Journal of Critical Care
Volume 25, Issue 2 , Pages 358.e1-358.e7, June 2010

The effects of methylene blue infusion on gastric tonometry and intestinal fatty acid binding protein levels in septic shock patients☆☆☆★

  • Frank M.P. van Haren

      Affiliations

    • Intensive Care Department, Waikato Hospital, Hamilton 3240, New Zealand
    • Corresponding Author InformationCorresponding author. Intensive Care Department, Waikato Hospital, Hamilton, New Zealand. Tel.: +64 7 8398899; fax: +64 7 839 8912.
    • ,
  • Peter Pickkers

      Affiliations

    • Intensive Care Department, Radboud University Nijmegen Medical Centre, Nijmegen 6500 HB, The Netherlands
    • ,
  • Norbert Foudraine

      Affiliations

    • Intensive Care Department, VieCuri Medical Centre, Venlo 5912 BL, The Netherlands
    • ,
  • Suzanne Heemskerk

      Affiliations

    • Intensive Care Department, Radboud University Nijmegen Medical Centre, Nijmegen 6500 HB, The Netherlands
    • Department of Pharmacology and Toxicology, Radboud University Nijmegen Medical Centre, Nijmegen 6500 HB, The Netherlands
    • ,
  • James Sleigh

      Affiliations

    • Intensive Care Department, Waikato Hospital, Hamilton 3240, New Zealand
    • ,
  • Johannes G. van der Hoeven

      Affiliations

    • Intensive Care Department, Radboud University Nijmegen Medical Centre, Nijmegen 6500 HB, The Netherlands

published online 09 April 2010.

Article Outline

Abstract 

Objective

We prospectively studied the effect of methylene blue (MB) infusion on gastric mucosal metabolism perfusion ratio, assessed by gastric tonometry, and on mucosal cell damage, assessed by urinary levels of intestinal fatty acid binding protein, in septic shock patients.

Methods

Methylene blue (MB) infusion (1 mg/kg per hour) during 4 hours in 10 consecutive patients with a proven or suspected bacterial infection and with severe vasodilatory shock, defined as a mean arterial pressure 70 mm Hg or lower for at least 1 hour despite adequate volume resuscitation and norepinephrine infusion at a rate ≥0.2 μg/kg per minute.

Results

Methylene blue infusion did not significantly change the P(g-a)CO2 gradient (P = .16). Post hoc analysis of the subgroup of patients with an elevated baseline P(g-a)CO2 gradient, defined as ≥20 mm Hg, showed that the median P(g-a)CO2 gradient (interquartile range [IQR]) decreased from 45 (41-56) mm Hg before infusion to 41 (28-52) at the end of the 4-hour infusion and decreased further to 32 (26-36) mm Hg 2 hours after cessation of MB infusion (P = .012). The median urinary intestinal fatty acid binding protein concentration at baseline was elevated (210 [79-437] pg/μmol creatinine) and did not change significantly after 24 hours (116 [53-601] pg/μmol creatinine, P = .15). The median mean arterial blood pressure (IQR) increased from 70 (69-71) mm Hg at baseline to 77 (67-83) mm Hg after 1 hour (P = .04), the norepinephrine dose did not change significantly. The median (IQR) cardiac index decreased from 4.4 (3.2-5.5) L min-1 m-2 at baseline to 3.6 (3.3-4.7) L min-1 m-2 after 2 h, returning back to baseline values after cessation of MB infusion P = .02).

Conclusion

Although MB infusion in patients with septic shock and advanced multi-organ failure increases mean arterial blood pressure and decreases cardiac index, it does not compromise the gastric mucosal perfusion metabolism ratio as indicated by tonometry, and by the release of a mucosal cellular injury marker.

Keywords: Septic shock, Methylene blue, Nitric oxide, Tonometry, iFABP

 

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1. Introduction 

Septic shock, resulting in refractory hypotension and progression to multiple organ failure, is the major cause of prolonged stay and death in noncoronary intensive care units with an estimated mortality between 50% and 60% [1], [2]. Part of the pathogenesis of vasodilation and organ dysfunction in septic shock involves the excessive production of nitric oxide (NO) by inducible NO synthase that comes to expression during inflammation [3]. NO stimulates the soluble intracellular enzyme guanylate cyclase, which increases the generation of cyclic guanosine monophosphate. Ultimately, this pathway leads to vasodilation, myocardial depression, increased vascular permeability, loss of gut barrier function, and organ dysfunction.

Non-selective inhibition of NO synthase by NG-monomethyl-l-arginine resulted in an overall increase in mortality in a phase III trial in septic patients [4]. Methylene blue (MB) has been shown to inhibit inducible NO synthase, scavenge NO, and to inhibit soluble guanylate cyclase, therefore acting in a more selective fashion in comparison with NG-monomethyl-l-arginine, potentially preserving other physiologically beneficial NO pathways [5], [6]. In septic patients, small trials, including 2 prospective randomized controlled studies, have demonstrated an increase in blood pressure mediated by an increase in systemic vascular resistance [7], [8], [9]. Methylene blue has been shown to be safe in humans and has been used for treatment of cyanide poisoning, methemoglobinemia, and malaria for many years [10].

Gastrointestinal mucosal hypoperfusion is thought to be important in septic shock patients, both as an indicator of inadequate resuscitation and as a mechanism by which multiple organ failure may occur [11]. Loss of gut barrier function may lead to translocation of bacteria, endotoxin, and other inflammatory mediators, thereby augmenting and sustaining systemic inflammation, and possibly resulting in distant organ dysfunction. Abnormalities in the NO system can be regarded as one of the mechanisms responsible for the gastrointestinal mucosal perfusion defects observed [12].

Gastric automated air tonometry is an easy and reproducible technique to estimate adequacy of splanchnic perfusion, and an increased gastric to arterial pCO2 gradient (P(g-a)CO2 gap) is a marker of mortality in ventilated intensive care patients [13].

Intestinal fatty acid binding protein (iFABP) is an intracellular epithelial protein in the intestinal mucosa. It has been shown to be a useful biochemical marker of enterocyte injury and gut ischemia in experimental models and in humans [14], [15], [16], and iFABP levels have been shown to correlate with clinical development of the systemic inflammatory response syndrome and with outcome in critically ill patients [17], [18].

To our knowledge, the effect of MB infusion on gastrointestinal perfusion and mucosal cell damage in septic shock patients has not been studied previously. We examined gastric tonometry and iFABP levels before, during and directly after a 4-hour infusion period of MB in patients with septic shock.

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2. Patients and methods 

2.1. Patients 

The study was approved by the Central Committee on Research Involving Humans in the Netherlands. Informed consent was obtained from the patient's nearest relative/next of kin. Consecutive patients admitted to the intensive care unit (ICU) with a proven or suspected bacterial infection and 2 or more systemic inflammatory response syndrome criteria [19] were screened for inclusion in this study. Patients were recruited within 24 hours of admission to the ICU when they met the criteria for septic shock [19] and had mean arterial pressures (MAP) ≤70 mm Hg despite adequate fluid replacement and a norepinephrine infusion at a rate of ≥0.2 μg/kg per minute for at least an hour before recruitment. Patients were excluded if they were <18 years, pregnant or lactating, or had proven myocardial ischemia or infarction <6 months prior to the study. Throughout the study, all patients received standard conventional therapy for septic shock and received low-dose hydrocortisone (200 mg/24 h). None of the patients received activated protein C.

A transpulmonary thermodilution catheter (PiCCO, Pulsion Medizintechnik, Munich, Germany) was inserted as per our routine practice for septic shock patients. Fluid resuscitation was guided by cardiac output and stroke volume variation as measured by pulse contour analysis [patients were considered to be fluid responsive if stroke volume variation (SVV) >12%] and per discretion of the treating intensivist.

2.2. Interventions 

A gastric tonometry catheter (Tonometrics-catheter, TONO-16F, Datex-Ohmeda Division, Helsinki, Finland) was inserted in the stomach. Calibration was performed according to the manufacturer's guidelines. Enteral feeding was discontinued and all patients received omeprazole 40 mg intravenously 1 hours before the first measurements. Immediately after data collection at baseline, patients received a continuous central venous infusion of 1 mg/kg per hour MB (1% wt/vol) for 4 h, which was provided by the department of pharmacy of the VieCuri Medical Centre. Infusion of norepinephrine was only increased during the study period if MAP dropped below 60 mm Hg despite additional fluid resuscitation. Norepinephrine infusion rate was decreased when MAP reached values >80 mm Hg. Data of all patients were analyzed.

2.3. Measurements 

We recorded demographic data as well as the severity of illness using APACHE II, number of failing organs, and SOFA-scores. Data on hospital mortality were collected after completion of the study.

Hourly transpulmonary thermodilution calibration measurements were performed (PiCCO) and global hemodynamic parameters including blood pressure, heart rhythm and rate, CI, SVV, extravascular lung water index, and urine output were recorded. Carbon dioxide partial pressure was measured in the stomach (PgCO2 in mm Hg) by automated air tonometry using an equilibration time of 10 minutes. Arterial carbon dioxide partial pressure (PaCO2 in mm Hg) was measured simultaneously (blood gas analyzer, Bayer, Meijdrecht, The Netherlands) and P(g-a)CO2 gap was calculated. Blood lactate levels were determined by routine clinical chemistry. Hematocrit and blood concentrations of hemoglobin, methemoglobin, and bilirubin were measured to assess possible side effects of MB administration, such as hemolytic anemia and methemoglobinemia [20], [21]. Urinary excretion of iFABP was measured using a commercially available ELISA (Synbio, HK406) at t = 0, 6, and 24 hours and calculated as ratio to urine creatinine concentration to correct for renal failure and urine dilution [22]. Using this assay in 15 healthy controls, urinary iFABP concentration was 5.4 ± 1.6 pg/mL (unpublished results).

2.4. Statistical analysis 

Values are given as mean ± SD or as median (range, 25%-75%), depending on their distribution. Data analysis was performed using repeated-measures ANOVA using SPSS 14.0 for Windows (SPSS Inc, Chicago, Ill). The Wilks' λ F test of the multivariate analysis was used to investigate whether a difference over time was significant and dependent on the baseline value. We used the Tukey-Kramer multiple comparison test for post hoc comparisons at different times.

The primary end point of this study was the effect of MB infusion on P(g-a)CO2 gap in patients with refractory septic shock. A change of 10 mm Hg in P(g-a)CO2 gap was considered to be relevant. In a previous study using the same method, we found a standard deviation of 9 mm Hg [23]. With these data and a significance-level α of .05, a sample size of 6 to 11 subjects was calculated to reach a power of 80% to 95%. Therefore, 10 patients were included in the study, which results in a power of 88% (PSPower V2.1.31).

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3. Results 

3.1. Patient characteristics 

The demographic and clinical characteristics of the patients are shown in Table 1.

Table 1. Demographic and clinical characteristics
Patient no.DiagnosisSexAge, yAPACHE IISOFAOutcome
1CellulitisFemale68349Died
2Abdominal sepsisFemale762310Died
3Abdominal sepsisMale833013Survived
4UrosepsisMale832115Died
5PneumoniaMale751810Died
6PneumoniaMale72309Died
7Necrotizing fasciitisFemale683415Died
8Abdominal sepsisFemale56329Survived
9Abdominal sepsisFemale58178Died
10Abdominal sepsisFemale572913Survived
Mean ± SD 70 ± 1026.8 ± 6.511.1 ± 2.5

APACHE II, Acute Physiology and Chronic Health Evaluation II; SOFA, Sepsis-Related Organ Failure Assessment.

The effects of MB on the urinary excretion of NO-metabolites and markers of renal injury in 9 of the current 10 patients were previously published [24].

All patients had failure of at least 3 organs, which is reflected by a mean SOFA score of 11.3 ± 2.5. Seven patients died in the ICU, one of refractory vasodilatory shock (within 12 h) and 6 patients because of progressive multiple organ failure. In the latter group, 2 patients died within 7 days, and the remaining 4 patients, within 28 days after the intervention. The mortality was high but in keeping with the mean calculated predicted mortality rate (61%) and reflects the severity of illness in this selected group of patients. The median stay at the ICU was 17 days (8-28 days), and the 3 survivors stayed 64 days (56-122) in the hospital.

Pathogenic organisms isolated by culture included Escherichia coli (n = 2), Pseudomonas aeruginosa (n = 3), Klebsiella pneumoniae (n = 1), and Enterobacter aerogenes (n = 1). All patients received adequate and timely antibiotic treatment (data not shown). In 3 patients, no positive cultures were obtained. Etiologies for infection included respiratory tract infection (n = 2), abdominal sepsis following abdominal surgery (n = 5), skin and soft tissue infection (n = 2), and urosepsis (n = 1).

3.2. Global hemodynamic measurements 

All patients were adequately fluid resuscitated. In 4 patients, SVV could not be used to predict fluid responsiveness due to atrial fibrillation (n = 3) or spontaneous breathing mode (pressure support ventilation, n = 1) [25]. These 4 patients were volume-challenged until no further increase in thermodilution cardiac output was noticed before commencement of the MB infusion. In the other 6 patients, median SVV (IQR) before MB infusion was 10.0% (6.3-10.8), indicating that further fluid administration would not result in an increase in stroke volume [26]. The effects of MB infusion on hemodynamic variables are shown in Fig. 1. The median MAP (IQR) increased from 70 (69-71) mm Hg at baseline to 77 (67-83) mm Hg after 1 hour (P = .04). The other time points were not significantly different from baseline. The median norepinephrine infusion rate did not change from baseline during MB infusion. In 2 patients, the norepinephrine infusion rate could be decreased (by 67% and 25%, respectively) because MAP was >80 mm Hg (as per protocol). The norepinephrine infusion rate was not changed in the other 8 patients.

  • View full-size image.
  • Fig. 1. 

    Box plots of median arterial pressure (A), norepinephrine infusion rate (B), CI (C), and extravascular lung water index (D) before, during and after MB infusion. *P = .04; **P = .02.

The median CI showed a decrease from 4.4 (3.2-5.5) L min-1 m-2 at the start of MB infusion to 3.6 (3.3-4.7) L min-1 m-2 after 2 hours of infusion and 3.9 (2.5-4.8) L min-1 m-2 after 4 hours, returning to baseline values 4.7 (2-0.6) L min-1 m-2 after MB infusion was stopped (P = .02). Values for extravascular lung water index were ≤10 mL/kg and were not affected by MB infusion (P = .28) (see Fig. 1D). Lactate levels were elevated (4.0 ± 3.6 mmol/L) and remained unchanged throughout the study period (P = .75).

3.3. Gastrointestinal variables 

For the total group of patients, the P(g-a)CO2 gap did not change significantly during or after MB infusion (P = .16, Fig. 2). The median P(g-a)CO2 gap at baseline and after MB infusion in patients with a normal baseline P(g-a)CO2 gap (<20 mm Hg) and in patients with an elevated baseline P(g-a)CO2 gap (≥20 mm Hg) is also shown in Fig. 2 (post-hoc analysis). In 4 patients with an elevated baseline P(g-a)CO2 gradient, the median P(g-a)CO2 gradient decreased from 45 (41-56) mm Hg before infusion to 41 (28-52) at the end of the 4-hour infusion, and decreased further to 32 (26-36) mm Hg 2 hours after infusion (P = .012). No significant change was found in 6 patients with a normal baseline P(g-a)CO2 gradient prior to the MB infusion (P = .57). No significant correlation was found between the P(g-a)CO2 gradient and infused dose of norepinephrine (r = 0.18, P = .65).

  • View full-size image.
  • Fig. 2. 

    Box plots of median P(g-a)CO2 gap in septic shock in all patients (A) and in patients with normal and elevated baseline P(g-a)CO2 gap (B) before, during, and after 4 hours of MB infusion. *P = .012.

Compared to healthy volunteers, the median urinary iFABP concentration at baseline was significantly elevated in all patients (841 pg/ml [525-2860]), indicating important mucosal cellular damage. Corrected for urine creatinine concentrations the median iFABP levels tended to decrease from 210 (79-437) pg/μmol creatinine at baseline to 116 (53-601) pg/μmol creatinine after 24 hours (P = 0.15). No significant correlation was found between the P(g-a)CO2 gradient and the iFABP levels (r = 0.14, P = 0.65).

3.4. Side effects 

There were no signs of hyperbilirubinemia or methemoglobinemia. The mean methemoglobin level was 0.7% ± 0.2% at baseline, 0.7% ± 0.2% after 3 hours, and 0.9% ± 0.1% after 6 hours. The hematocrit and levels of hemoglobin did not change after MB administration (data not shown). In addition, no significant deterioration in measures of oxygenation was found (data not shown). All MB-treated patients showed blue coloring of both urine and skin. No other side effects were observed.

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4. Discussion 

In the present study, we examined the effects of MB infusion in septic shock patients with advanced multi-organ failure on different measures of gastrointestinal perfusion and damage. Our results indicate that MB administration in septic shock patients may preserve gastro-intestinal perfusion and integrity. Methylene blue infusion at used dosages has no significant deleterious effects on the gastric mucosal metabolism perfusion rate as assessed by gastric tonometry despite a decrease in cardiac index (CI) associated with MB-infusion. In the small subgroup of patients with an abnormal P(g-a)CO2 gap (>20 mm Hg) at baseline, MB infusion resulted in a significant decrease in P(g-a)CO2. Due to the small number of patients and the well-known limitations of post hoc subgroup analyses, one should interpret these results with caution.

The urinary excretion of iFABP was highly elevated in all patients during this study, indicating significant mucosal cellular damage. A decreasing trend was shown after MB infusion, suggesting absence of further harm or possibly a protective effect of MB on enterocyte injury. These results should be interpreted with caution. The fall in corrected iFABP levels was not statistically significant. Other factors may have influenced the corrected iFABP levels such as: ongoing renal failure, which potentially could overestimate creatinine excretion; changes caused by sepsis resuscitation unrelated to MB. In addition, the high baseline levels of iFABP in our study population may influence the ability to detect small changes induced by the treatment.

Methylene blue infusion decreased the CI in our patient population and transiently increased the MAP. This finding of increased MAP and systemic vascular resistance has been reported in all studies of MB in sepsis [8], [27].

The effects of different vasopressors on gastrointestinal perfusion and mucosal cellular injury in septic shock is not straightforward and depends on the type of vasopressor used and the clinical situation of the patient [11]. We have previously shown in a comparable group of septic shock patients, that vasopressin infusion in patients treated with high dose norepinephrine resulted in a decrease in gastrointestinal perfusion, reflected by a significant increase in gastric-arterial pCO2 gap [23]. Differences between various vasoconstrictive agents is further illustrated by the observation of LeDoux et al, who showed that incremental doses of norepinephrine markedly increased MAP from 65 to 85 mm Hg but did not cause a significant change in gastrointestinal perfusion [28]. The influence of several other vasoactive therapies on gastrointestinal perfusion in septic shock has been described in a recent review article [29]. Adrenergic agents that increase blood pressure have variable effects on gastrointestinal perfusion. Our results suggest that, compared to other vasoactive drugs used in septic patients, MB may relatively preserve splanchnic mucosal perfusion.

An important mechanism that is potentially responsible for the effects of MB infusion is selective inhibition of production of NO and cyclic guanosine monophosphate by MB. Induction of the NO system induced by inflammation can be regarded as one of the key mechanisms responsible for the mucosal microcirculatory defects observed [11], [12]. Animal studies have shown that NO acts as a final common pathway of mediators and neural pathways in the gastrointestinal tract and also is a major inhibitory component of gastrointestinal function [30]. We have recently shown that MB infusion is associated with a decrease in NO production and an attenuation of the urinary excretion of renal tubular injury markers, indicating protection of renal function [24]. Methylene blue also reduced NO overproduction in the lungs in an animal sepsis model, which resulted in the attenuation of lung injury [31]. These results suggest that excessive concentrations of NO and free radicals may play a role in the development of lung and other organ injury. In our study however, no significant change in extravascular lung water was found during and after infusion of MB. This is consistent with the results of another study, where MB administration in septic patients did not change pulmonary vascular permeability as assessed by extravascular lung water [32].

Methylene blue administration at used dosage was found to be safe in the present study. This is consistent with previous studies and experience [27]. One case series reported the development of self-limiting postoperative encephalopathy in patients who received preoperative MB infusion for localization of parathyroid adenomas. The common factor in all 5 cases was female sex and preoperative use of serotonin-metabolism modifying agents [33]. Methylene blue should not be used in patients with documented hypersensitivity to MB and used cautiously in patients with glucose-6-phosphate dehydrogenase deficiency because of the risk of developing Heinz body anemia. Intensive care practitioners should also be aware of the fact that MB interferes with pulse oxymetry, resulting in falsely depressed oxygen saturation readings [34].

There are several limitations to this “proof of concept study.” Tonometry has known limitations and only provides information of the site of measurement. However, automated air tonometry has been well validated as a reproducible measure of mucosal metabolism perfusion ratio [11]. Because of large interindividual differences, we conducted a before-during-after design, as a large randomized placebo-controlled set-up was not feasible. In addition, the sample size is relatively small. It was, however, adequately powered to detect clinically significant changes in P(g-a)CO2 gap over time as the patients served as their own controls. Furthermore, having used the same design in a previous study where we administered vasopressin to septic shock patients, we found that vasopressin resulted in an increase of P(g-a)CO2 gap in all studied patients, independent of the baseline P(g-a)CO2 gap [23], illustrating the high sensitivity to detect putative deleterious effects of a vasoactive compound on gastric mucosal perfusion metabolism ratio. The patients included in the current study were severely ill, suffered from advanced multiorgan failure and needed high doses of norepinephrine, which makes generalization of the results to other patients with less severe septic shock difficult. Finally, we only studied the short-term effects of MB infusion in septic shock patients. Whether the effects would be different during ongoing infusion of MB remains unknown. Future studies should investigate the effects of MB in early septic shock, before the occurrence of significant organ failure and address the question whether MB infusion may prevent or ameliorate progression to organ failure by preserving gut perfusion. From a pathophysiological point of view, early administration of MB in hyperdynamic septic shock would be expected to be more efficacious than late in the course of the disease process [35]. In addition, a large-scale randomized controlled study is necessary to test the effects of MB infusion on clinically relevant endpoints such as organ failure and mortality.

In conclusion, although MB infusion in patients with severe septic shock and advanced multi-organ failure increases MAP and decreases CI, this does not result in significant changes in gastric mucosal perfusion metabolism ratio and release of a mucosal cellular injury marker.

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Acknowledgments 

The authors would like to thank Gaelle Dutu, (biostatistician, Waikato Clinical School) for her valuable guidance in the statistical analysis of this study.

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☆ The authors disclose no conflict of interest.

☆☆ The study was performed at the Intensive Care Department, VieCuri Medical Centre, Venlo, The Netherlands.

★ Trial registration at Australian New Zealand Clinical Trials Registry (www.anzctr.org.au). Registration number ACTRN12608000090314

PII: S0883-9441(10)00063-8

doi:10.1016/j.jcrc.2010.02.008

Journal of Critical Care
Volume 25, Issue 2 , Pages 358.e1-358.e7, June 2010

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