Nitroglycerin challenge identifies microcirculatory target for improved resuscitation in patients with circulatory shock

Abstract

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 (FCD_NG, RBCv_NG) 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 RBCv_NG. 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 FCD_NG 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 FCD_NG 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.

Keywords: Capillary recruitment; Critical care; Microcirculation; Microcirculatory reserve capacity; Resuscitation; Sublingual microcirculatory assessment.

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 FCD_NG and RBCv_NG (B). MS Massey score, MAP mean arterial pressure, FCD functional capillary density, RBCv red blood cell velocity, FCD_NG maximal recruitable functional capillary density, RBCv_NG maximal recruitable red blood cell velocity

Fig. 2

FCD and FCD_NG were lower in patients with circulatory shock as compared to the control group, while circulatory shock patients reached FCD_NG similar to FCD in patients without shock (A). Nitroglycerin response was similar in both groups (B, D). RBCv and RBCv_NG 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, FCD_NG maximal recruitable functional capillary density, RBCv_NG maximal recruitable red blood cell velocity, ΔFCG_NG FCD nitroglycerin response, ΔRBCv_NG RBCv nitroglycerin response

Fig. 3

Individual measurements of FCD and FCD_NG 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, FCD_NG maximal recruitable functional capillary density, RBCv_NG maximal recruitable red blood cell velocity, ∆FCD_NG functional capillary density reserve capacity, ∆RBCv_NG functional red blood cell velocity reserve capacity