (64–75)	65 (63–72)	71 (66–76)	0.06	
 Diastolic arterial pressure [mmHg]	52.5 (58.3–47.8)	54 (52–58)	53 (47–58)	0.59	
 Heart rate [s−1]	875 (73.5–102.8)	107 (93–113)	84 (69–92)	< 0.001	
 Central venous pressure [mmHg]	11.5 (9–15)	13 (10–17)	11 (9–13)	0.02	
 Vasopressor dependency index [1]	2.37 (0.6–5.6)	6.3 (5.5–9.0)	1.3 (0.3–3.3)	< 0.001	
Laboratory analysis	
 Lactate [mmol/l]	2.0 (1.2–4.2)	3.4 (3.0–7.8)	1.5 (1.0–3.0)	< 0.001	
 Hematocrit [1]	0.34 (0.30–0.40)	0.32 (0.29–0.34)	0.35 (0.28–0.38)	0.46	
 Hemoglobin [g/l]	110 (87–127)	102 (94–110)	112 (89–128)	0.67	
Clinical signs of microcirculatory impairment	
 Mottling score [1]	0 (0–1)	2 (0–2)	0 (0–0)	< 0.001	
 Capillary refill time [s]	4 (3–5)	5 (4–6)	4 (3–5)	< 0.01	
Outcome	
 28-day survival	37 (69%)	7 (54%)	29 (70%)	0.20*	
SAPS Simplified Acute Physiology Score, SOFA Sequential Organ Failure Assessment, ICU intensive care unit, VA-ECMO veno-arterial extracorporeal membrane oxygenation

P values were calculated via a mixed-effects model of each variable with circulatory shock status entered into the model as fixed effect. For categorical variables, the p values were calculated via a Chi-square test of independence (indicated with *). P values < 0.05 are highlighted in bold. Results for categorical variables are reported as n (%), continuous variables as mean ± standard deviation, or median (IQR) as appropriate

Native microcirculatory function in patients with and without circulatory sock

Patients with circulatory shock had a 15% lower FCD as compared to the control group (p < 0.01), while RBCv did not differ between the two groups (p = 0.48; Fig. 2A, Supplementary Table S1). 16 patients presented with elevated Mottling score [n = 8 (62%) and n = 8 (20%) in the circulatory shock and control groups, respectively] and 42 patients with prolonged capillary refill time (n = 11, 85% and n = 31, 76% in the circulatory shock and control groups, respectively; Table 1). No correlation was found between Mottling score and FCD, RBCv, or the nitroglycerin response in sublingual microcirculation (p > 0.05). Higher values of capillary refill time were associated with lower values of RBCv (r = − 0.82, p < 0.001) and higher ΔRBCvNG (r = − 0.71, p = 0.01) in patients with circulatory shock.Fig. 2 FCD and FCDNG were lower in patients with circulatory shock as compared to the control group, while circulatory shock patients reached FCDNG similar to FCD in patients without shock (A). Nitroglycerin response was similar in both groups (B, D). RBCv and RBCvNG were similar in both groups (C). Boxplots represent median and IQR, the whiskers represent range, and the dashed gray lines in B and D represent the zero effect line for the nitroglycerin response. FCD functional capillary density, RBCv red blood cell velocity, FCDNG maximal recruitable functional capillary density, RBCvNG maximal recruitable red blood cell velocity, ΔFCGNG FCD nitroglycerin response, ΔRBCvNG RBCv nitroglycerin response

Nitroglycerin response in the sublingual microcirculation

The sublingual nitroglycerin challenge increased FCD by 22% in patients with circulatory shock (within-group p = 0.03) and 13% in patients of the control group (within-group p < 0.001, Figs. 2A and 3A). FCDNG was 10% lower in patients with circulatory shock as compared to controls (between-group p = 0.03, Figs. 2A and 3B), but ΔFCDNG remained similar between the two groups (p = 0.19, Fig. 2B). Circulatory shock patients reached FCDNG similar to FCD in patients without shock (Fig. 2A). RBCvNG was similar to RBCv in both groups (within-group p > 0.05, Fig. 2C), with similar RBCvNG and ∆RBCvNG in both groups (between-group p = 0.97 and p = 0.25, Fig. 2B, D).Fig. 3 Individual measurements of FCD and FCDNG in patients with circulatory shock (A) and controls (B), demonstrating a consistent nitroglycerin response in both groups. C, D Shows linear correlation coefficients (color scale) between macrohemodynamic variables on the vertical axis and microhemodynamic variables on the horizontal axis. An association between sublingual RBCv and peripheral capillary refill time was shown in the circulatory shock group, and a negative association between RBCv and its nitroglycerin response, and systemic hematocrit was found in the control group. Correlation pairs with r ≥ 0.6 or r ≤ − 0.6, and p ≤ 0.05 after Bonferroni’s correction are encircled with a solid black line in both panels. CRT capillary refill time, VDI vasopressor dependency index, HR heart rate, MAP mean arterial pressure, CVP central venous pressure, Hct systemic hematocrit, FCD functional capillary density, RBCv red blood cell velocity, FCDNG maximal recruitable functional capillary density, RBCvNG maximal recruitable red blood cell velocity, ∆FCDNG functional capillary density reserve capacity, ∆RBCvNG functional red blood cell velocity reserve capacity

Outcome and relationship between macro- and microhemodynamic variables

Microcirculatory variables including nitroglycerin response were similar in 28-day survivors and non-survivors in both groups, with FCD and FCDNG of 18.0 ± 3.7 and 21.0 ± 3.1 in survivors, and 17.0 ± 3.6 and 20.0 ± 2.8 in non-survivors (p = 0.29 and p = 0.08, respectively). No clinically relevant association (r ≥ 0.6, p < 0.05) was found between FCD and its nitroglycerin response, and arterial or central venous blood pressure, cardiac output, heart rate, vasopressor dependency index, hematocrit, or capillary refill time (Fig. 3C, D, Supplementary Table S2). In the circulatory shock group, RBCv measured in the sublingual microcirculation was associated with capillary refill time measured on the fingernail (r = − 0.81, p < 0.001), while in the control group RBCv and its nitroglycerin response were negatively correlated to systemic hematocrit (r = − 0.65, p < 0.0001 for both variables). In the 13 patients with sepsis, with and without shock, 28-day mortality was associated with lower FCD and FCDNG (p = 0.018 and p = 0.012, respectively). In these patients, FCD was negatively associated with the vasopressor dependency index (r = 0.71, p < 0.001).

Discussion

In severely ill patients with circulatory shock, a lower FCD and FCDNG, but not RBCv and RBCvNG, was found after initial resuscitation, as compared to patients without circulatory shock. The response to a topical nitroglycerin stimulus of FCD and RBCv was similar in patients with circulatory shock as compared to patients without circulatory shock, and FCDNG in patients with circulatory shock was similar to that in native FCD in patients without circulatory shock. No association between nitroglycerin response and blood pressure or cardiac output was found regardless of the presence of circulatory shock.

Circulatory shock is associated with lower native microcirculatory diffusion capacity

Previous studies have shown impaired microcirculatory function in septic and cardiogenic shock [2, 6, 27]. These findings were based on the measurement of total vessel density combined with the subjective visual flow characteristics of red blood cells within the capillaries to enable the calculation of the perfused vessel density, as described in the first consensus on the evaluation of the microcirculation [28]. They mainly revealed an association between shock and the subjectively graded microvascular flow index (MFI) or proportion of perfused vessels (PPV) derived from vessel-by-vessel assessment of the former. In the present study, the data was collected in a severely ill cohort in both the shock and control group, as reflected by high SAPS and SOFA scores and 28-day mortality of 46 and 30%, respectively. Our data suggest, by quantifying the variables associated with diffusion and convection capacity of the oxygen carriers in the tissue, as suggested by the second consensus on the evaluation of the microcirculation [21, 28, 29], that the main variable affected by circulatory shock of any cause is FCD as opposed to RBCv, implying the microcirculatory diffusion capacity may be a more sensitive indicator of the presence of circulatory shock than changes in the convection capacity. Previous studies have further described an association between the presence of circulatory shock and abnormalities of the skin microcirculation such as capillary refill time and the mottling score [16, 17]. It has, however, remained unclear how these variables might be associated with the functional state of the sublingual microcirculation, which is regulated more similarly to the visceral microcirculation [30]. In the present study, sublingual RBCv was found to be associated with capillary refill time assessed in the peripheral microcirculation in the presence of circulatory shock. The same was not found to be true for FCD or the nitroglycerin response. In patients with circulatory shock, the peripheral capillary refill time may thus be more representative of the sublingual microcirculatory convection capacity as opposed to the sublingual microcirculatory diffusion capacity, meaning that FCD is a more sensitive indicator of the presence of circulatory shock than either RBCv or the capillary refill time.

Microcirculatory nitroglycerin response is preserved in patients with circulatory shock

The nitroglycerin response of the sublingual microcirculation has previously been suggested as a method to quantify the microcirculatory reserve capacity to adapt to deficiencies in oxygen availability in the tissue in healthy volunteers exposed to severe hypobaric hypoxia [22]. Correspondingly, data previously collected in mechanically ventilated patients suffering from COVID-19 have indicated that a similar mechanism to increase oxygen extraction capacity at the level of the tissue was preserved even in these critically ill patients [31–33]. These results contrasted earlier findings in patients suffering from septic and cardiogenic shock who presented with deteriorated microcirculatory function secondary to circulatory shock [2, 6]. In these patients, red blood cell flow in the sublingual microcirculation was increased by the topical application of acetylcholine, which stimulates the endothelial cells to release nitric oxide and nitroglycerin [2, 6, 23]. These studies, however, did not examine how the response described in circulatory shock compared to patients without circulatory shock. Nevertheless, these findings supported the hypothesis that the presence of a capillary reserve capacity would be able to be resuscitated by procedures to augment the oxygen extraction capacity of the tissues following circulatory shock. The present study showed that the sublingual microcirculatory response to nitroglycerin with respect to FCD was comparable regardless of the presence of circulatory shock indicating the preservation of a window to recruit the microcirculatory reserve following circulatory shock, and even in the presence of nitroglycerin as a direct nitric oxide donor as opposed to acetylcholine and thus bypassing the need to provision nitric oxide by the endothelial cells. This finding suggests that despite the inadequate oxygen availability in the tissue characteristic for circulatory shock, the regulatory mechanisms to increase oxygen extraction capacity in the tissue previously described in healthy volunteers seem not to occur in the presence of circulatory shock. A suggested failure of these underlying intrinsic compensatory mechanisms of the microcirculation in response to shock is further supported by the lower maximal recruitable FCD after the nitroglycerin challenge as compared to patients without circulatory shock. A contributing factor to this effect could be the presence of fluid overload related to volume resuscitation [34] as suggested by a higher central venous pressure—which effectively represents the outlet pressure of the systemic microcirculation—and/or cardiac congestion in patients suffering from circulatory shock, and also reduction of viscosity of blood possibly negatively affecting sheer stress related autoregulatory mechanisms. These latter explanations would be consistent with the negative nitroglycerin response with respect to RBCv and compatible with previous association of the microcirculatory convection capacity with microcirculatory tamponade caused by an increase in capillary outlet pressure [9, 35]. Another study, examining patients with cardiogenic shock after cardiac surgery, also reported a trend toward higher central venous pressure in non-responders to a nitroglycerin stimulus [23]. These data confirm the present finding of a preserved nitroglycerin response in the sublingual microcirculation in circulatory shock, also in the presence of circulatory failure after cardiac surgery. Furthermore, a reduced capillary density in patients undergoing major cardiac surgery has previously been associated with a highly positive fluid balance in the first 7 days after cardiac surgery [36, 37]. Finally, the association between persistent microcirculatory dysfunction after initial resuscitation and mortality, which has also been shown in previous studies mainly for patients suffering from septic shock [38], was confirmed in our data by both lower FCD and FCDNG in 28-day non-survivors as compared to survivors suffering from sepsis. Larger, longitudinal studies are warranted to differentiate the effects of different etiologies of circulatory shock and resuscitation measures on the microcirculatory hemodynamic variables and nitroglycerin response, and on outcome [39].

The nitroglycerin response in the sublingual microcirculation may identify a tissue perfusion target in circulatory shock

The main treatment goal in circulatory shock is the support of rapid restitution of tissue perfusion and oxygenation. Consistently, the restoration of inadequate tissue perfusion should be a main target for resuscitation. Our primary finding in this study, however, is that despite the application of standard resuscitation procedures, the FCD in resuscitated circulatory shock patients remains lower than in control patients. A second main finding is that a sublingual challenge by topical application of nitroglycerin identifies the amount of FCD still in need of recruitment to arrive at baseline FCD as found in control patients. This was shown in our study by the observation that the level of increased FCD in the resuscitated circulatory shock patients induced by the nitroglycerin challenge corresponds to baseline FCD in the control patients. The significance of these findings is that it may open the way to microcirculatory tissue perfusion guided resuscitation where a nitroglycerin challenge can quantitatively identify and define the tissue perfusion target needed to achieve adequate tissue perfusion.

Limitations

The present study has several limitations. First, it is observational in nature and was conducted without obtaining longitudinal measurements. The in vivo measurement of nitroglycerin response in the sublingual microcirculation could in future studies be used in a larger patient population and to describe longitudinal changes throughout ICU treatment. Further, due to the lack of previous data regarding the microcirculatory nitroglycerin response in patients with circulatory shock, the number of included patients was based on differences in FCD induced by circulatory shock. The study was not powered to perform a sub-analysis of patients with specific forms of circulatory shock, however the use of a common definition of circulatory shock, including septic and cardiogenic shock as previously described [40], allowed the systematic examination of common properties of circulatory shock. The results of this preliminary study serve as a validation of a physiological description of the mechanisms of circulatory shock in critically ill patients and as the basis for the inclusion of specific types of circulatory shock in larger cohorts in the future. Finally, the topical application of nitroglycerin, as performed in the present study, does not allow the prediction of the effect of systemic resuscitation measures, including the systemic application of vasodilators such as nitroglycerin as described previously [41, 42], but rather provides a tool for the assessment of the functional state of the microcirculation.

Conclusion

In the present study, critically ill patients suffering from circulatory shock were found to have a lower sublingual FCD as compared to patients without shock. The preserved response to a topical nitroglycerin stimulus after initial resuscitation, alongside the lower FCDNG, furthermore suggests an inability of the intrinsic regulation mechanisms to increase the microcirculatory oxygen extraction capacity associated with circulatory shock and thereby identifies a potential resuscitation target. These differences in microcirculatory hemodynamic function between patients with and without circulatory shock were neither reflected in blood pressure nor cardiac index, highlighting the potential of guiding resuscitation in these patients according to the measurement of tissue perfusion and tissue oxygen availability in future studies.

Supplementary Information

Supplementary Material 1.

Acknowledgements

The authors wish to thank all the patients and their relatives for their support of this study during the demanding time of critical illness.

Author contributions

MB: study coordination, data acquisition and analysis, writing the manuscript; PWG: data acquisition, editing the manuscript; AH: editing the manuscript; CI: editing the manuscript; MM: study design, editing the manuscript; MPH: study design, data analysis, writing and editing the manuscript. All authors read and approved the final manuscript.

Funding

The present project was supported by a University of Zurich Walter und Gertrud Siegenthaler Foundation grant issued to Dr. Hilty.

Availability of data and materials

The datasets generated and analyzed during the current study are not publicly available due to sensible personal clinical data, but are available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

The study was approved by the ethics committee of the University of Zurich (BASEC 2017-01564, ClinicalTrials.gov Identifier: NCT03651635) and was conducted in accordance with the Declaration of Helsinki. Written informed consent for participation from the patient, or in case of death or disability, from the next of kin or legal representative was sought for every patient included in the present study.

Consent for publication

Consent for publication from the patient, or in case of death or disability, from the next of kin or legal representative was sought for every patient included in the present study.

Competing interests

CI and MPH hold a patent on the use of AI to analyze microcirculatory images, have developed an automated microcirculatory analysis software platform, and hold shares in Active Medical BV (Leiden, The Netherlands). The other authors declare no conflicts of interest.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
==== Refs
References

1. Adams HA Baumann G Gänsslen A The definitions of the shock types Anasthesiol Intensivmed Notfallmed Schmerzther 2001 36 140 143 10.1055/s-2001-18174
Adams HA, Baumann G, Gänsslen A et al (2001) The definitions of the shock types. Anasthesiol Intensivmed Notfallmed Schmerzther 36:140–143. 10.1055/s-2001-1817410.1055/s-2001-18174
2. de Backer D Creteur J Preiser JC Dubois MJ Vincent JL Microvascular blood flow is altered in patients with sepsis Am J Respir Crit Care Med 2002 166 1 98 104 10.1164/rccm.200109-016OC 12091178
de Backer D, Creteur J, Preiser JC, Dubois MJ, Vincent JL (2002) Microvascular blood flow is altered in patients with sepsis. Am J Respir Crit Care Med 166(1):98–104. 10.1164/rccm.200109-016OC12091178 10.1164/rccm.200109-016OC
3. Sakr Y Dubois MJ de Backer D Creteur J Vincent JL Persistent microcirculatory alterations are associated with organ failure and death in patients with septic shock Crit Care Med 2004 32 9 1825 1831 10.1097/01.ccm.0000138558.16257.3f 15343008
Sakr Y, Dubois MJ, de Backer D, Creteur J, Vincent JL (2004) Persistent microcirculatory alterations are associated with organ failure and death in patients with septic shock. Crit Care Med 32(9):1825–1831. 10.1097/01.ccm.0000138558.16257.3f15343008 10.1097/01.ccm.0000138558.16257.3f
4. den Uil CA Lagrand WK van der Ent M Impaired microcirculation predicts poor outcome of patients with acute myocardial infarction complicated by cardiogenic shock Eur Heart J 2010 31 24 3032 3039 10.1093/eurheartj/ehq324 20829210
den Uil CA, Lagrand WK, van der Ent M et al (2010) Impaired microcirculation predicts poor outcome of patients with acute myocardial infarction complicated by cardiogenic shock. Eur Heart J 31(24):3032–3039. 10.1093/eurheartj/ehq32420829210 10.1093/eurheartj/ehq324
5. Kuiper JW Tibboel D Ince C The vulnerable microcirculation in the critically ill pediatric patient Crit Care 2016 20 352 10.1186/s13054-016-1496-x 27794361
Kuiper JW, Tibboel D, Ince C (2016) The vulnerable microcirculation in the critically ill pediatric patient. Crit Care 20:352. 10.1186/s13054-016-1496-x27794361 10.1186/s13054-016-1496-x
6. de Backer D Creteur J Dubois MJ Sakr Y Vincent JL Microvascular alterations in patients with acute severe heart failure and cardiogenic shock Am Heart J 2004 147 1 91 99 10.1016/j.ahj.2003.07.006 14691425
de Backer D, Creteur J, Dubois MJ, Sakr Y, Vincent JL (2004) Microvascular alterations in patients with acute severe heart failure and cardiogenic shock. Am Heart J 147(1):91–99. 10.1016/j.ahj.2003.07.00614691425 10.1016/j.ahj.2003.07.006
7. Bakker J Lactate levels and hemodynamic coherence in acute circulatory failure Best Pract Res Clin Anaesthesiol 2016 30 4 523 530 10.1016/j.bpa.2016.11.001 27931655
Bakker J (2016) Lactate levels and hemodynamic coherence in acute circulatory failure. Best Pract Res Clin Anaesthesiol 30(4):523–530. 10.1016/j.bpa.2016.11.00127931655 10.1016/j.bpa.2016.11.001
8. Guerci P Ergin B Ince C The macro- and microcirculation of the kidney Best Pract Res Clin Anaesthesiol 2017 31 3 315 329 10.1016/j.bpa.2017.10.002 29248139
Guerci P, Ergin B, Ince C (2017) The macro- and microcirculation of the kidney. Best Pract Res Clin Anaesthesiol 31(3):315–329. 10.1016/j.bpa.2017.10.00229248139 10.1016/j.bpa.2017.10.002
9. Ince C Hemodynamic coherence and the rationale for monitoring the microcirculation Crit Care 2015 19 Suppl 3 s8 10.1186/cc14726 26729241
Ince C (2015) Hemodynamic coherence and the rationale for monitoring the microcirculation. Crit Care 19(Suppl 3):s8. 10.1186/cc1472626729241 10.1186/cc14726
10. Lim N Dubois MJ de Backer D Vincent JL Do all nonsurvivors of cardiogenic shock die with a low cardiac index? Chest 2003 124 5 1885 1891 10.1378/CHEST.124.5.1885 14605064
Lim N, Dubois MJ, de Backer D, Vincent JL (2003) Do all nonsurvivors of cardiogenic shock die with a low cardiac index? Chest 124(5):1885–1891. 10.1378/CHEST.124.5.188514605064 10.1378/CHEST.124.5.1885
11. Hilty MP Pichler J Ergin B Assessment of endothelial cell function and physiological microcirculatory reserve by video microscopy using a topical acetylcholine and nitroglycerin challenge Intensive Care Med Exp 2017 5 1 26 10.1186/s40635-017-0139-0 28523563
Hilty MP, Pichler J, Ergin B et al (2017) Assessment of endothelial cell function and physiological microcirculatory reserve by video microscopy using a topical acetylcholine and nitroglycerin challenge. Intensive Care Med Exp 5(1):26. 10.1186/s40635-017-0139-028523563 10.1186/s40635-017-0139-0
12. de Backer D Creteur J Dubois MJ The effects of dobutamine on microcirculatory alterations in patients with septic shock are independent of its systemic effects Crit Care Med 2006 34 2 403 408 10.1097/01.CCM.0000198107.61493.5A 16424721
de Backer D, Creteur J, Dubois MJ et al (2006) The effects of dobutamine on microcirculatory alterations in patients with septic shock are independent of its systemic effects. Crit Care Med 34(2):403–408. 10.1097/01.CCM.0000198107.61493.5A16424721 10.1097/01.CCM.0000198107.61493.5A
13. Cecconi M De Backer D Antonelli M Consensus on circulatory shock and hemodynamic monitoring. Task force of the European Society of Intensive Care Medicine Intensive Care Med 2014 40 12 1795 1815 10.1007/s00134-014-3525-z 25392034
Cecconi M, De Backer D, Antonelli M et al (2014) Consensus on circulatory shock and hemodynamic monitoring. Task force of the European Society of Intensive Care Medicine. Intensive Care Med 40(12):1795–1815. 10.1007/s00134-014-3525-z25392034 10.1007/s00134-014-3525-z
14. Rhodes A Evans LE Alhazzani W Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016 Crit Care Med 2017 45 3 486 552 10.1097/CCM.0000000000002255 28098591
Rhodes A, Evans LE, Alhazzani W et al (2017) Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Crit Care Med 45(3):486–552. 10.1097/CCM.000000000000225528098591 10.1097/CCM.0000000000002255
15. Cruz DN Antonelli M Fumagalli R Early use of polymyxin B hemoperfusion in abdominal septic shock: the EUPHAS randomized controlled trial JAMA 2009 301 23 2445 2452 10.1001/JAMA.2009.856 19531784
Cruz DN, Antonelli M, Fumagalli R et al (2009) Early use of polymyxin B hemoperfusion in abdominal septic shock: the EUPHAS randomized controlled trial. JAMA 301(23):2445–2452. 10.1001/JAMA.2009.85619531784 10.1001/JAMA.2009.856
16. Ait-Oufella H Lemoinne S Boelle PY Mottling score predicts survival in septic shock Intensive Care Med 2011 37 5 801 807 10.1007/S00134-011-2163-Y 21373821
Ait-Oufella H, Lemoinne S, Boelle PY et al (2011) Mottling score predicts survival in septic shock. Intensive Care Med 37(5):801–807. 10.1007/S00134-011-2163-Y21373821 10.1007/S00134-011-2163-Y
17. Hernández G Cavalcanti AB Ospina-Tascón G Early goal-directed therapy using a physiological holistic view: the ANDROMEDA-SHOCK—a randomized controlled trial Ann Intensive Care 2018 8 1 1 10 10.1186/S13613-018-0398-2 29330618
Hernández G, Cavalcanti AB, Ospina-Tascón G et al (2018) Early goal-directed therapy using a physiological holistic view: the ANDROMEDA-SHOCK—a randomized controlled trial. Ann Intensive Care 8(1):1–10. 10.1186/S13613-018-0398-229330618 10.1186/S13613-018-0398-2
18. Califf RM Bengtson JR Cardiogenic shock N Engl J Med 1994 330 24 1724 1730 10.1056/NEJM199406163302406 8190135
Califf RM, Bengtson JR (1994) Cardiogenic shock. N Engl J Med 330(24):1724–1730. 10.1056/NEJM1994061633024068190135 10.1056/NEJM199406163302406
19. Sherman H Klausner S Cook WA Incident dark-field illumination: a new method for microcirculatory study Angiology 1971 22 5 295 303 10.1177/000331977102200507 5089888
Sherman H, Klausner S, Cook WA (1971) Incident dark-field illumination: a new method for microcirculatory study. Angiology 22(5):295–303. 10.1177/0003319771022005075089888 10.1177/000331977102200507
20. Aykut G Veenstra G Scorcella C Ince C Boerma C Cytocam-IDF (incident dark field illumination) imaging for bedside monitoring of the microcirculation Intensive Care Med Exp 2015 3 1 1 10 10.1186/S40635-015-0040-7 26215802
Aykut G, Veenstra G, Scorcella C, Ince C, Boerma C (2015) Cytocam-IDF (incident dark field illumination) imaging for bedside monitoring of the microcirculation. Intensive Care Med Exp 3(1):1–10. 10.1186/S40635-015-0040-726215802 10.1186/S40635-015-0040-7
21. Ince C Boerma EC Cecconi M Second consensus on the assessment of sublingual microcirculation in critically ill patients: results from a task force of the European Society of Intensive Care Medicine Intensive Care Med 2018 44 3 281 299 10.1007/s00134-018-5070-7 29411044
Ince C, Boerma EC, Cecconi M et al (2018) Second consensus on the assessment of sublingual microcirculation in critically ill patients: results from a task force of the European Society of Intensive Care Medicine. Intensive Care Med 44(3):281–299. 10.1007/s00134-018-5070-729411044 10.1007/s00134-018-5070-7
22. Hilty MP Merz TM Hefti U Ince C Maggiorini M Pichler Hefti J Recruitment of non-perfused sublingual capillaries increases microcirculatory oxygen extraction capacity throughout ascent to 7126 m J Physiol 2019 597 10 2623 2638 10.1113/JP277590 30843200
Hilty MP, Merz TM, Hefti U, Ince C, Maggiorini M, Pichler Hefti J (2019) Recruitment of non-perfused sublingual capillaries increases microcirculatory oxygen extraction capacity throughout ascent to 7126 m. J Physiol 597(10):2623–2638. 10.1113/JP27759030843200 10.1113/JP277590
23. Greenwood JC Talebi FM Jang DH Topical nitroglycerin to detect reversible microcirculatory dysfunction in patients with circulatory shock after cardiovascular surgery: an observational study Sci Rep 2022 12 1 15257 10.1038/s41598-022-19741-0 36088474
Greenwood JC, Talebi FM, Jang DH et al (2022) Topical nitroglycerin to detect reversible microcirculatory dysfunction in patients with circulatory shock after cardiovascular surgery: an observational study. Sci Rep 12(1):15257. 10.1038/s41598-022-19741-036088474 10.1038/s41598-022-19741-0
24. Sharawy N Mukhtar A Islam S Preliminary clinical evaluation of automated analysis of the sublingual microcirculation in the assessment of patients with septic shock: comparison of automated versus semi-automated software Clin Hemorheol Microcirc 2017 67 3–4 489 498 10.3233/CH-179232 28922146
Sharawy N, Mukhtar A, Islam S et al (2017) Preliminary clinical evaluation of automated analysis of the sublingual microcirculation in the assessment of patients with septic shock: comparison of automated versus semi-automated software. Clin Hemorheol Microcirc 67(3–4):489–498. 10.3233/CH-17923228922146 10.3233/CH-179232
25. Massey MJ LaRochelle E Najarro G The microcirculation image quality score: development and preliminary evaluation of a proposed approach to grading quality of image acquisition for bedside videomicroscopy J Crit Care 2013 28 6 913 917 10.1016/J.JCRC.2013.06.015 23972316
Massey MJ, LaRochelle E, Najarro G et al (2013) The microcirculation image quality score: development and preliminary evaluation of a proposed approach to grading quality of image acquisition for bedside videomicroscopy. J Crit Care 28(6):913–917. 10.1016/J.JCRC.2013.06.01523972316 10.1016/J.JCRC.2013.06.015
26. Hilty MP Guerci P Ince Y Toraman F Ince C MicroTools enables automated quantification of capillary density and red blood cell velocity in handheld vital microscopy Commun Biol 2019 2 1 217 10.1038/S42003-019-0473-8 31240255
Hilty MP, Guerci P, Ince Y, Toraman F, Ince C (2019) MicroTools enables automated quantification of capillary density and red blood cell velocity in handheld vital microscopy. Commun Biol 2(1):217. 10.1038/S42003-019-0473-831240255 10.1038/S42003-019-0473-8
27. Hilty MP Akin S Boerma C Automated algorithm analysis of sublingual microcirculation in an international multicentral database identifies alterations associated with disease and mechanism of resuscitation Crit Care Med 2020 48 10 864 875 10.1097/CCM.0000000000004491
Hilty MP, Akin S, Boerma C et al (2020) Automated algorithm analysis of sublingual microcirculation in an international multicentral database identifies alterations associated with disease and mechanism of resuscitation. Crit Care Med 48(10):864–875. 10.1097/CCM.000000000000449110.1097/CCM.0000000000004491
28. de Backer D Hollenberg S Boerma C How to evaluate the microcirculation: report of a round table conference Crit Care 2007 11 2 1 9 10.1186/cc6118
de Backer D, Hollenberg S, Boerma C et al (2007) How to evaluate the microcirculation: report of a round table conference. Crit Care 11(2):1–9. 10.1186/cc611810.1186/cc6118
29. Hilty MP Ince C Automated quantification of tissue red blood cell perfusion as a new resuscitation target Curr Opin Crit Care 2020 26 3 273 280 10.1097/MCC.0000000000000725 32345794
Hilty MP, Ince C (2020) Automated quantification of tissue red blood cell perfusion as a new resuscitation target. Curr Opin Crit Care 26(3):273–280. 10.1097/MCC.000000000000072532345794 10.1097/MCC.0000000000000725
30. Guven G Hilty MP Ince C Microcirculation: physiology, pathophysiology, and clinical application Blood Purif 2020 49 143 150 10.1159/000503775 31851980
Guven G, Hilty MP, Ince C (2020) Microcirculation: physiology, pathophysiology, and clinical application. Blood Purif 49:143–150. 10.1159/00050377531851980 10.1159/000503775
31. Wendel Garcia PD Fumeaux T Guerci P Prognostic factors associated with mortality risk and disease progression in 639 critically ill patients with COVID-19 in Europe: initial report of the international RISC-19-ICU prospective observational cohort EClinicalMedicine 2020 25 100449 10.1016/J.ECLINM.2020.100449 32838231
Wendel Garcia PD, Fumeaux T, Guerci P et al (2020) Prognostic factors associated with mortality risk and disease progression in 639 critically ill patients with COVID-19 in Europe: initial report of the international RISC-19-ICU prospective observational cohort. EClinicalMedicine 25:100449. 10.1016/J.ECLINM.2020.10044932838231 10.1016/J.ECLINM.2020.100449
32. Favaron E Ince C Hilty MP Capillary leukocytes, microaggregates, and the response to hypoxemia in the microcirculation of coronavirus disease 2019 patients Crit Care Med 2021 49 4 661 670 10.1097/CCM.0000000000004862 33405410
Favaron E, Ince C, Hilty MP et al (2021) Capillary leukocytes, microaggregates, and the response to hypoxemia in the microcirculation of coronavirus disease 2019 patients. Crit Care Med 49(4):661–670. 10.1097/CCM.000000000000486233405410 10.1097/CCM.0000000000004862
33. Hilty MP Favaron E Wendel Garcia PD Microcirculatory alterations in critically ill COVID-19 patients analyzed using artificial intelligence Crit Care 2022 26 1 311 10.1186/S13054-022-04190-Y 36242010
Hilty MP, Favaron E, Wendel Garcia PD et al (2022) Microcirculatory alterations in critically ill COVID-19 patients analyzed using artificial intelligence. Crit Care 26(1):311. 10.1186/S13054-022-04190-Y36242010 10.1186/S13054-022-04190-Y
34. Cusack R O’Neill S Martin-Loeches I Effects of fluids on the sublingual microcirculation in sepsis J Clin Med 2022 11 24 7277 10.3390/JCM11247277/S1 36555895
Cusack R, O’Neill S, Martin-Loeches I (2022) Effects of fluids on the sublingual microcirculation in sepsis. J Clin Med 11(24):7277. 10.3390/JCM11247277/S136555895 10.3390/JCM11247277/S1
35. Vellinga NAR Ince C Boerma EC Elevated central venous pressure is associated with impairment of microcirculatory blood flow in sepsis: a hypothesis generating post hoc analysis BMC Anesthesiol 2013 13 1 7 10.1186/1471-2253-13-17 23312034
Vellinga NAR, Ince C, Boerma EC (2013) Elevated central venous pressure is associated with impairment of microcirculatory blood flow in sepsis: a hypothesis generating post hoc analysis. BMC Anesthesiol 13:1–7. 10.1186/1471-2253-13-1723312034 10.1186/1471-2253-13-17
36. Uz Z Ince C Guerci P Recruitment of sublingual microcirculation using handheld incident dark field imaging as a routine measurement tool during the postoperative de-escalation phase—a pilot study in post ICU cardiac surgery patients Perioper Med 2018 7 1 1 8 10.1186/S13741-018-0091-X
Uz Z, Ince C, Guerci P et al (2018) Recruitment of sublingual microcirculation using handheld incident dark field imaging as a routine measurement tool during the postoperative de-escalation phase—a pilot study in post ICU cardiac surgery patients. Perioper Med 7(1):1–8. 10.1186/S13741-018-0091-X10.1186/S13741-018-0091-X
37. Yu R Kelly R Mink R Pilot study: can microcirculation be our guide to weaning vasoactives in children with septic shock? Crit Care Med 2023 51 1 620 620 10.1097/01.CCM.0000910708.11934.9E
Yu R, Kelly R, Mink R (2023) Pilot study: can microcirculation be our guide to weaning vasoactives in children with septic shock? Crit Care Med 51(1):620–620. 10.1097/01.CCM.0000910708.11934.9E10.1097/01.CCM.0000910708.11934.9E
38. Holley AD Dulhunty J Udy A Early sequential microcirculation assessment in shocked patients as a predictor of outcome: a prospective observational cohort study Shock 2021 55 5 581 586 10.1097/SHK.0000000000001578 32826808
Holley AD, Dulhunty J, Udy A et al (2021) Early sequential microcirculation assessment in shocked patients as a predictor of outcome: a prospective observational cohort study. Shock 55(5):581–586. 10.1097/SHK.000000000000157832826808 10.1097/SHK.0000000000001578
39. Duranteau J De Backer D Donadello K The future of intensive care: the study of the microcirculation will help to guide our therapies Crit Care 2023 27 1 190 10.1186/s13054-023-04474-x 37193993
Duranteau J, De Backer D, Donadello K et al (2023) The future of intensive care: the study of the microcirculation will help to guide our therapies. Crit Care 27(1):190. 10.1186/s13054-023-04474-x37193993 10.1186/s13054-023-04474-x
40. Boerma EC Ince C The role of vasoactive agents in the resuscitation of microvascular perfusion and tissue oxygenation in critically ill patients Intensive Care Med 2010 36 12 2004 2018 10.1007/s00134-010-1970-x 20811874
Boerma EC, Ince C (2010) The role of vasoactive agents in the resuscitation of microvascular perfusion and tissue oxygenation in critically ill patients. Intensive Care Med 36(12):2004–2018. 10.1007/s00134-010-1970-x20811874 10.1007/s00134-010-1970-x
41. Spronk PE Ince C Gardien MJ Mathura KR van Straaten HMO Zandstra DF Nitroglycerin in septic shock after intravascular volume resuscitation Lancet 2002 360 9343 1395 1396 10.1016/S0140-6736(02)11393-6 12423989
Spronk PE, Ince C, Gardien MJ, Mathura KR, van Straaten HMO, Zandstra DF (2002) Nitroglycerin in septic shock after intravascular volume resuscitation. Lancet 360(9343):1395–1396. 10.1016/S0140-6736(02)11393-612423989 10.1016/S0140-6736(02)11393-6
42. Boerma EC Koopmans M Konijn A Effects of nitroglycerin on sublingual microcirculatory blood flow in patients with severe sepsis/septic shock after a strict resuscitation protocol: a double-blind randomized placebo controlled trial Crit Care Med 2010 10.1097/CCM.0b013e3181b02fc1 20335714
Boerma EC, Koopmans M, Konijn A et al (2010) Effects of nitroglycerin on sublingual microcirculatory blood flow in patients with severe sepsis/septic shock after a strict resuscitation protocol: a double-blind randomized placebo controlled trial. Crit Care Med. 10.1097/CCM.0b013e3181b02fc120335714 10.1097/CCM.0b013e3181b02fc1
