Intensive Care Med (1995) 21:1027-1031

9 Springer-Verlag 1995

B. Gachot Short-term effects of methylene blue on

J. P. Bedos
B. Veber hemodynamicsand gas exchange in humans
M. Wolff
B. Regnier
with septic shock

Abstract Objective. The aim of this (p = 0.027). The PaOz/FIO2 de-

Received: 24 June 1994
Accepted: 15 November 1994 study was to investigate the acute creased from 229.2 _+54.4 to
effects of methylene blue (MB), an 162.2 +44.1 mmHg (p = 0.028),
inhibitor of the L-arginine nitric without significant modification of
oxide pathway, in patients with intrapulmonary shunting. Heart
septic shock. rate, cardiac index, right atrial
Design. A prospective, open, single- pressure, DO2, VO2, oxygen extrac-
dose study. tion and arterial lactate were essen-
Setting." The medical ICU of a uni- tially unchanged. Sequential
versity hospital. measurements of arterial pressure
Patients: Six patients with severe demonstrated a return to baseline
septic shock. level in 2-3 h. All but one patients
Interventions: Complete died, three in shock and two in
hemodynamic values were recorded multiple organ failure.
before and 20 rain after the infusion Conclusions: MB induces systemic
of intravenous MB (3 nag kg- 1). and pulmonary vasoconstriction in
Arterial pressure was then patients with septic shock, without
monitored during the next 24 h or significant decrease in cardiac in-
until death. dex. The worsening of arterial oxy-
Measurements and results: Methyl- genation following MB injection
ene blue increased the mean arterial may limit its use in patients with the
pressure from 69.7 _+4.5 to adult respiratory distress syndrome.
83.7 _+5.1 mmHg (p = 0.028) and Larger studies are required to deter-
the mean pulmonary artery pres- mine whether MB improves the
The study was supported by the D6bgation
fi la Recherche Clinique, Assistance sure, from 34.3 _+7.2 to outcome of patients with septic
Publique-H6pitaux de Paris 38.7 _+8.0 mmHg (p = 0.023). Sys- shock.
temic vascular resistance index was
B. Gachot ( ~ ) 9J.P. B6dos. B. Veber. increased from 703.1 + 120.6 to Key words: Endothelium 9 Nitric
M. Wolff. B. R+gnier 903.7 _+152.2 dyne.s.cm -s. m - 2 oxide- L-arginine' Vasodilation 9
Clinique de R6animation des Maladies
Infectieuses, H6pital Bichat-Claude (p = 0.028) and pulmonary vascular Methylene blue 9 Hemodynamics 9
Bernard, 46, rue Henri Huchard, F-75018 resistance index, from 254.6 + 96.9 Gas exchange 9 Septic shock -
Paris, France to 342.2 _+_118.9 dyne.s.cm - 5.m- 2 Critical illness
1028

Introduction 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
Fatal outcome in septic shock is often related to refrac- beats rain 1), the requirement for mechanical ventilation, fever
tory hypotension with high cardiac output and marked (>38.3 ~ oliguria (<0.5 ml kg -1 h-1 for at least 1 h) and lactic
systemic vasodilation [1]. A low-molecular-weight, free acidosis. Associated organ failures included acute renal failure [15]
radical with a very short half-life, nitric oxide (NO), is (all patients), severe acute lung injury [16] (Murray Score >2.5, four
patients), hematological failure [15] (three patients) and hepatic
now thought to mediate vasodilation and resistance to failure [17] (three patients). All patients were in shock, and at the
vasoconstrictor agents observed in this setting [2]. Ex- time of the study their arterial pressure was stabilized with the use of
perimental studies suggest that this overproduction of epinephrine (1.9 +0.8 btg kg 1 rain- 1, n = 5) and/or norepinephrine
NO is related to the induction of a calcium-indepen- (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
dent isoform of NO synthase in both endothelial and study period. Clinical diagnoses included pneumonia (three pa-
smooth-muscle cells by certain cytokines and en- tients), gangrenous cholecystitis (one patient) and primary septi-
dotoxine [3]. Nitric oxide has been shown experi- cemia (two patients). Blood cultures yielded gram-positive cocci (two
patients), gram-negative bacilli (one patient) and were sterile in three
mentally to act by stimulating the soluble guanylate
patients. Underlying disease included HIV infection (three patients)
cyclase of smooth muscle cells, with subsequent in- and hepatic cirrhosis (two patients). Patients were monitored via
crease of cyclic G M P [2, 3]. Thus, inhibition of the C- catheters in the pulmonary artery and the femoral or radial artery.
arginine NO pathway can be achieved by inhibiting Hemodynamic and oxygen transport variables were determined
before and 20 rain after the intravenous administration of methylene
either NO synthase or soluble guanylate cyclase. blue (3 mgkg-1 in 10 min through an individual central venous
Methylene blue (MB), or bis(dimethylamino) phenaza- line). Arterial pressure was then monitored during the next 24 h or
thionium chloride trihydrate, has been used safely for until death.
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 Hemodynamic measurements and calculations
calcium-dependent NO synthase isoform [6], MB is
mainly an inhibitor of the soluble guanylate cyclase. Cardiac output was determined by the thermodilution technique,
with each measurement being performed in triplicate. All parameters
Thus, since the microbicidal properties of NO and its were indexed according to body surface area. Arterial (CaO2) and
cytotoxicity against tumor cells in vitro appears to be venous (CvO2) oxygen contents were calculated using the standard
mediated by other mechanisms [7], inhibition of equation. Oxygen delivery (DO2) was calculated as the product of
guanylate cyclase in septic shock could attenuate the 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
hemodynamic effects of N O while respecting cyclic extraction ratio (OER) was calculated as the ratio between VO 2 and
GMP-independent effects. Experimentally, MB has DO 2. Intrapulmonary shunting (Qsp/Qt) was assessed with the
been shown to restore vascular responsiveness of rat standard formula.
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]. Statistical analysis
In addition, recent preliminary studies suggest that MB
Values are expressed as mean _+SEM. Hemodynamic parameters
increases arterial pressure and systemic vascular resis- and blood gases were compared with baseline values using the
tance in patients with septic shock [11,127. Wilcoxon matched-pairs signed-rank test. A p < 0.05 was considered
The aim of this work was to assess the acute effects significant.
of methylene blue on hemodynamics and gas exchange
in patients with severe septic shock.
Results

Methods The modifications of hemodynamic parameters follow-

ing MB are shown in Fig. 1. The administration of
The study was approved by Bichat-Claude Bernard Hospital's Eth- methylene blue was followed by a marked increase in
ics Committee, and relatives gave informed consent. 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
Patients rate (p =0.752). Although the overall cardiac index
appears unmodified (p =0.345), individual assessment
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 shows that it was significantly diminished in one pa-
simplified acute physiologic score [-131 was 16.2 _+1.4 at the time of 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) (p = 0.028) and p u l m o n a r y (p =0.027) vascular resis-
on systolic, diastolic and mean arterial blood pressure tance indexes was observed. P u l m o n a r y artery occlu-
(mean • b-h Individual hemodynamic parameters (open
circles) before (time 0) and 20 min after intravenous administration
sion pressure and right atrial pressure were unchanged
of methylene blue. Filled squares with error bars are mean_+SEM: overall (p = 0.068 and p = 0.285, respectively). N o sig-
b mean pulmonary artery pressure (mmHg); c cardiac index nificant modification of oxygen delivery, oxygen con-
(1 min -1 m-2); d systemic vascular resistance index (dyne s cm -s sumption, oxygen extraction ratio, shunt fraction or
m 2); e pulmonary vascular resistance index (dyne.s.cm S.m-2);
f pulmonary artery occlusion pressure (mmHg), g right atrial pres- arterial lactate was observed (Table 1). Significant
sure (mmHg); h heart rate (beats min-1) 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.
 1031

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