Case report

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Methylene blue for the treatment of refractory septic
shock secondary to listeriosis in a paediatric patient
Jesús Angel Domínguez-­Rojas ‍ ‍,1,2 Patrick Caqui,3 Abel Sanchez,3
Alvaro J Coronado Munoz ‍ ‍4

1
Deparment of Pediatrics, SUMMARY literature those are commonly used in paediatric
National Hospital Edgardo Current therapies frequently used for refractory septic septic shock, as reported in observational studies
Rebagliati Martins, Lima, Peru shock include hydrocortisone, vasopressin, extracorporeal and case reports. Methylene blue is not included
2
Deparment of Critical Care, or mentioned in the septic shock guidelines. The
membrane oxygenation (ECMO) support, inodilators,
Instituto Nacional De Salud Del
levosimendan and methylene blue. The evidence for use of methylene blue has been reported in pilot
Niño Breña, Lima, Peru
3
Department of Pediatrics, these treatments is very limited. We present a case of a trials and observational studies for the treatment
Hospital Nacional Hipolito 5-­year-­old patient with refractory septic shock, secondary of distributive shock, vasoplegia and cardiogenic
Unanue, Lima, Peru to Listeria monocytogenes meningitis. She presented shock. The evidence for paediatric patients is
4
Deparment of Pediatrics, The with status epilepticus and developed septic shock. limited. However, it is a therapy easy to administer
University of Texas Health Shock persisted despite multiple high-­dose vasoactive and unexpensive. We present a case of refractory
Science Center at Houston, medications. ECMO support was not available. The septic shock in a paediatric patient that was treated
Houston, Texas, USA medical team decided to use methylene blue to revert with methylene blue.
the vasoplegia, with excellent results. Shortly after the
Correspondence to administration, vasopressors were weaned off and the
Dr Alvaro J Coronado Munoz; CASE PRESENTATION
​alvaro.​j.c​ oronadomunoz@​uth.​ high lactate cleared. She developed severe neurological We present the case of a 5-­year-­old patient, with
tmc.e​ du sequelae due to brain haemorrhage secondary to the history of 14 days with fever, nausea and non-­

Group A. Protected by copyright.

Listeria meningitis. The evidence supporting methylene bloody, non-­ bilious vomiting. She presented
Accepted 21 January 2022 blue for refractory septic shock in paediatric patients seizures at home, described as generalised tonic-­
is limited. This case represents the effectiveness of this clonic episodes, self-­limited. The patient does not
therapy without secondary effects. have any family medical history and there were not
known COVID-­ 19 contacts. She did not receive
the 12 months-­ old the Haemophilus influenzae
BACKGROUND b vaccine. No history of previous admissions or
Approximately a quarter of paediatric patients with surgeries.
sepsis can develop septic shock and the mortality At arrival to the hospital, her heart rate was 96
varies from 4% to 50%.1 2 This wide interval is bpm, respiratory rate 24 bpm, temperature is 38°C,
associated to the severity of illness, comorbidities saturation 97% at room air, her blood pressure was
and geographical location. Delays in diagnosis and 84/48 mm Hg (20th percentile for age and height).
instauration of treatment have been associated to She was somnolent, in postictal state. On neurolog-
mortality from septic shock. The mortality in sepsis ical exam, her pupils were symmetric and reactive
is associated to fluid-­refractory shock and/or multi- to light, she had nuchal rigidity, Kernig and Brudz-
organ disfunction.3 Septic shock can be difficult inski signs were positive. No petechia or rashes
to manage and the therapies to maintain adequate were identified. She had normal quality pulses and
haemodynamics are limited. The initial treatment capillary refill was less than 2 s. The rest of her
includes fluid resuscitation and early administration exam was unremarkable. Gram-­positive bacilli were
of antibiotics. Patients with fluid-­refractory shock identified in the cerebrospinal fluid and antibiotic
require vasoactive medications. The 2020 Surviving treatment was started. She was admitted with diag-
Sepsis Campaign International Guidelines for the nosis of bacterial meningitis. While being treated in
Management of Septic Shock and Sepsis-­Associated the emergency department, she became lethargic.
Organ Dysfunction in Children include weak Because of the acute change of mental status, she
recommendations for vasopressin for patients with was hospitalised in the paediatric critical care unit
fluid-­refractory and catecholamine-­resistant shock. for close neurological observation.
The authors suggest that hydrocortisone or no
hydrocortisone can be used in patients with fluid-­ INVESTIGATIONS
refractory and cathecolamine-­resistant shock. They The initial investigations included a negative
© BMJ Publishing Group
Limited 2022. No commercial also suggest using veno-­ arterial-­
extracorporeal RT-­PCR, IgG and IgM SARS-­ CoV2 tests, severe
re-­use. See rights and membrane oxygenation (ECMO) in patients with leucocytosis, elevated CRP, metabolic acidosis and
permissions. Published by BMJ. refractory to all treatments shock.4 Advanced life respiratory alkalosis compensation. Her lactate
support with ECMO is not available in all centres was 2.5 mmol/L. She had normal liver enzymes
To cite: Domínguez-­Rojas JA,
Caqui P, Sanchez A, et al. BMJ or countries across the world. The authors did and normal renal function. The clotting times were
Case Rep 2022;15:e243772. not issue a recommendation for other therapies, mildly prolonged. Her cerebrospinal fluid study had
doi:10.1136/bcr-2021- including levosimendan and inodilators, due to the gram-­positive bacilli are presented in table 1. Rapid
243772 lack of paediatric trials. However, reviewing the sputum tuberculosis detection test was negative. An
Domínguez-­Rojas JA, et al. BMJ Case Rep 2022;15:e243772. doi:10.1136/bcr-2021-243772 1
Case report

BMJ Case Rep: first published as 10.1136/bcr-2021-243772 on 28 February 2022. Downloaded from http://casereports.bmj.com/ on March 1, 2022 at World Health Organisation (HINARI) -
Table 1 Cerebrospinal fluid (CSF) studies
Admission Day 6
Aspect Turbid Transparent
Leucocytes/mm3 800 6
Mononucleates 0% 0%
Polymorphonuclears 100% 0%
Gram Bacilli gram positive 2+ ---
Glucose, mg/dL 10 114
Proteins, g/dL 277.5 77.3
Adenosine deaminase, U/L 12 2
HSV; enterovirus Negative ---
AFB Negative Negative
Culture Listeria monocytogenes Negative
AFB, Acid-­Fast Bacillus; HSV, Herpes simplex virus.

initial brain tomography showed brain oedema, no shifting of

midline.

TREATMENT
The initial antibiotics included ceftriaxone 100 mg/kg/day,
vancomycin 15 mg/kg/dose every 6 hours for meningitis. Dexa-
methasone 0.6 mg/kg/day was started as part of the meningitis
protocol in Peru. It is part of the protocol because of the high Figure 1 Distal extremities ischaemia seen on day 3 of admission.
incidence of tuberculosis. Phenytoin was started to treat and to

Group A. Protected by copyright.

prevent seizures. days the lactic acid continued to decrease, from 10.2 mmol/L
before administration, to 2 mmol/L at 24 hours after methy-
OUTCOME AND FOLLOW-UP lene blue administration. There was improvement of the urine
On admission to the paediatric critical care unit, she was intu- output. Forty-­eight hours after the administration of the methy-
bated for concerns of airway protection and mechanical ventila- lene blue all pressors were weaned-­off. The doses of vasoactive
tion was started. She became hypotensive and fluid resuscitation drugs, blood pressures and lactate levels are demonstrated in
was initiated. On exam, she presented warm extremities, capil- figure 2.
lary refill less than 1 s and bounding pulses. After the third 20 Once haemodynamic stability was achieved, a CT angiography
mL/kg bolus was given, norepinephrine was started at 0.5 μg/kg/ (CTA) was obtained. The CTA showed subarachnoid haemor-
min. She continued hypotensive and epinephrine and dopamine rhages, the largest of 7 mm of diameter in the left parietal area,
were added. Knowing the results of the gram-­positive bacilli on diffused vasogenic cerebral oedema, predominantly in the left
CSF, ampicillin 200 mg/kg/day and amikacin 15 mg/kg/day were hemisphere, and multiple areas of ischaemia (figure 3). After
added to the antibiotic coverage. On day 3 of admission, the assessing her neurological state, she was extubated 2 weeks after
cerebrospinal fluid (CSF) culture came back positive to Listeria admission. Her neurological state was severely compromised
monocytogenes. Culture sensitivities were not available the deci- with hypertonic extremities and left hemiparesis. She was verbal
sion was tocontinue therapy with ampicillin and amikacin. On and she was able to protect her airway. She was discharge to the
day 3 of admission, the patient remained hypotensive despite floor and then to a paediatric rehabilitation inpatient unit.
three vasopressors. Vasopressin and levosimendan were started.
The laboratory results presented values consistent with dissemi- DISCUSSION
nated intravascular coagulation and enoxaparin 1 mg/kg/day was Listeria infections are more frequent in newborns and immuno-
started for thrombosis prophylaxis. suppressed paediatric patients. However, several cases have been
The patient persisted hypotensive despite vasoactive therapy, reported in immunocompetent paediatric patients.5–11 According
including five drugs at moderate to high doses, and rising lactic to the Danish study examining the Listeria meningitis between
acid. She had a peak of lactate of 10.2 mmol/L on day 5 of 2000 and 2017, by Vissing et al, the annual incidence of this infec-
admission. That day, she started presenting microangiopathic tion in immunocompetent children is 0.014 per 100 000 chil-
changes (figure 1). An echocardiogram was performed on day dren.11 The clinical course of these patients has been associated
5 of admission, showing preserved left ventricle function, a with high mortality. The case we present had refractory septic
cardiac index 4.9 L/min/m2 and a cardiac output of 3.9 L/min. shock to all treatments. Refractory septic shock is associated with
The mixed venous saturation was 73%. We added hydrocorti- high mortality.3 There are no specific definitions for fluid resistant
sone 100 mg/m2/day and calcium gluconate. An ECMO consul- shock, catecholamine-­resistant shock, or refractory septic shock to
tation was done to an outside hospital but no paediatric pumps all treatment in the literature. The most important study of ECMO
were available. As a last resource, methylene blue 0.5% at 1 mg/ as therapy for refractory septic shock in paediatrics, included
kg, diluted in dextrose, was administer as a slow bolus. Within persistent acidosis (pH ≤7.15), arterial lactate ≥4, base excess less
5 hours of the administration, vasoplegia improved. This was than—10 and in-­hospital cardiac arrest.12 The suggested definition
measured by normalisation of the blood pressures. Vasopressors from the European Society of Paediatric and Neonatal Intensive
were weaned, except norepinephrine and epinephrine. There Care for refractory septic shock includes: blood lactate >8 mmol/L
was also an improvement of the lactic acidosis. In the following or increase of 1 mmol/L after 6 hours of resuscitation and high
2 Domínguez-­Rojas JA, et al. BMJ Case Rep 2022;15:e243772. doi:10.1136/bcr-2021-243772
 Case report

BMJ Case Rep: first published as 10.1136/bcr-2021-243772 on 28 February 2022. Downloaded from http://casereports.bmj.com/ on March 1, 2022 at World Health Organisation (HINARI) -
Figure 2 Treatment graphic of blood pressure, vasoactive drugs and lactic acid before and after methylene blue treatment. VIS, vasoactive-­inotropic
score.

dependency of vasoactive medication, defined with a vasoactive-­ and improving stroke volume index without side effects.17 The
inotropic score (VIS) >200, or myocardial dysfunction defined as cultures of these patients included gram-­negative and gram-­positive

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the occurrence of a resuscitation-­responsive cardiac arrest in PICU bacteria. The effect of methylene blue reversing vasoplegia in refrac-
or echocardiographic left ventricle ejection fraction less than 25% tory shock would not be limited to a gram-­negative septic shock
or cardiac index less than 2.2 L/min/m2.3 Our patient met the but in different aetiology refractory septic shock. In paediatrics the
lactate criteria and the VIS criteria as demonstrated in figure 2.13 evidence is limited. In 2020, a systematic review examining the use
The echocardiogram showed preserved function. The next support of methylene blue for refractory shock in children was published.
level required and proposed for this patient was ECMO, but it was The authors reported 17 case reports, 4 case series, 2 retrospective
not available. The treatment of methylene blue was a last effort to cohort studies and 1 single trial.18 The trial was done in patient post-
reverse the vasoplegia and shock. The response to this therapy was cardiopulmonary bypass. The systematic review included patients
excellent and it probably changed the outcome of this case. requiring methylene blue for different aetiologies of refractory shock,
Methylene blue is an inhibitor of guanylate cyclase, blocking the including postbypass cardiac surgery, anaphylactic shock and septic
release of cyclic guanosine monophosphate, preventing vascular shock. The quality of the information collected was qualified as poor
smooth muscle relaxation, improving muscular tone.14 Nitric oxide by the authors according to their review methods. However, all the
(NO) can be decreased, but it is a secondary effect and not a direct studies included, reported improvement in patients’ mean arterial
inhibition of the NO synthase. The use of methylene blue has been pressure and the possibility of weaning vasopressors and inotropic
studied in septic shock, anaphylactic shock and postcardiovascular support with the administration of methylene blue. Interestingly, in
surgery vasoplegia.15 16 The use of methylene blue in refractory septic that study they included the results of a survey of paediatric critical
shock has been described in the literature, counting with observa-
care providers and their experience using methylene blue for shock.
tional studies, case series and case reports. A pilot randomised trial
From 157 physician that reported having used methylene blue for
in adult patients was published in 2001. They enrolled 20 patients,
refractory shock, 34% reported seeing an improvement.
10 receiving methylene blue and 10 controls. Patients in the treat-
Secondary effects of methylene blue include haemolysis, wors-
ment group had a reduction of 87% on requirement of vasopressors
ening of pulmonary function, and serotonin syndrome. A potential
effect of methylene blue is worsening pulmonary hypertension. These
potential secondary effects are commonly described in patients that
have received large doses. Other minor side effects include short-
ness of breath, nausea and vomiting. Another noticeable change
is the discolouration of skin and urine. Haemolysis secondary to
methylene blue is mostly seen in patients with glucose-­6-­phosphate
dehydrogenase (G6PD). The side effects have been reported more
frequently in patients with higher doses.19 20 Our patient did not
present any effect besides blue discolouration of body fluids. The
authors of a case series, including seven patients receiving methylene
blue for distributive shock in paediatric patients, did not report any
side effects. All the patients were screened for G6PD, and no side
effects were reported. The administration of methylene blue used
Figure 3 Brain CTA (axial and coronal views), showing multiple was a low-­dose bolus and low-­dose infusion. This regimen also has
subarachnoid haemorrhages, areas of ischaemia and vasogenic oedema. been described by other authors to decrease the effect on pulmonary
CTA, CT angiography. hypertension.21 The effect of methylene blue on the inhibition of
Domínguez-­Rojas JA, et al. BMJ Case Rep 2022;15:e243772. doi:10.1136/bcr-2021-243772 3
 Case report

BMJ Case Rep: first published as 10.1136/bcr-2021-243772 on 28 February 2022. Downloaded from http://casereports.bmj.com/ on March 1, 2022 at World Health Organisation (HINARI) -
NO is also an important point of discussion. NO protects against REFERENCES
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Jesús Angel Domínguez-­Rojas http://orcid.org/0000-0001-6141-6622 methylene blue to inhibit nitric oxide actions in the hemodynamics of human septic
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4 Domínguez-­Rojas JA, et al. BMJ Case Rep 2022;15:e243772. doi:10.1136/bcr-2021-243772