Available via license: CC BY 4.0
Content may be subject to copyright.
Regul. Mech. Biosyst., 8(1) 91
Regulatory Mechanisms
in Biosystems
ISSN 2519-8521 (Print)
ISSN 2520-2588 (Online)
Regul. Mech. Biosyst., 8(1), 91–97
doi: 10.15421/021716
Central hemodynamic and splanchnic circulation
in children with meningococcal septic shock
M. A. Georgiyants*, V. A. Korsunov*, O. M. Olkhovska**
*Kharkiv Medical Academy of Postgraduate Education, Kharkiv, Ukraine
**Kharkiv National Medical University, Kharkiv, Ukraine
Article info
Received 12.01.2017
Received in revised form
12.02.2017
Accepted 16.02.2017
Kultury Str., 11/83,
Kharkiv, 61058, Ukraine
Tel. +38-066-523-32-13
Е-mail: eniram@bigmir.net
Ugrickogo Str., 16,
Kharkiv, 61000, Ukraine
Tel. +38-050-300-05-16
Е-mail: korsunoff@ukr.net
N’uton Str., 123/37,
Kharkiv, 61162, Ukraine
Tel. +38-095-193-12-44
Е-mail: onixol19@gmail.com
Georgiyants, M. A., Korsunov, V. A., & Olkhovska, O. M. (2017). Central hemodynamic and splanchnic circulation
in children with meningococcal septic shock. Regulatory Mechanisms in Biosystems, 8(1), 91–97.
doi: 10.15421/021716
Meningococcal infection is caused by the bacterium Neisseria meningitidis (also termed meningococcus). Invasive
meningococcal disease remains a rare infectious disease not only with high mortality but also with important morbidity
and remains as a leading cause of sepsis and septic shock. The pathogenic mechanisms of microcirculatory disorders in
meningococcal septic shock have been subject to controversy. This article presents the results of a study of 11 paediatric
patients’ (4 boys and 7 girls) with meningococcal septic shock (Group I) who were hospitalized at the Regional
Children's Infectious Hospital from 2009 to 2011. The average age of the patients was 37.4 ± 8.4 mo. Septic shock was
diagnosed according to International Pediatric Sepsis Consensus Conference: definitions of criteria for sepsis and organ
dysfunction in paediatrics. Heart rate, respiratory rate, systolic blood pressure, diastolic blood pressure, average blood
pressure, SpO2 were monitored. The cardiac output, ejection fraction, fraction shortening, stroke volume were measured
by ultrasound in M-mode by Teichholz method. Blood circulation in the a. mesenterica, a. hepatica, a. lienalis, a. renal
sinister, v. porta, v. lienalis, v. renal sinister was determined by impulse Doppler’s wave. Acid-base and electrolytes
level in serum, nitric oxide (NO), endothelin I, creatinine, C-reactivity protein and lactate blood level were measured.
The control group consisted of 21 healthy children (9 boys and 12 girls), aged 37.5 ± 5.4 mo. in average (Group II).
We used t-criteria (Student’s) and correlation with R-criteria (Spearmen) for statistical analysis. The data showed a
statistically significant lower fraction of ejection, fraction of shortening, stroke volume in Group I. Moreover, our data
showed a statistically high level of mesenterial and portal blood flow rate and high pulse index in v. renal sinister
compared to healthy children. The blood level of NO was increased in Group I as well as in Group II. Direct
correlations were determined between the level of NO and mesenteric, hepatic arterial and venous blood flow rate.
Statistically significant inverse correlations between the level of NO and pulse resistive index in splanchnic vessels were
discovered as well as inverse correlations between the NO level and the indicator of the severity of condition on PRISM
scale (r = –0.952). At the same time, we have found no correlation between splanchnic circulation value and cardiac
output. Based on the results of this study, we consider that NO has organ protective effects in children with
meningococcal sepsis. Future research should aim to introduce new strategies of intensive care for patients with
meningococcal septic shock with early use of inotrope and NO-donor therapy in fluid restriction combination.
Keywords: meningococcal sepsis; сhildren; nitric oxide; portal circulation
Introduction
Meningococcal infection (MI) was first described by Vieus-
seux, Switzerland in 1805. Meningococcus (Neisseria meningitidis)
was first identified in the cerebrospinal fluid of a patient with
meningitis by Weichselbaum in 1887. According to WHO, MI has
caused 171,000 deaths all over the world since the year 2000
(Hamborsky, 2015).
N. meningitidis leads to 500,000 cases of meningitis and septi-
cemia in the world annually. Recent foreign data indicate a 5–15%
mortality rate of meningococcal diseases (Sadarangani et al., 2015).
It remains highly distressing that MI can kill healthy people of any
age within a few hours of the onset of the first symptoms.
In 1919 W. W. Herrick pointed out, regarding meningococcal
infection, "there is no other infection that kills so quickly" and this
statement is still correct almost 100 years later. Meningococcal
disease is the leading infectious factor in the death in children in the
UK, despite the success of vaccination against meningococcus group
C. High mortality is not the only problem posed by meningococcal
infection – more than a third of surviving patients have one or more
clinically significant physical, cognitive or functional defects.
Overall, one in ten affected children can suffer such serious
consequences as amputations and brain damage (Viner et al., 2012).
Deaths and severe disability are usually associated with the fulminant
course of meningococcal sepsis, the frequency of which is 10–20%
and the mortality up to 80–100%. The leading factor of death and
serious complications of the skin and soft tissue with MI is septic
shock (Nadel, 2016). In pathogenesis of septic shock the main role is
played by disorders of the microcirculation and tissue perfusion or
microcirculatory distress, which are based on the damage to the endo-
thelium (De Backer et al., 2013; Ince et al., 2016). Long-term persis-
tence of these disorders despite intensive therapy is one of the leading
factors in the formation of multiple organ failure syndrome and
unfavourable outputs in septic shock (De Backer et al., 2013).
It is known that two groups of mediators are involved in the
regulation of vascular tone: vasoconstrictors (catecholamines, vaso-
Regul. Mech. Biosyst., 8(1)
92
pressin, angiotensin II, endothelin, leukotrienes) and vasodilators
(prostaglandins, serotonin, histamine, nitric oxide, atrial natriuretic
peptide) (Boisrame-Helms et al., 2013). There is a hypothesis that
explains the development of septic vasodilatation by an imbalance
between vasodilators and vasoconstrictors in favour of vasodilators.
However, vasodilatation affects not all vascular areas, but some
vascular pools can be in a state of spasm, leading to a redistribution
of blood flow through different parts of the microvasculature, as it
is shown in patients with severe sepsis that the number of microvas-
culature vessels with normal blood circulation (<20 μm) is signifi-
cantly lower, compared to healthy volunteers (De Backer, 2014).
Many studies have demonstrated that the slowdown of blood flow
in micro vessels persists and causes a disturbance of oxygen con-
sumption by tissues after solution resuscitation (Corrêa et al., 2016).
In the experimental models of septic shock the rapid reduction in
microcirculatory blood flow was detected, the formation of vessels
with the ability to block blood circulation, increase in blood flow
heterogeneity and reduction of the density of capillaries. It is em-
phasized that these disorders can occur in the absence of intensive
hemodynamic changes and arterial hypotension (De Backer, 2014).
Due to redistribution of blood flow, microcirculatory disorders lead
to the development of multiple organ failure in septic shock
syndrome and have to be corrected immediately by intensive care
(Lupp et al., 2013). Thus, according to published data, vasodilation
and vasoconstriction simultaneously appear in septic shock and are
both responsible for damage to vital organs. However, in common-
ly adopted intensive care the major aim is to remove arterial
hypotension (predominantly vasodilation) by using sympathomime-
tic drugs, which cause more severe vasoconstriction and closing of
the vicious circle of septic shock. Nitric oxide (NO) is considered as
the main vasodilator. The lifetime of NO is about 6 sec. after which
it turns into nitrates (NO2–) and nitrite (NO3–). In septic shock NO
formation is stimulated by LPS and pro-inflammatory cytokines
from L-arginine due to the action of enzyme isoforms of NO-
synthase. The formation of NO may also be as a result of restora-
tion from NO2– and NO3– by nitrate reductase systems (Zhao et al.,
2015). The effect of NO on the microorganism is realized through
activation of soluble guanylate cyclase in the endothelium. Conse-
quently, synthesis of cyclic guanosine monophosphate increases,
causing the relaxation of blood vessels and as a result – hypotension
and increased capillary leakage (Zhao et al., 2015). Thus, an excess
of NO in septic shock can reduce systemic and pulmonary vascular
resistance, which in turn reduces the systemic and pulmonary blood
pressure. Its abundance is also associated with the development of
myocardial dysfunction and increased oxygen consumption. Howe-
ver, in septic shock vasodilatation and its effects are also likely to
occur due to hypoxia and activation of potassium channels, lactic
acidosis, and vasopressin deficiency.
Thus, in recent years, the alternative concept of the role of
L-arginine and NO in septic shock has been formulated. According
to this concept, as the result of the activation of the second path
using inducible nitric oxide synthase, hyperproduction of NO is
compensatory in nature due to the inhibition of NO production by
constitutive NO-synthase III type that provides a sufficient level of
NO required for maintaining adequate organ perfusion.
Thus, it has been suggested that, primarily affected by the pre-
valence of septic shock, vasoconstrictors improve organ perfusion
due to the overproduction of NO (Duran-Bedolla et al., 2014). It is
important to remember that if septic shock in adults is often accom-
panied by high cardiac output and low peripheral vascular resis-
tance (predominant occurrence of vasodilation), then septic shock
in children often has the opposite hemodynamic profile – low cardi-
ac output and elevated or normal vascular resistance.
That's why the leading symptom of septic shock in adults is
blood pressure reduction and in children – microcirculatory disor-
ders (Dellinger et al., 2013). Therefore, it is logical to assume that a
vasoconstrictor effect is dominant in children with septic shock.
This assumption is more logical regarding meningococcal septic
shock, thanks to expressive microcirculation disorders that cause
necrosis of the skin and soft tissue more frequently than in any other
diseases and the pathognomonic sign of meningococcemia-dissemi-
nated hemorrhagic rash with necrosis.
However, according to the concept of blood flow heterogeneity
in septic shock, a question arises: Is vasoconstriction present in all
vascular pools in children with meningococcal septic shock?
The greatest interest lies in the state of blood circulation in the
organs of the splanchnic zone (intestines, liver), which is the largest
vascular area and normally requires up to 25% of cardiac output
and characterizes multiple aspects of homeostasis (Prin et al., 2015).
There is an evident interest in the condition of the renal circulation,
because damage and dysfunction of the kidneys and organs of the
splanchnic zone are integral components of the multiple organ fai-
lure syndrome. Meanwhile, the data about microcirculatory changes
in these organs during septic shock remain highly controversial
(Gomez et al., 2014; Bernal, 2016). The next question concerns the
relationship between the cardiac output and the state of regional
circulation. Unfortunately, in the sources available to us, we have
found only a few papers devoted to the analysis of the central he-
modynamic in children with meningococcal septic shock and were
unable to locate even a single work on the state of the splanchnic
organs and renal blood flow. Meanwhile, there are publications on
the use of Doppler ultrasound for blood flow investigation of the
afferent and efferent renal vessels and mentioning the high efficien-
cy of this method for the prediction of acute kidney injury (Schnell
et al., 2012). Thus, there is significant difference in opinion on the
state of splanchnic and renal perfusion in cases of MI, dependence
of blood perfusion on the balance of nitric oxide and endothelin.
These aspects have not been researched in children with meningo-
coccal septic shock, which is why the current investigation was
carried out.
The purpose of the study was to assess the state of splanchnic
(top mesenteric, common hepatic, splenic artery, splenic and portal
venous) blood flow and renal blood flow in children with meningo-
coccal septic shock and make a subsequent comparison of the obtai-
ned data with the serum concentration of nitric oxide and endothelin I.
We also set the of goal of determining the relationship between the
level of nitric oxide, endothelin and serum parameters of renal and
splanchnic circulation, systemic inflammatory response and the
severity of organ failure in children with meningococcal septic shock.
Materials and methods
The study involved 11 children (4 boys and 7 girls) aged from
7 months to 9 years (34.9 ± 8.5 months on average), who were hos-
pitalized in the ICU of Regional Children’s Infectious Diseases
Hospital (Kharkiv) in the years 2009–2011 and diagnosed with
septic shock of meningococcal etiology (Group 1). Diagnosis of
septic shock was established on the basis of criteria of the Interna-
tional Pediatric Sepsis Consensus Conference: definitions for sepsis
and organ dysfunction in pediatrics (2005). The severity was evalu-
ated on the basis of Glasgow Meningococcal Septicaemia Progno-
stic Score (GMSPS) – 9, 0.0 ± 1.3 points on average; scale of septic
multiple organ failure SOFA – 10.1 ± 1.2 points and PRISM GPA
scale – 20.4 ± 3.2 points on average.
Monitor observation of patients included the determination of the
heart rate (HR), skin and rectal temperature gradient, electrocardio-
graphy, systolic (SBP), diastolic (DBP) and mean arterial pressure
(MBP), central venous pressure (CVP), the frequency of respiratory
movements (RR), pulse oximetry (SpO2) (monitors UM-300).
Simultaneously with intensive care measures (providing venous
access, sedation, oxygen or endotracheal intubation, blood analysis
and antibiotics therapy) all children underwent additional examina-
tion – M-mode echocardioscopy and pulsed-wave Doppler scan of
blood flow in the liver (AH), splenic (AL ) and upper mesenteric
(AM) arteries, portal (VP) and splenic (VL) veins (ultrasound scan-
ner "Ultima PA"). HR, end-diastolic (LVEDD) and end-systolic
(LVESD) size of the left ventricle was measured. According to the
formula Teichholz et al. (1976), indices of left ventricular end-sys-
Regul. Mech. Biosyst., 8(1) 93
tolic (LVESV) and end-diastolic volume (LVEDV), stroke volume
(SV), stroke index (SI), ejection fraction (EF), contraction fraction
(FS) were calculated. Cardiac output (HMV), cardiac index (CO)
index and total peripheral vascular resistance (SVRI) were calcula-
ted by well-known formulae (Butterworth and Mackey, 2013). Also
the diameter of blood vessels (D) of the portal vein, hepatic artery,
splenic artery, upper mesenteric artery and splenic vein, the maxi-
mum (Vmax) and minimum (Vmin) blood flow speeds in these vessels
were measured. According to the well-known formulae, the average
blood flow velocity (Vmean), Pulse Code (RA), resistance index (IR),
blood flow volume Q, the ratio of blood flow to the body weight Q/m
and the indices of volumetric blood flow in the hepatic IBS AH and
upper mesenteric artery IBS AM and their relationship to the CO
(IBC/CO AH and IBC /CO AM) were calculated.
Besides, we determined the hepatic vascular index (HVI), sple-
noportal index (LPI), Doppler portal index (DPI), common hepatic
blood volume flow (CHBV), hepatic portal ratio (HPR). With all
patients the pulsed-wave Doppler scan blood flow in the left renal
artery (Aren S) and (Vren S) vein was performed and the average
flow velocity (Vmean), pulsation index (PI) and resistance index (IR)
were calculated based on the results of maximum (Vmax) and
minimum (Vmin) flow rate. Parameters of acid-base status and gases
of arterial and central venous blood were measured by analyzer
AVL – 995 and Gastat – mini. The level of hemoglobin (Hb) was
determined by the colorimetric method. The calculation of oxygen
supply DO2, oxygen consumption VO2 and an index of tissue
oxygen extraction was carried out by known formulae. The level of
glucose was determined by analyzer "Exsan – G". C-reactive
protein and endothelin І was measured by immuno-enzyme analysis
(ELISA-test, USA), creatinine – by the method of Jaffe, content of
blood lactate – enzymatic method with "Olvex diagnosticum"
(Russia) by biochemical analyzer Stat Fax 1904+. The content of
NO was assessed by serum final metabolites (nitrites/nitrates) by
colorimetric method using the Griess reagent in the Central Re-
search Laboratory of Kharkov National Medical University.
The control group (Group II) was formed of 21 practically
healthy children (9 boys and 12 girls) (average age 37.5 ± 5.4 mo).
The parameters of central hemodynamics indices, Doppler parame-
ters of blood circulation in the vessels of splanchnic zone, kidneys
and NO metabolites content and serum endothelin І were establi-
shed in the control group. Statistical processing of the obtained data
was carried out by means of Statistica 7.0 (StatSoft Inc., USA)
applications.
The test of normality was carried out according to the Kolmo-
gorov-Smirnov criterion. Output data were subordinated to a normal
distribution, so the significance of differences between groups was
determined by the t-test (Student's test) and correlations between the
parameters – using the rank correlation coefficient R (Spearman).
Results and discussion
Patients of the study Group I and the control Group II were not sig-
nificantly different in age and anthropometric parameters and therefore
can be comparable for further analysis of hemodynamic parameters and
indicators of splanсhnological and renal blood flow (Table 1).
Table 1
General characteristics of Groups (Mean ± SE)
Indices Group I, n = 11 Group II, n = 21 P
Age, mo 34.9 ± 8.5 37.5 ± 5.4 0.761
Height, cm 106.1 ± 4.6 99.0 ± 5.9 0.243
Body weight, kg 14.9 ± 1.9 14.3 ± 2.3 0.782
Body area, m2 0.66 ± 0.05 0.63 ± 0.06 0.603
Children from Group I showed signs of systemic inflammatory
response in the form of fever, tachypnea, tachycardia, leukocytosis
(or leukopenia), increased levels of C-reactive protein (normally
less than 6 mg/l), which gave rise to the diagnosis of meningococcal
sepsis based on combination of abundant hemorrhagic rash and
results of bacteriological examination (emphasis of meningococcal
groups A, B or C in the blood or nasal-throat) (Table 2). Indicators of
central hemodynamics in Group I were characterized by significantly
increased heart rate and reduced rates of systolic, diastolic and com-
mon arterial pressure. These changes are typical of decompensated
septic shock. Indicators of the diastolic-end and systolic- end dimen-
sions and volumes of the left ventricle in Group I and Group II did not
differ significantly, but due to the decrease of EDLVD and increase of
ESLVD, we investigated a decrease in the left ventricular systolic
function, which includes ejection and contraction fractions. Stroke
volume and left ventricular stroke indices were significantly lower in
Group I compared to Group II. However, integrated cardiac output
indices – the volume of blood and heart index were similar in both
groups. Despite reduced SV and SI, significant differences between
MHV and CO in both groups were absent due to tachycardia in
Group I. The total peripheral vascular resistance was not significantly
different between the groups (Table 3).
Table 2
Indicators of systemic inflammatory response
and clinical signs of shock in Group I patients, n = 11 (Mean ± SE)
Indices Group I
HR, 1/min 163.3 ± 6.3
RR, 1/min 65.2 ± 4.1
The number of leukocytes, 109/l 14.9 ± 2.7
Body temperature, ˚С 39.2 ± 0.3
С-reactive protein, mg/l 98.2 ± 13.5
Time of filling the capillaries, s 5.6 ± 0.4
Bad peripheral pulse, % 100.0
Table 3
Indicators of central hemodynamics in patients (Mean ± SE)
Indices Group I, n = 11 Group II, n = 21 P
SBP, mm Hg. 79.8 ± 2.0 101.5 ± 1.0 1.0·10–7
DBP, mm Hg. 43.4 ± 3.0 57.3 ± 1.4 0.001
MBP, mm Hg. 55.5 ± 2.6 72.1 ± 1.1 2.0·10–6
EDLVD, mm 28.9 ± 0.02 30.4 ± 0.07 0.540
ESLVD, mm 21.9 ± 0.02 18.8 ± 0.07 0.137
EDLVV, ml 35.5 ± 7.40 37.2 ± 2.79 0.830
ESLVV, ml 18.5 ± 4.42 11.3 ± 1.03 0.118
SV, ml/m2 17.0 ± 3.11 25.8 ± 1.89 0.025
SІ, ml/min/m2 24.7 ± 2.97 43.7 ± 2.25 5.6·10–5
HMV, l/min 2.7 ± 0.44 2.6 ± 0.16 0.775
СO, l/min/m2 4.0 ± 0.42 4.4 ± 0.22 0.394
EF, % 51.0 ± 3.0 70.0 ± 1.0 1.0·10–6
FS, % 25.0 ± 1.0 38.0 ± 1.0 1.0·10–7
SVRІ, dinscm-5m2 1150.2 ± 132.9 1371.8 ± 68.4 0.152
Thus, the indicators for analysis of central hemodynamics in
children with meningococcal septic shock give reasons to recognize
a significant deterioration of left ventricular systolic function as the
leading factor of hemodynamic disorders, which in time offsets a
significant increase in the heart rate. Despite the rather high cardiac
output at normal ISVR of patients in Group II there was significant
hypotension. We can assume that the second important factor which
causes hemodynamic instability in the examined patients was the
relative angioparesis, which made it impossible to maintain normal
blood pressure. Analysis of acid-base status in patients of Group I
indicates that they suffered from decompensated metabolic acidosis
with increased anion interval. The possible reason for this was
hyperlactatemia. Moderate anemia, hypercalcemia and increased
creatinine were also observed. Usually, hypercalcemia is an atypical
phenomenon for septic shock, but in our opinion, it was caused by
the introduction of calcium to patients in prehospital emergency
care. The increased level of creatinine indicates acute kidney dama-
ge in patients of Group I. Transport and consumption of oxygen
were characterized by the moderate decrease in oxygen delivery
with saved oxygen consumption, which is typical for the subcom-
pensated state (Table 4).
Analysis of the blood flow in arterial vessels in the splanchnic
zone shows the differences between Group I and the control Group II.
Blood flow in the hepatic artery in Group I was characterized by
Regul. Mech. Biosyst., 8(1)
94
significant growth of diastolic velocity Vmin accompanied by a sig-
nificant decrease of pulsating index and resistance index compared
to Group II. These changes follow the development of angioparesis
in the hepatic artery. However, the volume flow rates of Groups I
and II were not significantly different. So angioparesis may be vie-
wed as compensatory within autoregulation of circulation in the
internal organs to promote the required volume of blood circulation
in the systemic arterial hypotension (Table 5).
In a. mesenterica of Group I we observed an almost double growth
of Vmax was observed up to 181.6 ± 26.4 sm/s, statistically unreliable
tendency to increase the pulse index and resistance index with significant
increase in the blood flow volume relating to body weight Q/m to 75.3 ±
11.0 ml/min/m2 compared to 46.6 ± 4.5 ml/min/m2 in Group II. Such
changes of mesenteric blood flow should be considered as arterial
congestion or excessive arterial blood supply, which leads to partial
compensation in the form of arterial spasm development as
autoregulation mechanisms of organ blood flow. We can exclude
postprandial increase in blood flow in a. mesenterica because of the
critical condition of children on empty stomachs who were admitted to
the intensive care.
Table 4
Indicators of acid-base, fluid and electrolyte balance,
oxygen transport and oxygen consumption in Group I patients,
n = 11, (Mean ± SE)
Indices Group I, n = 11
Hb, g/l 105.9 ± 4.7
PaO2, mm Hg 124.4 ± 21.1
SaO2,% 95.3 ± 1.6
PCvO2, mm Hg 53.2 ± 5.4
SvO2, % 76.2 ± 4.1
PaCO2, mm Hg 30.1 ± 1.6
pH 7.27 ± 0.06
AB, mmol/l 15.5 ± 1.9
BB, mmol/l 34.9 ± 3.3
BE, mmol/l –11.6 ± 3.5
A gap, mmol/l 34.9 ± 3.3
Na+ , mmol/l 146.4 ± 3.6
K+ , mmol/l 4.69 ± 0.76
iCa++ , mmol/l 1.43 ± 0.34
Cl– ,mmol/l 105.8 ± 2.4
Venous blood Lactate, mmol/l 6.51 ± 2.17
Creatinine, mkmol/l 187.3 ± 45.5
DO2, l/min/m2 517.9 ± 44.0
VO2, l/min/m2 124.7 ± 32.5
ITEO2, % 21 ± 4
Blood flow in a. lienalis in patients in Group I was not signifi-
cantly different in comparison with indicators of Group II (Table 5).
Blood flow in v. portae in Group I was characterized by statistically
significant increase of maximum, minimum and average linear blood
flow compared with Group II. Increase of volumetric flow only had a
statistically unreliable tendency. Indicators in the splenic vein flow
had no significant differences between the study groups (Table 6).
Thus, in our opinion, the changes in blood flow in the portal
vein should be also considered as a compensatory reaction to
increase the blood supply of the liver. Taking into account the
background of septic shock, we can consider a growing need for
oxygen because of indirect systemic inflammatory response among
the reasons for increased blood flow of the liver. In compensatory
reaction to the arterial hypotension, we can observe the activation of
Kuepfer macrophages and synthesis of acute phase proteins.
In analysis of the indices of blood flow in the hepatic artery, we
haven’t found any significant differences between Groups I and II.
However, the blood flow volume index and its relation to body
weight in Group II in the upper mesenteric artery were significantly
higher than in Group I. The presence of significant differences
between the indicators HVI, DPI and HPR reflect the relatively
higher proportion of blood supply to the liver with the portal system
and relatively smaller one with the hepatic artery system together
with a statistically unreliable tendency to increase the overall
volume of hepatic blood flow (Table 7).
Table 5
State of blood flow in blood vessels (Mean ± SE)
Indices Group I, n = 11 Group II, n = 21 P
AH
Vmax, cm/s 90.8 ± 18.1 63.7 ± 3.1 0.008
Vmin, cm/s 27.1 ± 5.4 14.3 ± 1.1 0.678
Vmean, cm/s 48.1 ± 9.0 28.0 ± 3.0 0.073
PI 1.30 ± 0.11 1.61 ± 0.06 0.135
IR 0.69 ± 0.03 0.78 ± 0.01 0.182
D, cm 0.28 ± 0.03 0.32 ± 0.03 0.786
Q, ml/min 249.8 ± 47.4 291.8 ± 44.1 0.212
Q/m, ml/min/m2 20.5 ± 5.2 20.4 ± 1.4 0.030
AМ
Vmax, cm/s 181.6 ± 26.4 100.4 ± 4.6 0.064
Vmin, cm/s 21.4 ± 2.1 25.8 ± 9.0 0.064
Vmean, cm/s 74.8 ± 9.7 50.6 ± 7.2 0.057
PI 2.08 ± 0.09 1.72 ± 0.19 0.817
IR 0.87 ± 0.02 0.76 ± 0.07 0.807
D, cm 0.41 ± 0.02 0.41 ± 0.01 0.241
Q, ml/min 1075.4 ± 237.9 698.0 ± 149.1 0.315
Q/m, ml/min/m2 75.3 ± 11.1 46.6 ± 4.5 0.378
AL
Vmax, cm/s 97.2 ± 15.1 67.3 ± 3.0 0.064
Vmin, cm/s 26.2 ± 4.0 17.9 ± 1.3 0.064
Vmean, cm/s 50.1 ± 7.5 31.2 ± 3.3 0.057
PI 1.43 ± 0.06 1.45 ± 0.06 0.817
IR 0.73 ± 0.02 0.73 ± 0.01 0.807
D, cm 0.31 ± 0.02 0.34 ± 0.01 0.241
Q, ml/min 467.0 ± 124.1 330.6 ± 38.7 0.315
Q/m, ml/min/m2 34.1 ± 10.7 24.2 ± 2.3 0.378
Table 6
State of blood flow in the portal and splenic veins (Mean ± SE)
Indices Group I, n = 11 Group II, n = 21 P
VP
Vmax, cm/s 29.1 ± 4.2 16.6 ± 0.7 0.010
Vmin, cm/s 14.5 ± 1.3 11.2 ± 0.5 0.007
Vmean, cm/s 17.0 ± 1.5 13.0 ± 0.6 0.007
PI 0.45 ± 0.03 0.42 ± 0.02 0.122
IR 0.34 ± 0.02 0.33 ± 0.01 0.129
D, cm 0.56 ± 0.05 0.58 ± 0.02 0.356
Q, ml/min 489.9 ± 95.0 328.0 ± 32.5 0.131
Q/m, ml/min/m2 38.0 ± 9.5 24.5 ± 1.3 0.178
VL
Vmax, cm/s 20.6 ± 3.2 22.1 ± 1.2 0.667
Vmin, cm/s 16.2 ± 3.0 16.2 ± 1.1 0.998
Vmean, cm/s 17.7 ± 3.1 18.2 ± 1.1 0.881
PI 0.31 ± 0.07 0.34 ± 0.04 0.672
IR 0.24 ± 0.04 0.27 ± 0.03 0.534
D, cm 0.56 ± 0.05 0.40 ± 0.02 0.947
Q, ml/min 246.5 ± 57.8 237.1 ± 27.9 0.888
Q/m, ml/min/m2 18.0 ± 4.6 17.5 ± 1.6 0.912
Table 7
Indices of portal blood flow in the hepatic
and upper mesenteric arteries (Mean ± SE)
Indices Group I, n = 11 Group II, n = 21 P
ІBС АН 1795.9 ± 373.8 1202.8 ± 168.5 0.175
ІВС АM 7324.3 ± 1423.6 2860.4 ± 568.7 0.011
IBC/CI АH 47.8 ± 9.0 28.3 ± 5.0 0.083
IBC/СI АM 194.7 ± 41.8 68.4 ± 16.6 0.013
HVI, cm/s 16.7 ± 2.2 6.7 ± 0.3 0.001
LPI, % 67.6 ± 21.2 78.0 ± 7.4 0.667
DPI 0.35 ± 0.03 0.50 ± 0.05 0.012
CHBV, ml/min 739.7 ± 136.4 563.4 ± 41.2 0.220
HPR 0.56 ± 0.08 0.74 ± 0.09 0.025
No significant differences in blood flow parameters between
Groups I and II were found. Indicators of blood flow in the left
renal vein showed no differences between Groups I and II , except
that the pulse index (PI) in patients of Group I with meningococcal
septic shock was significantly higher than in Group II. Thus, in
patients with septic shock of meningococcal etiology a substantial
Regul. Mech. Biosyst., 8(1) 95
and clinically significant renal venous vasoconstriction was obser-
ved (Table 8).
Table 8
State of blood flow in the left renal artery and vein (Mean ± SE)
Indices Group I, n = 11 Group II, n = 21 P
Aren S
Vmax, cm/s 55.1 ± 8.6 68.0 ± 3.7 0.182
Vmin, cm/s 14.9 ± 2.8 16.8 ± 1.3 0.539
Vmean, cm/s 28.3 ± 4.5 33.8 ± 1.7 0.257
PI 1.46 ± 0.16 1.52 ± 0.08 0.762
IR 0.72 ± 0.04 0.75 ± 0.02 0.546
Vren S
Vmax, cm/s 19.8 ± 3.0 17.2 ± 0.9 0.402
Vmin, cm/s 9.9 ± 1.5 11.6 ± 0.5 0.276
Vmean, cm/s 13.2 ± 1.8 13.5 ± 0.6 0.880
PI 0.73 ± 0.15 0.41 ± 0.03 0.042
IR 0.45 ± 0.07 0.32 ± 0.02 0.056
Basically, the results of our data on the specificity of venous
vasoconstriction, which is mostly characterized by a decrease in
diastolic flow velocity and the development of acute kidney damage
are similar to those of other researchers (Fig. 1). Correlation analysis
of indicators of renal venous flow revealed the presence of significant
connection between Vmin in the renal vein and creatinine (R = –0.840,
P < 0.05). The Pulse Index of renal veins in Group II never exceeded
the mark of 0.53 (Max = 0.53, Min = 0.22) (Fig. 2). To assess the
impact of vasoactive mediators on blood flow distribution to different
vascular zones, we explored the content of total serum metabolites of
nitric oxide (NO2– + NO3–) and concentration of endothelin I in blood.
It was found that children in Group I had a significant increase of
nitric oxide metabolites in comparison to those in Group II. Despite a
tendency to slight increase of endothelin I concentration in Group I,
there were no significant difference between the groups (Table 9).
Table 9
Content of NO final metabolites and serum lactate (Mean ± SE)
Indic es Group I, n = 11 Group II, n = 21 P
The total NO metabolites, mkmol/l 51.3 ± 8.3 29.3 ± 2.5 0.014
Endothelin I, pmol/l 0.70 ± 0.35 0.24 ± 0.01 0.264
Fig. 1. Renal blood flow in baby with septic shock
Fig. 2. Renal blood flow in healthy child
In order to determine the presence of relations between the
states of regional blood flow , we conducted a correlation analysis
of systemic inflammatory response, severity and studied vasoactive
mediators. This analysis revealed strong positive relations between
cumulative NO metabolites, speed of blood flow through the
vessels in the splanchnic zone, diameter of vessels, pulse index and
index of resistance. The direction of these connections testified the
dependence of the vascular zone on NO, which has the ability of
NO to cause vasodilation in liver and upper mesenteric artery,
splenic and portal veins. The direct relation of NO with the number
of polymorphic nuclear neutrophils and reverse assessment scale of
PRISM may indicate the increased production of NO which has a
positive impact on patients recovering from meningococcal septic
shock. Unlike NO, the endothelin correlation with indicators of
vascular tone is evidence of its vasoconstrictive effect. Besides,
endothelin had a direct relation with C-reactive protein. Based on
our obtained data, we set ourselves the question about the role of
cardiac output in influence on the performance of regional circulation.
Regul. Mech. Biosyst., 8(1)
96
In order to answer this question, we conducted a correlation analysis
between the cardiac output measure and those indicators that demon-
strated a close correlation with vasoactive mediators. In none of the
cases did the SO have significant correlations with indicators of regio-
nal blood flow and systemic inflammatory response or severity of the
examined patients’ status (Table 10). We haven’t found any signifi-
cant correlation between indicators of central hemodynamics and NO,
which may probably refute the traditional view of the ability of NO to
cause myocardial depression in sepsis (Table 11).
Table 10
Correlation between cardiac output, vasoactive mediators,
indicators of organ blood flow, systemic inflammatory
response and the severity of Group І
Indices R P
Vmin AH – CO –0.200 > 0.05
Vmin AH - NO –0.710 < 0.05
IR VP – CO –0.083 > 0.05
IR VP – NO –0738 < 0.05
PI VP – CO –0.083 > 0.05
PI VP – NO –0.738 < 0.05
D AM – CO 0.368 > 0.05
D AM – NO 0.826 < 0.05
Vmax VL – CO 0.000 > 0.05
Vmax VL – NO 0.785 < 0.05
Vmin VL – CO 0.000 > 0.05
Vmin VL – NO 0.780 < 0.05
Vmean VL – CO 0.000 > 0.05
Vmean VL – NO 0.780 < 0.05
PRISM – CO 0.118 > 0.05
PRISM – NO –0.952 < 0.05
Polymorphonuclear neutrophils – CO 0.358 > 0.05
Polymorphonuclear neutrophils – NO 0.845 < 0.05
IR VL – CO –0.283 > 0.05
IR VL – endothelin І 0.730 < 0.05
PI VL – CO –0.283 > 0.05
PI VL – endothelin І 0.730 < 0.05
D AL – CO 0.193 > 0.05
D AL – endothelin І –0.672 < 0.05
D VP – CO –0.122 > 0.05
D VP – endothelin І –0.666 < 0.05
IR VL – CO –0.283 > 0.05
IR VL – endothelin І 0.732 < 0.05
PI VL – CO – 0.283 > 0.05
PI VL – endothelin І 0.732 < 0.05
С-reactive protein – CO –0.383 > 0.05
С-reactive protein – endotelin І 0.808 < 0.05
Table 11
Correlation between indicators of central hemodynamics
and NO metabolites in the Group І
Indices R P
MAP – NO 0.443 > 0.05
EDLVD – NO 0.060 > 0.05
ESLVD – NO 0.059 > 0.05
SV – NO 0.084 > 0.05
CO – NO 0.071 > 0.05
EF – NO 0.132 > 0.05
SVRІ – NO 0.500 > 0.05
Thus, our obtained data on the state of central hemodynamics
of children with meningococcal septic shock in general are similar
to the work of Have et al. (2000) – the only ultrasound research
conducted on hemodynamics in meningococcus infected children,
which also showed a significant reduction in left ventricular systolic
function and its prognostic significance in poor output. However,
our findings may create a discussion on important role of
hypovolemia in the development of septic shock in children.
Identifying the truth on this matter is extremely important, because
the current existing recommendations on the management of septic
shock (including meningococcal shock in children) give preference
to aggressive infusion therapy as the first step in treatment (Brierley
et al., 2009; Nadel, 2016). However, the results of our studies show
the negative effects of aggressive infusion in patients with systolic
heart failure! At the same time , we observe another approach to
using infusion therapy in adults with septic shock, which includes
minimization of the liquid volumes (Malbrain et al., 2014; Malbrain
et al., 2015; Chen and Kollef, 2015). In a recent published study, the
benefits of restrictive fluid therapy in comparison with standard
infusion at septic shock in adults were presented (Hjortrup et al.,
2015). The study RENAL showed that negative daily water balance
was associated with clinical improvement in these patients (Bellomo
et al., 2012).
The researched changes in the regional blood flow distribution
in the splanchnic areas in patients with meningococcal septic shock
indicate that the organs in splanchnic areas are not exposed to
ischemia. On the contrary, in terms of early septic shock we found
hyper perfusion on the basin of the upper mesenteric artery and
increase (mainly due to portal) of total hepatic blood flow, which
may well reflect increased oxygen need in the liver and intestine.
The latter could be reached through the activation of immune cells
(associated with intestine lymphoid tissue and liver Kuepfer
macrophages) and their participation in the systemic inflammatory
response. Also hemodynamic lesion of these organs may rather be
due to the hyper perfusion than ischemia. The same applies to the
kidneys. The role of direct prerenal ischemia in the development of
acute kidney damage in sepsis is becoming more doubtful. Kidney
damage and venous hypertension indicate intraorganic microcircu-
latory disorders, which were proven in the form of the pulse growth
index of the main renal veins found in our study (Zarbok et al., 2014).
The role of NO molecules in meningococcal septic shock
should be revised. The image of "sinister monster" responsible for
cardiac dysfunction and uncontrolled arterial hypotension in septic
shock should be rejected, because NO played a leading role in
maintaining microcirculation and perfusion in vital parts of the
vascular system (Duran-Bedolla et al., 2014).This is proved by the
leading foreign publications, as well as the results of correlation
analysis in our study. Unlike the current Guidelines SSC (2016), the
data we obtained can be a theoretical basis for the application of
NO donor in complex intensive therapy of hemodynamic disorders
associated with meningococcal septic shock with the aim of
improving the outcomes.
Conclusions
Meningococcal septic shock in children is characterized by
significant impairment of the central hemodynamics, which consists
in lowering blood pressure, tachycardia, and suppression of left
ventricular systolic function. The data we have obtained on the
nature of hemodynamic disorders in children suffering from menin-
gococcal septic shock should be used to substantiate a more cau-
tious approach to infusion therapy and earlier use of drugs with po-
sitive inotropic effects.
Given the significant increase of NO production, which correlates
with splanchnic circulation indicators, we can assume that hyper-
production of NO and hyperperfusion in the splanchnic zones play a
protective role against the development of organ failure, because they
are associated with a lower score on the PRISM scale.
The increased resistance index in the main renal veins in
patients with meningococcal septic shock is closely correlated with
the creatinine level, so it can be used as a non-invasive sign of acute
kidney injury. In contrast to the recommendations of the Surviving
Sepsis Campaign (2016) concerning the undesirable use of arginine
to increase the level of NO in adults with septic shock, the use of
arginine and other donors of NO in children with meningococcal
septic shock should be the subject of further research.
References
Bellomo, R., Cass, A., Cole, L., Finfer, S., Gallagher, M., Lee, J., Lo, S.,
McArthur, C., McGuiness, S., Norton, R., Myburgh, J., Scheinkestel, C., &
Su, S. (2012). An observational study fluid balance and patient outcomes
Regul. Mech. Biosyst., 8(1) 97
in the randomized evaluation of normal vs. augmented level of
replacement therapy trial. Critical Care Medicine, 40(6), 1753–1760.
Bernal, W. (2016). The liver in systemic disease: Sepsis and critical illness.
Clinical Liver Disease, 7(4), 88–91.
Boisrame-Helms, J., Kremer, H., Schini-Kerth, V., & Meziani, F. (2013). Endothelial
dysfunction in sepsis. Current Vascular Pharmacology, 11(2), 150–160.
Carcillo, J. A., & Fields, A. I. (2002). Clinical practice parameters for hemodyna-
mic support of pediatric and neonatal patients in septic shock. Critical Care
Medicine, 30(6), 1365–1378.
DiLorenzo, A. N., & Schell, R. M. (2014). Morgan Mikhail’s clinical anesthesio-
logy, 5th Edition. Anesthesia and Analgesia, 119(2), 495–496.
Chen, C., & Kollef, M. H. (2015). Targeted fluid minimization following
initial resuscitation in septic shock. Chest, 148(6), 1462–1469.
Corrêa, T. D., Filho, R. R., Assunção, M. S. C., Silva, E., & Lima, A. (2017).
Vasodilators in septic shock resuscitation. Shock, 47(3), 269–275.
De Backer, D., Orbegozo Cortes, D., Donadello, K., & Vincent, J. L. (2013).
Pathophysiology of microcirculatory dysfunction and the pathogenesis
of septic shock. Virulence, 5(1), 73–79.
De Backer, D., Donadello, K., Sakr, Y., Ospina-Tascon, G., Salgado, D.,
Scolletta, S., & Vincent, J. L. (2013). Microcirculatory alterations in
patients with severe sepsis. Critical Care Medicine, 41(3), 791–799.
Dellinger, R. P., Levy, M. M., Rhodes, A., Annane, D., Gerlach, H., Opal,
S. M., Sevransky, J. E., Sprung, C. L., Douglas, I. S., Jaeschke, R., Osborn,
T. M., Nunnally, M. E., Townsend, S. R., Reinhart, K., Kleinpell, R. M.,
Angus, D. C., Deutschman, C. S., Machado, F. R., Rubenfeld, G. D.,
Webb, S. A., Beale, R. J., Vincent, J. L., & Moreno, R. (2013). Surviving
sepsis campaign. Critical Care Medicine, 41(2), 580–637.
Duran-Bedolla, J., de Oca-Sandoval, M. A. M., Saldana-Navor, V.,
Villalobos-Silva, J. A., Rodriguez, M. C., & Rivas-Arancibia, S. (2014).
Sepsis, mitochondrial failure and multiple organ dysfunction. Clinical
and Investigative Medicine, 37(2), 58–69.
Gomez, H., Ince, C., De Backer, D., Pickkers, P., Payen, D., Hotchkiss, J., &
Kellum, J. A. (2014). A unified theory of sepsis-induced acute kidney
injury. Shock, 41(1), 3–11.
Hamborsky, J., & Kroger, A. (Eds.). (2015). Epidemiology and prevention
of vaccine-preventable diseases. Public Health Foundation, 512.
Hagmolen of ten Have, W., Wiegman, A., van den Hoek, G. J., Vreede, W. B.,
& Derkx, H. H. F. (2000). Life-threatening heart failure in meningococcal
septic shock in children: Non-invasive measurement of cardiac parameters
is of important prognostic value. European Journal of Pediatrics, 159(4),
277–282.
Hjortrup, P. B., Haase, N., Bundgaard, H., Thomsen, S. L., & Winding, R. (2016).
Restricting volumes of resuscitation fluid in adults with septic shock after
initial management: The CLASSIC randomised, parallel-group, multicentre
feasibility trial. Intensive Care Medicine, 42(11), 1695–1705.
Ince, C., Mayeux, P. R., Nguyen, T., Gomez, H., Kellum, J. A., Ospina-
Tascón, G. A., & De Backer, D. (2016). The endothelium in sepsis.
Shock, 45(3), 259–270.
Lupp, C., Baasner, S., Ince, C., Nocken, F., Stover, J. F., & Westphal, M.
(2013). Differentiated control of deranged nitric oxide metabolism:
A therapeutic option in sepsis? Critical Care, 17(3), 311.
Malbrain, M. L. N. G., Marik, P. E., Witters, I., Cordemans, C., Kirkpatrick,
A. W., Roberts, D. J., & Van Regenmortel, N. (2014). Fluid overload, de-
resuscitation, and outcomes in critically ill or injured patients: A systematic
review with suggestions for clinical practice. Anestezjologia Intensywna
Terapia, 46(5), 361–380.
Malbrain, M. L. N. G., Van Regenmortel, N., & Owczuk, R. (2015). It is time to
consider the four D’s of fluid management. Anestezjologia Intensywna
Terapia, 47, 1–5.
Nadel, S. (2016). Treatment of meningococcal disease. Journal of
Adolescent Health, 59(2), S21–S28.
Prin, M. (2015). Hepatosplanchnic circulation in cirrhosis and sepsis. World
Journal of Gastroenterology, 21(9), 2582.
Rhodes, A., Evans, L. E., Alhazzani, W., Levy, M. M., Antonelli, M., Ferrer, R.,
Kumar, A., Sevransky, J. E., Sprung, C. L., Nunnally, M. E., Rochwerg, B.,
Rubenfeld, G. D., Angus, D. C., Annane, D., Beale, R. J., Bellinghan, G. J.,
Bernard, G. R., Chiche, J. D., Coopersmith, C., De Backer, D. P., French,
C. J., Fujishima, S., Gerlach, H., Hidalgo, J. L., Hollenberg, S. M., Jones,
A. E., Karnad, D. R., Kleinpell, R. M., Koh, Y., Lisboa, T. C., Machado,
F. R., Marini, J. J., Marshall, J. C., Mazuski, J. E., McIntyre, L. A., McLean,
A. S., Mehta, S., Moreno, R. P., Myburgh, J., Navalesi, P., Nishida, O.,
Osborn, T. M., Perner, A., Plunkett, C. M., Ranieri, M., Schorr, C. A., Seckel,
M. A., Seymour, C. W., Shieh, L., Shukri, K. A., Simpson, S. Q., Singer, M.,
Thompson, B. T., Townsend, S. R., Van der Poll, T., Vincent, J. L.,
Wiersinga, W. J., Zimmerman, J. L., Dellinger, R. P. (2017). Surviving
sepsis campaign: International guidelines for management of sepsis and
septic shock: 2016. Intensive Care Medicine, 74.
Sadarangani, M., Scheifele, D. W., Halperin, S. A., Vaudry, W., Le Saux,
N., Tsang, R. (2015). Outcomes of invasive meningococcal disease in
adults and children in Canada between 2002 and 2011: A prospective
cohort study. Clinical Infectious Diseases, 60(8), e27–e35.
Schnell, D., Deruddre, S., Harrois, A., Pottecher, J., Cosson, C., Adoui, N.,
Benhamou, D., Vicaut, E., Azoulay, E., Duranteau, J. (2012). Renal
resistive index better predicts the occurrence of acute kidney injury than
cystatin C. Shock, 38(6), 592–597.
Viner, R. M., Booy, R., Johnson, H., Edmunds, W. J., Hudson, L., Bedford, H.,
Kaczmarski, E., Rajput, K., Ramsay, M., Christie, D. (2012). Outcomes of
invasive meningococcal serogroup B disease in children and adolescents
(MOSAIC): A case-control study. The Lancet Neurology, 11(9), 774–783.
Zhao, Y., Vanhoutte, P. M., & Leung, S. W. S. (2015). Vascular nitric oxide:
Beyond eNOS. Journal of Pharmacological Sciences, 129(2), 83–94.
Zarbock, A., Gomez, H., & Kellum, J. A. (2014). Sepsis-induced acute kidney
injury revisited. Current Opinion in Critical Care, 20(6), 588–595.
