Table A1. The effect of vasodilating agents on

Table A1. The effect of vasodilating agents on microcirculatory blood flow

The response of the microcirculation to different therapeutic interventions aimed at vasodilating patients with sepsis and septic shock.

Ref Drug Study Type n Improves Microvascular Flow? Comments

CONSORT / Cochrane

Collaboration risk of bias score [11]

[12] GTN – loading dose 2mg, then fixed rate infusion 2mg/hr

Prospective, double-blinded RCT

70

No improvement in sublingual microvascular flow. Improved central to toe temperature gradient & SOFA scores.

Protocol included fluid boluses until SV increment <10% or PCWP >18mmHg. Dobutamine added if CO <2.5l/min or ScvO2<70%. May have affected microvascular flow.

30 / 37

[11]

GTN 0.5mg bolus, infusion 2mg/hr & increased until flow improved

Prospective, interventional

8 Increase in small, medium & large vessel MFI (p=0.018, 0.012 & 0.012 respectively)

Ensured MAP>60mmHg and CVP>12mmHg prior to GTN. Poor baseline flow noted. Ketanserin 2mg/hr may have influenced results.

High

[13]

Micorcirculatory protocol (GTN, enoximone, dopamine, dexamethasone)

Prospective, open RCT

65 Non-statistically significant improvement in mortality & SOFA score in intervention arm

No microvascular measurements taken in standard arm.

31 / 37

[14] Inhaled nitric oxide 40ppm

Blinded RCT 50 No significant difference in microvascular flow (SDF), SOFA score, ScvO2 or lactate.

Selected septic patients with poor microvascular flow (SDF) who had received macrocirculatory resuscitation goals.

32 / 37

[15] Papaverine 30mg bolus

Interventional pilot study

14 Transient improvement in PPV & PVD in vasopressor dependent septic shock

No significant improvement in flow at 60 minutes High

[16] Ketanserin 0.03 to 0.12 mg/kg/hr


10 Improvement in sPPV & MFI 6 patients required an increase in vasopressors and 3 had to discontinue ketanserin for refractory hypotension

High

[17] Magnesium Sulphate 2g over 30 mins

Open label, interventional

14 No improvement in microvascular flow

Met resuscitation goals prior to commencing magnesium. No improvement in any microvascular parameter

High

Table A2. The effect of inotropic and vasoconstrictor medication on microcirculatory blood flow.

The response of the microcirculation to different therapeutic interventions aimed at vasoconstricting patients with sepsis and septic shock.


CONSORT / Cochrane

Collaboration risk of bias score(21)

[18] Dobutamine 5µ/kg/min

Prospective, open label

22 Improved capillary perfusion

Improvement in sPPV from 48 ± 15% to 67 ± 11% p=0.01. Addition of acetylcholine further improved sPPV to 98% ± 1% p=0.001. Decreases in lactate 2.3 +/-0.7 vs 2.1 +/- 0.7 (p=0.001) correlated with microvascular improvement.

High


RCT 20 No difference in microcirculatory parameters

Selected those with impaired microvascular flow (Lac >2.4)

29 / 37


Prospective, open label

23 Improvement in those with poor baseline

Adequate fluid resuscitation prior to starting dobutamine, all patients on norepinephrine. Improvement in all measurements of microvascular flow (sPVD, sPPV and MFI) for those with poor baseline microvascular flow.

High

[21]

Levosimendan 0.2mcg/kg vs Dobutamine 5µ/kg/min

Prospective double-blinded RCT

40 Improvement in microvascular flow (MFI, HI and sPVD) with Levosimendan.

Significant improvement in HI & MFI when compared to Dobutamine. No improvement in markers or organ hypoperfusion (lactate, SvO2)

25 / 37

[23] Norepinepherine 0.18 – 0.41µ/kg/min


16 No improvement in microvascular flow

No improvement in any measurements of microvascular flow on SDF but increase in PtO2 and RBC flux on LDF

High

[22] Norepinepherine 0.48±0.43 – 0.74±0.67 µ/kg/min

Prospective, observational

20 No change in microvascular flow, lactate or gastric mucosal to arterial pCO2.

Stepwise increase in MAP from 65 to 75 to 85mmHg

High

[24] Norepinepherine 23±22 - 47±39 µ/kg/min


10 No change in microvascular flow No significant change in gastric arterial to intra-mucosal PCO2, lactate, skin capillary blood flow or RBCV on LDF

High

[25] Norepinepherine 5.9 – 51.4 µ/min

Prospective interventional

13 Improvement in microvascular flow

Considerable inter-patient variability in response as measured by SDF-imaging (n=6 of 13). Improvement in muscle oxygenation with an increase in MAP from 65 to 85 mmHg (NIRS)

High

[26] Norepinepherine 0.04-0.68 µ/kg/min


19 Improved microcirculatory flow when MAP increased to patients' 'normal' MAP

Average MAP taken from previous 2 years of GP records.

High

[27]

Norepinepherine(NA) + AVP (0.04 U/min) vs NA + terlipressin (1 mcg/kg/hr) vs NA + placebo

Prospective double-blinded RCT

60

AVP & TP decreased amount of norepinepherine required to reach MAP 65-75 without decreasing microvascular flow.

Used intermittent fluid boluses to maintain CVP +/-3mmHg form baseline which may have affected results.

16.5 / 37

[28]

Terlipressin 0.5mg bolus (Patients already on norepinepherine titrated to MAP 65-75)

Prospective interventional

20 Improvement in microvascular flow (MFI, sPPV & HI)

Improved microvascular flow but no improvement in downstream markers (ScvO2, lactate). All patients received hydrocortisone & 3 received Activated Protein C.

High

Table A3. The effect of alternative pharmacological agents on microcirculatory blood flow.

This includes beta adrenoreceptor blockers and the immunomodulatory drug Activated Protein C (currently off-market).


CONSORT / Cochrane

Collaboration risk of bias score(1)

[6]

Esmolol infusion titrated to achieve

HR<95 25-2000mg/hr


25 Improvement in microvascular flow index

despite CI decrease

Increase in PaO2 and pH with esmolol. All patients received hydrocortisone infusion which could have influenced results. No

change in perfused vessel density or proportion of perfused vessels

High

[29]

Activated Protein C (APC)

24µg/kg/hr for 96 hrs


13 Improvement in all microvascular

parameters (MFI, TVD, PVD & PPV)

MAP, base excess, lactate, PaO2/FiO2 & SOFA score all improved significantly. APC currently

not licenced for use. High

[30]

Activated Protein C (APC)

24µg/kg/hr for 96 hrs


40 sPVD was significantly increased both from baseline and in comparison to

control arm High

[34] Hydrocortisone

50mg qds Prospective,

interventional 20

Improvement in microvascular flow (sPVD and sPPV) with 50mg qds. of

hydrocortisone

Results were independent of synACTHen test results. 5 patients were also taking APC and 2

patients died during the study. High

Table A4. CONSORT Score

Randomised controlled trials were scored as per CONSORT scoring [12]

Reference 12 13 14 20 21 27

Criteria

Title and

abstract

1a 1 1 1 1 1 0

1b 1 1 1 1 1 1

Introduction 2a 1 1 1 1 1 1

Background

and objectives

2b 1 1 1 1 1 1

Methods 3a 1 1 1 1 1 1

Trial design 3b n/a n/a n/a n/a n/a n/a

4a 1 1 1 1 1 1

Participants 4b 1 1 1 1 1 1

5 1 1 1 1 1 1

Interventions 6a 1 1 1 1 1 0.50

Outcomes 6b n/a 1 n/a n/a n/a n/a

7a 1 1 1 1 1 1

Sample size 7b n/a 1 n/a n/a n/a n/a

Randomisation: 8a 1 1 1 1 0 0

Sequence 8b 1 1 1 1 0 0

generation 9 1 1 1 1 0 0

Allocation

concealment

mechanism

10 1 0 1 1 0 0

Implementation 11a 1 0 1 1 0 0

Blinding 11b 1 1 1 1 1 1

12a 1 1 1 1 1 0.5

Statistical

methods

12b 1 1 1 1 1 0

Results 13a 1 1 1 0 1 0

Participant flow

(a diagram is

strongly

recommended)

13b 1 1 1 0 1 0

14a 1 1 1 1 1 1

Recruitment 14b 1 1 1 1 1 1

15 1 1 1 1 1 1

Baseline data 16 1 1 1 1 1 0.5

Numbers

analysed

17a 1 1 1 1 1 1

Outcomes and

estimation

17b n/a n/a n/a n/a n/a n/a

18 1 1 1 1 1 1

Ancillary

analyses

19 0 0 1 0 0 0

Harms

Discussion 20 1 1 1 1 1 1

Limitations 21 1 1 1 1 1 1

Generalisability 22 1 1 1 1 0 1

Interpretation

Other

information

23 0 1 1 1 1 1

Registration 24 0 1 1 1 1 1

Protocol 25 1 0 0 0 0 0

Funding 1 0 0 0 0 0 0

TOTAL 30 31 32 29 25 16.5

Table A5 Higgins, Altman, Cochrane Collaboration Risk of Bias Assessment

Interventional studies scored over six domains as high or low risk of bias.

Ref

Selection

bias

Performance

bias

Detection

bias

Attrition

bias

Reporting

bias

Other

bias

Overall

Score

11 High High High High Low Low High




18 High High High Low Low High High






26 High High High High Low low High




30 High High High High Low High High

34 High High High High Low High High

Documents

Table A1. The effect of vasodilating agents on