Intensive Care Med (1995) 21:1027-1031
9 Springer-Verlag 1995
B. Gachot
J. P. Bedos
B. Veber
M. Wolff
B. Regnier
Received: 24 June 1994
Accepted: 15 November 1994
The study was supported by the D6bgation
fi la Recherche Clinique, Assistance
Publique-H6pitaux de Paris
B. Gachot ( ~ ) 9J.P. B6dos. B. Veber.
M. Wolff. B. R+gnier
Clinique de R6animation des Maladies
Infectieuses, H6pital Bichat-Claude
Bernard, 46, rue Henri Huchard, F-75018
Paris, France
Short-term effects of methylene blue on
hemodynamicsand gas exchange in humans
with septic shock
Abstract Objective. The aim of this
study was to investigate the acute
effects of methylene blue (MB), an
inhibitor of the L-arginine nitric
oxide pathway, in patients with
septic shock.
Design. A prospective, open, single-
dose study.
Setting." The medical ICU of a uni-
versity hospital.
Patients: Six patients with severe
septic shock.
Interventions: Complete
hemodynamic values were recorded
before and 20 rain after the infusion
of intravenous MB (3 nag kg- 1).
Arterial pressure was then
monitored during the next 24 h or
until death.
Measurements and results: Methyl-
ene blue increased the mean arterial
pressure from 69.7 _+4.5 to
83.7 _+5.1 mmHg (p = 0.028) and
the mean pulmonary artery pres-
sure, from 34.3 _+7.2 to
38.7 _+8.0 mmHg (p = 0.023). Sys-
temic vascular resistance index was
increased from 703.1 + 120.6 to
903.7 _+152.2 dyne.s.cm -s. m - 2
(p = 0.028) and pulmonary vascular
resistance index, from 254.6 + 96.9
to 342.2 _+_118.9 dyne.s.cm - 5.m- 2
(p = 0.027). The PaOz/FIO2 de-
creased from 229.2 _+54.4 to
162.2 +44.1 mmHg (p = 0.028),
without significant modification of
intrapulmonary shunting. Heart
rate, cardiac index, right atrial
pressure, DO2, VO2, oxygen extrac-
tion and arterial lactate were essen-
tially unchanged. Sequential
measurements of arterial pressure
demonstrated a return to baseline
level in 2-3 h. All but one patients
died, three in shock and two in
multiple organ failure.
Conclusions: MB induces systemic
and pulmonary vasoconstriction in
patients with septic shock, without
significant decrease in cardiac in-
dex. The worsening of arterial oxy-
genation following MB injection
may limit its use in patients with the
adult respiratory distress syndrome.
Larger studies are required to deter-
mine whether MB improves the
outcome of patients with septic
shock.
Key words: Endothelium 9 Nitric
oxide- L-arginine' Vasodilation 9
Methylene blue 9 Hemodynamics 9
Gas exchange 9 Septic shock -
Critical illness
1028
Introduction
Fatal outcome in septic shock is often related to refrac-
tory hypotension with high cardiac output and marked
systemic vasodilation [1]. A low-molecular-weight, free
radical with a very short half-life, nitric oxide (NO), is
now thought to mediate vasodilation and resistance to
vasoconstrictor agents observed in this setting [2]. Ex-
perimental studies suggest that this overproduction of
NO is related to the induction of a calcium-indepen-
dent isoform of NO synthase in both endothelial and
smooth-muscle cells by certain cytokines and en-
dotoxine [3]. Nitric oxide has been shown experi-
mentally to act by stimulating the soluble guanylate
cyclase of smooth muscle cells, with subsequent in-
crease of cyclic G M P [2, 3]. Thus, inhibition of the C-
arginine NO pathway can be achieved by inhibiting
either NO synthase or soluble guanylate cyclase.
Methylene blue (MB), or bis(dimethylamino) phenaza-
thionium chloride trihydrate, has been used safely for
many years for the treatment of nitrate poisoning [4]
and methemoglobinemia [5]. Although one experi-
mental study suggests an inhibitory effect of MB on the
calcium-dependent NO synthase isoform [6], MB is
mainly an inhibitor of the soluble guanylate cyclase.
Thus, since the microbicidal properties of NO and its
cytotoxicity against tumor cells in vitro appears to be
mediated by other mechanisms [7], inhibition of
guanylate cyclase in septic shock could attenuate the
hemodynamic effects of N O while respecting cyclic
GMP-independent effects. Experimentally, MB has
been shown to restore vascular responsiveness of rat
aortic rings treated with endotoxin [8,9], and to re-
verse endotoxin-induced hypotension in vivo [10],
without detrimental effect on regional blood flows [11].
In addition, recent preliminary studies suggest that MB
increases arterial pressure and systemic vascular resis-
tance in patients with septic shock [11,127.
The aim of this work was to assess the acute effects
of methylene blue on hemodynamics and gas exchange
in patients with severe septic shock.
Methods
The study was approved by Bichat-Claude Bernard Hospital's Eth-
ics Committee, and relatives gave informed consent.
Patients
Six patients were studied from October 1992 to December 1993.
They were aged 42.5 _+4.8 years and four of them were male. Their
simplified acute physiologic score [-131 was 16.2 _+1.4 at the time of
admission to the ICU. All patients met the criteria for the diagnosis
of severe sepsis as previously defined [14]. In all patients, these
criteria included clinical evidence of infection, tachycardia (>90
beats rain 1), the requirement for mechanical ventilation, fever
(>38.3 ~ oliguria (<0.5 ml kg -1 h-1 for at least 1 h) and lactic
acidosis. Associated organ failures included acute renal failure [15]
(all patients), severe acute lung injury [16] (Murray Score >2.5, four
patients), hematological failure [15] (three patients) and hepatic
failure [17] (three patients). All patients were in shock, and at the
time of the study their arterial pressure was stabilized with the use of
epinephrine (1.9 +0.8 btg kg 1 rain- 1, n = 5) and/or norepinephrine
(3.9 + 1.0 pg kg- i min- 1, n = 4); in the absence of clinical deteriora-
tion, the doses of inotropic drugs remained unchanged during the
study period. Clinical diagnoses included pneumonia (three pa-
tients), gangrenous cholecystitis (one patient) and primary septi-
cemia (two patients). Blood cultures yielded gram-positive cocci (two
patients), gram-negative bacilli (one patient) and were sterile in three
patients. Underlying disease included HIV infection (three patients)
and hepatic cirrhosis (two patients). Patients were monitored via
catheters in the pulmonary artery and the femoral or radial artery.
Hemodynamic and oxygen transport variables were determined
before and 20 rain after the intravenous administration of methylene
blue (3 mgkg-1 in 10 min through an individual central venous
line). Arterial pressure was then monitored during the next 24 h or
until death.
Hemodynamic measurements and calculations
Cardiac output was determined by the thermodilution technique,
with each measurement being performed in triplicate. All parameters
were indexed according to body surface area. Arterial (CaO2) and
venous (CvO2) oxygen contents were calculated using the standard
equation. Oxygen delivery (DO2) was calculated as the product of
cardiac index (CI) and CaO 2 (DO; = C a O 2 x CI x 10). Oxygen up-
take (VOz) was calculated using the Fick equation. The oxygen
extraction ratio (OER) was calculated as the ratio between VO 2 and
DO 2. Intrapulmonary shunting (Qsp/Qt) was assessed with the
standard formula.
Statistical analysis
Values are expressed as mean _+SEM. Hemodynamic parameters
and blood gases were compared with baseline values using the
Wilcoxon matched-pairs signed-rank test. A p < 0.05 was considered
significant.
Results
The modifications of hemodynamic parameters follow-
ing MB are shown in Fig. 1. The administration of
methylene blue was followed by a marked increase in
arterial blood pressure (from 69.7 _+4.5 to 83.7 _+5.1
mmHg, p =0.028) and pulmonary artery pressure
(p =0.023), without significant modification or heart
rate (p =0.752). Although the overall cardiac index
appears unmodified (p =0.345), individual assessment
shows that it was significantly diminished in one pa-
tient (Fig. 1). A concomitant increase in systemic
 1029

200 8O 2
systolic

150
A
---o I
mean
diastolic
7O J 0

60

100 5O

40
5O -'--'--~~
3O
C ! I i i
0 120 180
20 0 20
60 0 20

1500-- 800 40

J
1250

I000
600
3O J
~400
/5-
750
2O
200
500

I
250 0 10 0 210
0 2O 0 20

30 !8( time (rain)

.......r
16( S
14(
C~
< 2O ::12

~2(
T T
loo I
o I

10 8e I I I

0 20 0 20

time (min) time (min)

Fig. 1 a Effects of intravenous methylene blue (injected at time 0)
on systolic, diastolic and mean arterial blood pressure
(mean • b-h Individual hemodynamic parameters (open
circles) before (time 0) and 20 min after intravenous administration
of methylene blue. Filled squares with error bars are mean_+SEM:
b mean pulmonary artery pressure (mmHg); c cardiac index
(1 min -1 m-2); d systemic vascular resistance index (dyne s cm -s
m 2); e pulmonary vascular resistance index (dyne.s.cm S.m-2);
f pulmonary artery occlusion pressure (mmHg), g right atrial pres-
sure (mmHg); h heart rate (beats min-1)
(p = 0.028) and p u l m o n a r y (p =0.027) vascular resis-
tance indexes was observed. P u l m o n a r y artery occlu-
sion pressure and right atrial pressure were unchanged
overall (p = 0.068 and p = 0.285, respectively). N o sig-
nificant modification of oxygen delivery, oxygen con-
sumption, oxygen extraction ratio, shunt fraction or
arterial lactate was observed (Table 1). Significant
changes in blood gases were seen: the P a O 2 / F I O 2
decreased from 229.2 _+54.4 to 162.2 _+44.1 m m H g
(p =0.028) and PaCO2 increased from 46.5 _+4.8 to
50.8 _+5.7 m m H g (p =0.042).
1030

Table 1 Effects of intravenous methylene blue (MB) on derived including platelet aggregation [2] and glomerular
hemodynamic parameters and arterial blood lactate (mean _+SEM) injury [28], both of which are mediated by guanylate
in six patients with septic shock (Ca02, Cv02 arterial, venous
oxygen content, DO2 oxygen delivery, CI cardiac index, V02 oxygen cyclase.
uptake, OER oxygen extraction ratio, Qsp/Qt intrapulmonary In our study, we observed significant changes in
shunting) blood gases, with worsening hypoxemia and hyper-
capnia. Although fictitious pulse oximeter desatura-
Baseline After MB P-value
tion has been described following methylene blue
DO2 887.7 _+156.9 855.2 _+176.7 0.345 administration [29], true modifications of gas ex-
(ml rain - t m -2) change have not whether with methylene blue or with
C/a-v)O~ 2.3 _+0.4 2.8 +_0.5 0.i16 NO synthase inhibitors. Since four of our patients had
(rot,O/o) severe acute lung injury, this effect was of clinical
VO2 140.2 _+16.5 171.2 _+38.8 0.463 importance. Despite the absence of significant modifi-
(ml rain- 1 m - z)
cation of the shunt fraction, the decrease in PaOa in
OER (%) 18.8 -+4.1 23.1 -+4.7 0.116
our patients was probably related to the pulmonary
Qsp/Qt (%) 41.2 -+5.9 43.2 _+5.8 0.528
artery vasoconstriction, thus worsening the matching
Arterial lactate 7.5 _+2.5 9.1 _+4.4 0.715 of ventilation with perfusion. In addition, inhaled NO
(mmol 1 1)
appears to improve oxygenation in patients with the
adult respiratory distress syndrome [30]. The hyper-
capnia we observed in our patients probably depends
on the same mechanism, since inhaled NO at 36 ppm
also decreased PaCO2 in this setting [30~. Another
The changes in systolic, diastolic and mean arterial possibility could be bronchoconstriction, since NO
blood pressure were transient, and a return to baseline has been shown to modulate bronchial tone in hu-
level was observed in 2-3 h (Fig. 1). All but one patient mans [31]. This point has not been investigated in our
died, three in refractory shock (6-42 h following study.
methylene blue administration) and two in multiple ]The presence of cirrhosis in two of our patients may
organ failure (on days 10 and 12, respectively). have contributed to the severity of vasodilation as well
as the clinical response to methylene blue, since persis-
tent induction of NO synthase is thought to account for
Discussion the hemodynamic changes associated with cirrhosis
[3]. Moreover, in one patient with cirrhosis and pre-
After administration of MB, we observed increased sumed septic shock, methylene blue was responsible for
systemic vascular resistance and blood pressure in six a temporary increase in blood pressure with concomi-
patients with septic shock. This antivasodilatory effect tant systemic vasoconstriction [32]. Cardiac output
was not accompanied by a constant decrease in car- was increased, once more suggesting that methylene
diac index, as reported with various L-arginine com- blue does not behave like other inhibitors of the L-
petitive inhibitors in animal [18-21] and clinical arginine pathway.
[22-24] studies. This decrease in cardiac index was In summary, MB appears to be able to restore
associated with a fall in oxygen delivery and consump- systemic vascular tone in patients with septic shock.
tion in one dog study [21]; furthermore, it may lead to Contrary to the situation with NO synthase inhibitors,
a fall in splanchnic blood flow [25] and could explain systemic vasoconstriction was not accompanied by
the worsening of intestinal and hepatic endotoxin- a constant decrease in cardiac index, which suggests
induced damage observed experimentally with NO that MB may be less deleterious to microcirculatory
synthase inhibitors [26,271. Increased left ventricular blood flow. The concomitant pulmonary vasoconstric-
work has been demonstrated following MB adminis- tion was probably responsible for a marked deteriora-
tration in 14 patients with septic shock [11], thus tion in gas exchange that may clearly limit the clinical
confirming that methylene blue may be less detrimen- use of MB in patients with acute lung injury. Further
tal than NO synthase inhibitors to cardiac function. studies are needed to demonstrate if MB and specific
No significant short-term modification of arterial lac- inhibitors of the L-arginine pathway improve mortality
tate was observed in our study, further suggesting that in patients with septic shock. Unless such an effect on
methylene blue administration was not deleterious to survival rate is demonstrated, the use of these com-
tissue perfusion. However, inhibition of the L-arginine pounds should not be recommended in human septic
NO pathway may produce other detrimental effects, shock.

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