Methylene blue? Therapeutic Alternative in the Management of Septic Shock Refractory to Norepinephrine

1. Introduction

Septic shock is characterized by systemic inflammation that evolves to a vasoplegic syndrome and it is associated with hypotension, low systemic vascular resistance (SVR) and increased requirements of fluids and vasopressors [1, 2]. Thereby the organism is unable to achieve adequate perfusion of the target organs due to the lack of vascular tone and vasodilation. This vasodilation is produced by an autonomic dysregulation in the release of inflammatory mediators, such as L-arginine which ends up producing an increase in nitric oxide (NO) synthesis and cyclic guanosine monophosphate (cGMP) for final activation of soluble guanylate cyclase (sGC) in vascular smooth muscle [3, 4, 5].

Despite advances in vasopressor therapy, prolonged hypotension and poor tissue perfusion can lead to multiple organ failure (MOF) and achieving 20 - 50% of mortality in the cases of sepsis [1, 6].

Methylene blue has been used in perioperative and intensive care of patients with distributive shock, septic and anaphylactic, as well as cardiac surgery and liver transplantation [7, 8, 9, 10]. This is due to its ability to antagonize the deep vasodilation by inhibiting certain cytokines of endothelial damage such as nitric oxide synthase (iNOS) and sGC, thereby producing blockage in both the synthesis and mode of action of NO.

The aim is to describe a case of a secondary vasoplegic syndrome due to norepinephrine refractory septic shock and the response to methylene blue, reviewing the latest evidence of this therapeutic alternative.

2. In practice

We present the clinical case of a 60-year-old man (weight 98 Kg), paraplegic due to a spinal cord injury 20 years ago, with unknown drug allergies and with a history of hypertension treatment with nebivolol, candesartan, mirtazapine and alfuzosin. The patient went to the emergency department for a long evolution decubitus pressure ulcer with a necrotic slough of about 40 cm in sacrum and trochanter (Fig. 1). After performing blood test, a leukocytosis 21,900 /$\mu$L, renal failure with creatinine 2.26 and K${}^{\mathrm{+}}$ 6.3 mmol/L and procalcitonin $>$ 40 ng/ml were evidenced, all compatible with septic features.

Fig. 1.Decubitus Pressure Ulcer.

Thus treatment of intravenous antibiotic therapy with imipenem and vancomycin was started, and after an assessment done by the plastic surgery service an urgent surgical treatment was finally decided.

At the entrance to the operating room the blood pressure was 60/30 mmHg so treatment was initiated with crystalloid and colloid to expand intravascular volume and 200 $\mu$g phenylephrine and norepinephrine infusion of 0.5 $\mu$g/kg /min. Anesthesia was induced with midazolam 2 mg, fentanyl 250 $\mu$g, propofol 150 mg and rocuronium 80 mg and it remained with sevoflurane 1 - 2%, continuous infusion of rocuronium 25 mg/h, fentanyl 50 $\mu$g/h bolus and continuous infusion remifentanil 0.03 - 0.15 $\mu$g/kg /min. Central venous access at the right jugular was channeled, and invasive arterial blood pressure and continuos cardiac output monitoring through access of the left radial artery was performed. Mechanical ventilation was started with inspired fraction of 50%, a volume 550 ml with a rate of 15 to 17 breaths per minute and positive end-expiratory pressure (PEEP) of 7 cm H${}_2$O maintaining arterial saturations above of 95%.

At the beginning of the surgery the following hemodynamic parameters and arterial blood gases were observed: pH 7.12, pCO${}_2$ 53 mmHg, K${}^{\mathrm{+}}$ 6.2 mmol / L, lactate 3.8 mmol/L and Hb 9.3 g/dL; blood pressure was maintained at 70/40 mmHg, heart rate at 110 beats/min, EtCO${}_2$ at 50 mmHg, SpO${}_2$ at 95% and central venous pressure (CVP) at 16 mmHg.

After two hours of evolution the patient remained with hemodynamic deterioration with blood pressure of 70/30 mmHg despite of administration of 3 IU/hour of vasopressin infusion and giving a maximum dose of norepinephrine at 2 $\mu$g/kg /min, so it was decided to use methylene blue (Fig. 2). Methylene blue was administered with an interval of 20 minutes, two intravenous bolus doses of 50 mg up to a total of 1 mg/kg without adverse effects of interest, except for a brief interference in the accuracy of the pulse oximetry and greenish staining urine (Fig. 3).

Fig. 2.Use of Vasoactive Drugs and Hemodynamic Parameters During Anesthesia in the Operating Room.
Phenylephrine, $\alpha$1 adrenergic agonist; NE, norepinephrine $\alpha$1 $\alpha$2 and $\beta$1 adrenergic agonist; vasopressin, V1 vasopressor and V2 antidiuretic effect; MB, methylene blue inhibits nitric oxide synthase (iNOS) and soluble guanylate cyclase (sGC).

Fig. 3.Central Methylene Blue Bolus.

After half an hour of the methylene blue administration, hemodynamic improvement was evidenced and it was maintained over time for 3 hours allowing to decrease norepinephrine infusion to 1 $\mu$g/kg /min and normalizing blood pressure at 100/70 mmHg.

During seven hours of surgery crystalloid 4500 ml and colloid 1500 ml were administered, with an approximate blood loss of 1700 ml. Total diuresis was maintained at 2450 ml under furosemide administration of 10 mg/hour. Furthermore it was necessary 7 red blood cell concentrates and 2 platelets pool maintaining at the end of the surgery a hematocrit of 17 % and haemoglobin of 5.3 g/dL.

Severe metabolic acidosis (pH 7.12) and hyperkalemia (K${}^{\mathrm{+}}$ 6.2 mmol/L) were managed with bicarbonate total dose of 500 ml (1 molar) and a 4 g of calcium gluconate. Control coagulopathy was achieved (international normalized ratio 1.5, prothrombin activity 42%, fibrinogen derivative 10 g/L) using 20 mg of vitamin K, tranexamic acid 1.5 g and a unit of fresh frozen plasma (FFP).

During the surgery, the debridement of the necrotic tissue that spread from the skin to internal compartments of the gluteus, thigh and left leg with involvement of the coxofemoral joint, rectal wall, and external anal sphincter was performed (Fig. 4).

Fig. 4.Amputation and Disarticulation of Left Coxofemoral Joint and Musculocutaneous Reconstruction.

Finally, with the collaboration of Traumatology Service an amputation and disarticulation of left coxofemoral joint and musculocutaneous reconstruction using the anterior compartment of thigh was carried out.

After completing the surgery the patient was transferred to the ICU and in the first post-surgery hours the patient maintained a severe septic shock with MOF and severe metabolic acidosis so that a continuous venovenous hemodiafiltration was started. Twenty-eight days later the patient was discharged from the ICU to the spinal cord injury ward managed by the Plastic Surgery Service.

3. Discussion

One of the causes of the resistance to the use of norepinephrine and vasopressin in our patient may be the chronic treatment with alfuzosin and nebivolol. Alfuzosin is a drug used for benign prostatic hyperplasia that blocks the effect of $\alpha$1 adrenergic receptors, lowering blood pressure by post-synaptic blockade, inhibiting the vasoconstrictive effect of norepinephrine [12]. On the other hand, nebivolol is a selective third-generation beta-blocker against beta-1 receptors with vasodilation effects mediated by the release of NO [13].

Although methylene blue is not new, since Schneider et al. [14] first described it in sepsis shock patients, the data of its usage are limited [15]. Most of the observational studies and only two existing clinical trials in the literature to date (Kirov et al., including 20 patients [16] and Memis et al., including 30 patients [17]) evidence a significant increase in mean arterial pressure (MAP), pulmonary artery pressure, and SVR after use.

Other observational studies as Andresen et al [18] further showed a decrease in serum lactate at 24 hours due to selective increase of mesenteric flow. Juffermans et al. [19] concluded that methylene blue causes a transient effect and dose-dependent increasing cardiac output, MAP and SVR, although like Zhang et al. [20] demonstrated that high doses of methylene blue (5 to 20 mg/kg) worsened myocardial depression, and from 7 mg/kg may even compromise splanchnic perfusion [19].

If methylene blue is compared during sepsis with other NO inhibitors, vasopressin decreases cardiac output while methylene blue does not change or even increases cardiac output [1, 11, 21].

Although the delayed onset of the hemodynamic response of methylene blue is transient and does not modify the natural history of septic shock, it allows a dose reduction of vasopressors, inotropic support, fluid therapy and blood transfusions thereby reducing renal, respiratory complications and accelerating postoperative recovery, having described a reduction in mortality of up to 21.4% in patients with vasoplegic syndrome [1, 22, 23, 24].

The dosing schedule is a single intravenous dose of methylene blue 1 to 2 mg/kg, and a second dose can be repeated after 20 minutes and a continuous infusion at 2 mg/kg within 6 hours in patients who persists the hypotension after at least an infusion of 0.5 µg/kg /min of norepinephrine [1, 3, 23].

4. Conclusions

It is relevant to mention that it should be early administered and not be administered only as a rescue measure since its effect and usefulness diminish significantly once MOF is has been established [1, 22].

Although more randomized studies are needed to identify its exact role in septic shock, as it has been demonstrated in our patient, methylene blue is already considered as a rescue, adjuvant and second-line therapeutic alternative to manage patients with persistent hypotension despite the use of various vasopressors during the perioperative management of the vasoplegic syndrome secondary to septic shock while etiological treatment is performed.

Acknowledgements

Other contributing authors from the Research Group in Anesthesia, Resuscitation, and Perioperative Medicine of Institute for Health Research Aragón (IIS Aragón) for this study are: Jesús Gil-Bona, Fernando Martínez-Ubieto, Luis Alfonso Muñoz-Rodríguez, Guillermo Pérez-Navarro, Berta Pérez-Otal, Natividad Quesada-Gimeno, Lucía Tardós-Ascaso, Sara Visiedo-Sanchez.

Conflicts of interest

There is no conflict of interest on the part of any author.

Autor Contribution

Each author has participated sufficiently in the work to take public responsibility for appropriate portions of the content.

Informed Consent Statement

Informed written consent was obtained from the patient for publication of this report and any accompanying images.

Ethical Approval

The study was approved by the Clinical Research Ethics Committee of the Miguel Servet University Hospital in Zaragoza.

Supportive foundations

Supported by ERDF (FEDER) Operational Programme of Institute for Health Research Aragón (IIS Aragón) No. B26_17D.