Open Access

Efficacy of single-dose intravenous immunoglobulin administration for severe sepsis and septic shock

  • Nobuyuki Hamano1Email author,
  • Kenichiro Nishi1,
  • Aki Onose2,
  • Akihisa Okamoto1,
  • Takeshi Umegaki3,
  • Etsuko Yamazaki3,
  • Kiichi Hirota3,
  • Hiroe Ookura4,
  • Hakuo Takahashi5 and
  • Koh Shingu3
Journal of Intensive Care20131:4

DOI: 10.1186/2052-0492-1-4

Received: 3 July 2013

Accepted: 13 September 2013

Published: 23 October 2013

Abstract

Background

Although some studies conducted outside of Japan have addressed the effectiveness of intravenous immunoglobulins (IVIG) in treating infections, the dosing regimens and amounts used in Japan are very different from those reported. Here, we investigate the effectiveness of single-dose administration of IVIG in sepsis patients in Japan.

Methods

We analyzed 79 patients admitted to the intensive care unit (ICU) of a tertiary care institution due to severe sepsis or septic shock. Patients were randomly divided into a group that was administered standard divided doses of IVIG (5 g/day for 3 days, designated the S group) or a group that was administered a standard single dose of IVIG (15 g/day for 1 day, H group); freeze-dried sulfonated human IVIG was used. The longitudinal assessment of procalcitonin (PCT) levels, C-reactive protein (CRP) levels, white blood cell count, blood lactate levels, IL-6 levels, Sequential Organ Failure Assessment (SOFA) score, and Systemic Inflammatory Response Syndrome (SIRS) was conducted. We also assessed mechanical ventilation duration (days), ICU stay (days), 28-day survival rate, and 90-day survival rate.

Results

The study showed no significant differences in PCT levels, CRP levels, 28-day survival rate, and 90-day survival rate between the two groups. However, patients in the H group showed improvements in the various SIRS diagnostic criteria, IL-6 levels, and blood lactate levels in the early stages after IVIG administration. In light of the non-recommendation of IVIG therapy in the Surviving Sepsis Campaign Guidelines 2012, our findings of significant early post-administration improvements are noteworthy. IVIG's anti-inflammatory effects may account for the early reduction in IL-6 levels after treatment, and the accompanying improvements in microcirculation may improve blood lactate levels and reduce SOFA scores. However, the low dosages of IVIG in Japan may limit the anti-cytokine effects of this treatment. Further studies are needed to determine appropriate treatment regimens of single-dose IVIG.

Conclusions

In this study, we investigated the effectiveness of single-dose IVIG treatment in patients with severe sepsis or septic shock. Although there were no significant effects on patient prognoses, patients who were administered single-dose IVIG showed significantly improved IL-6 levels, blood lactate levels, and disease severity scores.

Keywords

Severe sepsis Intravenous immunoglobulins Single-dose administration

Background

Sepsis refers to a set of syndromes that occur as a result of a systemic inflammatory response to an infection. Without appropriate treatment, there is a high incidence of supervening disseminated intravascular coagulation (DIC) or multiple organ failure (MOF) [1], leading to extremely poor outcomes for patients.

In 2004, the Surviving Sepsis Campaign Guidelines (SSCG), a set of comprehensive management guidelines for the treatment of sepsis, were published [2]; the most recent revision—SSCG 2012—was published in 2013 [3]. These guidelines contain details on initial resuscitation, antimicrobial therapy, and infection source control. Although the use of intravenous immunoglobulins (IVIG) has been approved for the treatment of immune diseases such as idiopathic thrombocytopenic purpura and Kawasaki disease, its use in severe infections or sepsis has yet to be approved by the US Food and Drug Administration (FDA) and has also been discouraged in SSCG 2012 as a treatment for adult sepsis patients. However, IVIG has been shown to be effective in treating severe infections [4, 5], and several reviews have demonstrated the efficacy of IVIG as a supplemental drug for treating sepsis [69]. In the early stage of sepsis, low concentration of immunoglobulins is predicted because IgG production in patients with primary infection needs 1–2 weeks, and lots of IgG are burned up for inhibiting bacteria and toxin in secondary infection. Therefore, it is expected that IVIG administration for treatment of sepsis is effective [10]. Furthermore, there are reports [11, 12] that a single dose of IVIG for Kawasaki disease and idiopathic thrombocytopenic purpura is more effective than divided doses. In Japan, IVIG administration is approved for severe infection, but the standard dosages and administration (5 g/day for 3 days) are far below the amount on several reports set forth above. Therefore, we tested the hypothesis that a single-dose IVIG treatment in patients with severe sepsis and septic shock in Japan is more effective than divided doses.

Methods

This study was approved by an internal ethics committee at its inception. In addition, the purpose of the study was explained to candidate research subjects or their legal representatives either verbally or in writing, and written informed consent was obtained for each participant before their inclusion in the study.

Study sample

The study sample comprised patients who were admitted to the intensive care unit (ICU) of a tertiary care urban hospital between July 2009 and August 2012, and fulfilled the diagnostic criteria for severe sepsis or septic shock [13]. All study participants were immediately started on early goal-directed therapy [14] after diagnosis of severe sepsis or septic shock, using therapeutic strategies compliant with SSCG 2008 [15]. Patients were excluded from analysis if they fulfilled the following criteria: patients aged 17 years or younger, patients with existing allergies to IVIG or antibiotics, patients with severe liver dysfunction or kidney disease (except for organ dysfunctions that can be caused by sepsis), patients with malignant neoplasms, patients in an immunodeficient state, patients who had acute myocardial infarctions or heart failures within 6 weeks prior to the index admission, patients (or their legal representatives) who did not consent to participating in the study, and patients deemed inappropriate for the study by the principal investigating clinician.

Research subjects were randomly allocated into two groups: a standard divided IVIG dose (5 g/day for 3 days) group designated as the S group and a standard single dose (15 g/day for 1 day) group designated as the H group. These regimens were based on dosages and administration approved for severe infection in Japan.

In both groups, treatment using freeze-dried sulfonated human IVIG was initialized within 24 h of diagnosing sepsis. Patient characteristics were evaluated using age; gender; height; weight; Acute Physiology and Chronic Health Evaluation (APACHE) II score; APACHE II score excluding Glasgow Coma Scale (GCS), APACHE(−GCS); Sequential Organ Failure Assessment (SOFA) score; SOFA score excluding GCS, SOFA(−GCS); disease severity classification; and underlying disease that led to sepsis.

The various values of the following diagnostic criteria were longitudinally assessed throughout each patient's hospitalization episode: procalcitonin (PCT) levels, C-reactive protein (CRP) levels, white blood cell (WBC) count, blood lactate levels, SOFA score, SOFA(−GCS) score, and Systemic Inflammatory Response Syndrome (SIRS).

In addition, we also analyzed the following outcome measures to evaluate patient prognosis: mechanical ventilation duration (in days), ICU stay duration (in days), 28-day survival rate, and 90-day survival rate. With the day of initial IVIG administration designated as day 1, the longitudinal assessments of patient baseline and clinical characteristics were conducted on days 1, 2, 3, 4, and 8 (Figure 1). Various parameters for day 1 were assessed on ICU admission, and assessments for days 2 and 3 of the S group were conducted prior to IVIG administration for that day. Also, plasma IL-6 was extracted and cryopreserved at the various time points, and IL-6 plasma concentration was measured using chemiluminescent enzyme immunoassay (Human IL-6 CLEIA, Fujirebio Corp., Tokyo, Japan).
Figure 1

Schedule of IVIG administration and clinical data collection time points. White arrows indicate IVIG administration, whereas black arrows indicate data collection. IVIG, intravenous immunoglobulin.

Many of the research subjects in this study had undergone mechanical ventilation or had been administered sedatives, but assessments of the central nervous system in such patients have been reported to be heavily dependent on the individual assessor [16]. Therefore, we have included APACHE II scores and SOFA scores that omit GCS assessment, which measures the level of patient consciousness. In addition, APACHE II scores should be evaluated by using the worst value in the first 24 h, under normal circumstances. However, we evaluated APACHE II scores by the worst value from ICU admission to initial IVIG administration, as IVIG should be administered as soon as possible for treating sepsis.

Statistical analysis

For assessments of patient characteristics between the two groups, we used the unpaired t test, Mann-Whitney U test, chi-square test for independence, and Fisher's exact test as appropriate for the data type for each variable. Transitions in clinical data were assessed using unpaired t tests. Changes in the various time points within each of the two groups were also analyzed using one-way analysis of variance (ANOVA), followed by a multiple comparison using Scheffe's method. Continuous variables were presented as mean values ± standard error of the mean (SEM), whereas ordinal variables were presented as median values (interquartile range (IQR)).

Patient prognoses were measured using Kaplan-Meier survival curves and the log-rank test. Statistical significance was set at P < 0.05. All statistical analyses were conducted using JMP, version 10.0 (SAS Institute Inc., Cary, NC, USA).

Results

Patient characteristics

Patient characteristics are presented in Table 1. The 79 research subjects in the study had a mean age of 67.2 ± 1.5 years, and the 28-day and 90-day survival rates were 86.1% and 78.5%, respectively. The APACHE II score was 27 (IQR 8–42), and the SOFA score was 10 (IQR 3–17). The most frequent source of infection for both groups was generalized peritonitis. The H group had a slightly higher proportion of men, whereas the S group had more patients presenting with urinary tract infections. However, there were no differences between the two groups with respect to the proportion of patients with severe sepsis or septic shock, and no statistically significant differences in patient characteristics were observed.
Table 1

Patient characteristics ( n = 79)

 

S group (n= 42)a

H group (n= 37)a

P value

Age (years)

66.7 ± 2.0

67.7 ± 2.2

0.744

Gender (male/female)

21/21

25/12

0.057

Body height (cm)

159.9 ± 1.4

161.4 ± 1.6

0.465

Body weight (kg)

54.6 ± 2.0

53.5 ± 2.0

0.699

APACHE II score

25.5 (13–39)

27 (8–43)

0.115

APACHE II(−GCS)

17 (8–29)

17 (8–32)

0.936

SOFA score

11 (3–15)

10 (4–17)

0.462

SOFA(−GCS)

8 (2–14)

6 (1–13)

0.117

Clinical stratification (sever sepsis/septic shock)

4/38

5/32

0.418

Source of infection

   

 Generalized peritonitis

15 (35.7%)

13 (35.1%)

 

 Pneumonia

4 (9.5%)

6 (16.2%)

 

 Urinary tract

6 (14.3%)

2 (5.4%)

 

 Bacteremia

4 (9.5%)

3 (8.1%)

 

 Cellulitis

2 (4.8%)

2 (5.4%)

 

 Biliary tract

2 (4.8%)

1 (2.7%)

 

 Others

5 (11.9%)

6 (16.2%)

 

 Unknown

4 (9.5%)

4 (10.8%)

 

aPatients in the S group were administered a standard IVIG dose of 5 g/day for 3 days; patients in the H group were administered a single high dose of 15 g/day for 1 day. Continuous variables: mean ± SEM; ordinal variables: median (interquartile); nominal variables: percentage. APACHE II, Acute Physiology and Chronic Health Evaluation II; APACHE II(−GCS), APACHE II without Glasgow Coma Scale; SOFA, Sequential Organ Failure Assessment; SOFA(−GCS), SOFA without Glasgow Coma Scale.

Temporal transitions in clinical data

There were no significant differences in temporal transitions in PCT values observed between the two groups (Figure 2a). Similar results were observed for CRP values and WBC count (Figure 2b,c). There was a statistically significant difference in blood lactate levels on day 2 between both groups (P = 0.02), as shown in Figure 3. The H group was found to have significantly lower SOFA and SOFA(−GCS) scores in the early stages after IVIG administration (SOFA score for day 3: P = 0.04; SOFA(−GCS) score for day 3: P = 0.04), with differences continuing for the first week (Figure 4a,b). With regard to the various diagnostic criteria for SIRS, we also observed significantly lower scores (day 2: P < 0.01) in the H group in the early stages after IVIG administration (Figure 4c).
Figure 2

Time course results of laboratory data. (a) PCT levels, (b) CRP levels, and (c) WBC count. Solid lines indicate the H group, and dashed lines indicate the S group.

Figure 3

Time course results of blood lactate levels. *P < 0.05 when compared with the S group. Solid line indicates the H group, and dashed line indicates the S group.

Figure 4

Time course results of (a) SOFA score, (b) SOFA(−GCS), and (c) SIRS criteria. *P < 0.05, **P < 0.01 when compared with the S group. Solid lines indicate the H group, and dashed lines indicate the S group. SOFA, Sequential Organ Failure Assessment; GCS, Glasgow Coma Scale; SIRS, Systemic Inflammatory Response Syndrome.

In addition, the results revealed a general tendency for temporal reductions in IL-6 levels in the H group across the time points, although this tendency was not found to have overall statistical significance. However, Figure 5 shows a statistically significant reduction (P < 0.01) in IL-6 levels in the H group between day 1 and day 2, whereas this was not observed in the S group. For the difference between day 2 and day 3, both groups showed a significant reduction in IL-6 levels.
Figure 5

Time course of IL-6 levels. *P < 0.01 compared with day 1 (H group only); P < 0.01 compared with day 2 (both groups), using one-way ANOVA, followed by a multiple comparison using Scheffe's method. Solid line indicates the H group, and dashed line indicates the S group. IL-6, Interleukin-6.

Clinical course

There were no significant differences in mechanical ventilation duration between the two groups or in the proportions of patients who had undergone tracheal intubation. Additionally, there were also no significant differences in ICU stay duration.

Patient prognosis

Kaplan-Meier survival curves and the log-rank test demonstrated that the H group tended to have higher, albeit non-significant, 28-day survival rates and 90-day survival rates when compared with the S group (not shown in the figure).

Discussion

Despite dramatic progress in treatment modalities, mortality rates for patients with serious sepsis remain high [17, 18], and a meta-analysis conducted by Friedman et al. [19] has shown the mortality rate associated with septic shock patients to be 49.7%. Factors such as the overall increases in patient age, advances in drug therapies, increasingly complex surgical procedures, and the emergence of multiple drug-resistant bacteria are thought to contribute to the continued increase in the number of patients with sepsis [20]. There is, therefore, an urgent need to further advance treatment modalities and adjunctive therapies.

In SSCG 2008 [15], the administration of IVIG was recommended in children due to a study [21] that demonstrated reduced mortality as a result of this treatment. However, this recommendation did not extend to include adult patients. Subsequently, the recommendation for IVIG administration was rescinded in the SSCG 2012 [3] due to studies such as the large-scale multi-institutional collaborative SBITS study involving 624 adult patients [22] and an investigation of 3,493 children [23]. In contrast, while the Japanese Guidelines for the Management of Sepsis [24] have not acknowledged the ameliorative effects of IVIG treatment on mortality rates, they have recognized that its use may be considered in the early stages of therapy as a means to reduce mechanical ventilation duration and improve survival rates in the ICU [22].

The regimen and dosage of IVIG in Japan are substantially lower than in many other countries. A study conducted in Japan in 2000 [25] analyzed the effects when patients with infections who showed no improvement in symptoms after 3 days of antibiotic therapy were administered IVIG (5 g/day for 3 days). When compared with similar patients who were not administered IVIG, the IVIG group showed significant improvements in disease symptoms. Although the negative conversion rate of the causative organism and the CRP rate of change were not significantly different between the two groups, a composite score comprised of fever and other symptoms was developed to measure the effectiveness of the therapy, which showed that the IVIG group had significantly higher effectiveness. However, the definition for severe sepsis was unclear, and the outcome measures used (reductions in fever and improvements in symptoms) were relatively ambiguous. Therefore, the utilization standards, regimen, and dosages reported in this study may be inconclusive.

Accordingly, we have conducted an investigation of the effectiveness of single-dose IVIG in patients with severe sepsis or septic shock. In this randomized controlled study, we did not observe significant differences between the two groups in CRP levels (a standard infection marker), PCT levels (which are thought to reflect the severity of sepsis) [26, 27], ICU stay duration, and patient prognoses. However, when compared with the standard divided doses IVIG group, the standard single-dose IVIG group was shown to have better results in the early post-administration stages for factors such as IL-6 levels, blood lactate levels, and SOFA score.

The mechanism of action for IVIG against infections has been reported to include the stimulation of Fc receptor-mediated antibiotic-dependent cellular cytotoxicity, neutralization of toxins and viruses, suppression of cytokine activity, promotion of complement-mediated bacteriolysis, and opsonization of targets to promote phagocytosis [28]. As some aspects of the mechanism still remain unclear, it would not be possible to conclusively explain the findings of this study. However, the fact [29] that IVIG formulations include anti-IL-6 antibodies may account for the early reduction in IL-6 levels after treatment, and the accompanying improvements in microcirculation may ostensibly improve blood lactate levels and reduce the SOFA score. A multi-institutional study has shown that improvements to blood lactate levels are associated with reductions in mortality risk [30], and these findings resulted in the reestablishment of the normalization of blood lactate levels at a recommended measure in SSCG 2012 [3]. From this perspective, the single-dose administration of IVIG could therefore also be thought of as being an effective treatment. In this study, we did not observe any adverse events occurring as a result of IVIG administration such as anaphylactoid symptoms or thrombocytopenia.

There were several limitations in this study. First, there may be a large degree of variation in the time to treatment among the research subjects. Next, the dosage of IVIG was not based on subject body weight but was standardized for all subjects. Also, we did not account for the anti-cytokine effects from other treatments such as blood purification therapy, steroids, sivelestat, and recombinant thrombomodulin. Additionally, there is a possibility that the pathology of sepsis differs according to the underlying illnesses. Finally, the levels of IgG in the blood were not assessed prior to administering IVIG, and there may therefore be a large degree of variation in these levels among the subjects.

A minimum of 2.0 g/kg body weight of immunoglobulins has been reported to be necessary in order to sufficiently neutralize the rise of IL-6 levels due to sepsis [31], which would be difficult to achieve in Japan given the reduced anti-cytokine effects from the lower immunoglobulin dosages. More studies are needed to further understand the costs, risk of infection, mechanism of utility, appropriate dosages, and modes of administration of single-dose IVIG treatment.

Conclusions

In this study, we shed light on the effectiveness of single-dose IVIG treatment in patients with severe sepsis or septic shock in Japan. Although the study did not show any significant effects on patient prognoses, subjects who were administered a standard single dose of IVIG showed significantly improved early-stage IL-6 levels, blood lactate levels, and disease severity scores when compared with patients administered with standard divided doses.

Declarations

Authors’ Affiliations

(1)
General Intensive Care Unit, Hirakata Hospital, Kansai Medical University
(2)
Division of Anesthesiology, National Center for Global Health and Medicine
(3)
Department of Anesthesiology,Hirakata Hospital, Kansai Medical University
(4)
Department of Clinical Laboratory,Hirakata Hospital, Kansai Medical University
(5)
Department of Clinical Sciences and Laboratory Medicine, Hirakata Hospital, Kansai Medical University

References

  1. Dhainaut JF, Yan SB, Joyce DE: Treatment effects of drotrecogin alfa (activated) in patients with severe sepsis with or without overt disseminated intravascular coagulation. J Thromb Haemost 2004, 2: 1924-1933. 10.1111/j.1538-7836.2004.00955.xView ArticlePubMedGoogle Scholar
  2. Dellinger RP, Carlet JM, Masur H: Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med 2004, 32: 858-873. 10.1097/01.CCM.0000117317.18092.E4View ArticlePubMedGoogle Scholar
  3. Dellinger RP, Levy MM, Rhodes A: Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013, 41: 580-637. 10.1097/CCM.0b013e31827e83afView ArticlePubMedGoogle Scholar
  4. Kaul R, McGeer A, Norrby-Teglund A: Intravenous immunoglobulin therapy for streptococcal toxic shock syndrome - a comparative observational study. The Canadian Streptococcal Study Group. Clin Infect Dis 1999, 28: 800-807. 10.1086/515199View ArticlePubMedGoogle Scholar
  5. Kyne L, Warny M, Qamar A: Association between antibody response to toxin A and protection against recurrent Clostridium difficile diarrhea. Lancet 2001, 357: 189-193. 10.1016/S0140-6736(00)03592-3View ArticlePubMedGoogle Scholar
  6. Turgeon AF, Hutton B, Fergusson DA: Meta-analysis: intravenous immunoglobulin in critically ill adult patients with sepsis. Ann Intern Med 2007, 146: 193-203. 10.7326/0003-4819-146-3-200702060-00009View ArticlePubMedGoogle Scholar
  7. Laupland KB, Kirkpatrick AW, Delaney A: Polyclonal intravenous immunoglobulin for the treatment of severe sepsis and septic shock in critically ill adults: a systematic review and meta-analysis. Crit Care Med 2007, 35: 2686-2692. 10.1097/01.CCM.0000295312.13466.1CView ArticlePubMedGoogle Scholar
  8. Kreymann KG, de Heer G, Nierhaus A: Use of polyclonal immunoglobulins as adjunctive therapy for sepsis or septic shock. Crit Care Med 2007, 35: 2677-2685. 10.1097/01.CCM.0000295263.12774.97View ArticlePubMedGoogle Scholar
  9. Pildal J, Gotzsche PC: Polyclonal immunoglobulin for treatment of bacterial sepsis: a systematic review. Clin Infect Dis 2004, 39: 38-46. 10.1086/421089View ArticlePubMedGoogle Scholar
  10. Nimmerjahn F, Ravetch JV: Anti-inflammatory actions of intravenous immunoglobulin. Annu Rev Immunol 2008, 26: 513-533. 10.1146/annurev.immunol.26.021607.090232View ArticlePubMedGoogle Scholar
  11. Durongpisitkull K, Gurugaj VJ, Park JM: The prevention of coronary artery aneurysm in Kawasaki disease: a meta-analysis on the efficacy of aspirin and immunoglobulin treatment. Pediatrics 1995, 96: 1057-1061.Google Scholar
  12. Benesch M, Kerbl R, Lackner H: Low-dose versus high-dose immunoglobulin for primary treatment of acute immune thrombocytopenic purpura in children: results of a prospective, randomized single-center trial. J Pediatr Hematol Oncol 2003, 25: 797-800. 10.1097/00043426-200310000-00011View ArticlePubMedGoogle Scholar
  13. Bone RC, Balk RA, Cerra FB: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 1992, 101: 1644-1655. 10.1378/chest.101.6.1644View ArticlePubMedGoogle Scholar
  14. Rivers E, Nguyen B, Havstad S: Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001, 345: 1368-1377. 10.1056/NEJMoa010307View ArticlePubMedGoogle Scholar
  15. Dellinger RP, Levy MM, Carlet JM: Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008, 36: 296-327. 10.1097/01.CCM.0000298158.12101.41View ArticlePubMedGoogle Scholar
  16. Tallgren M, Backlund M, Hynninen M: Accuracy of Sequential Organ Failure Assessment (SOFA) scoring in clinical practice. Acta Anaesthesiol Scand 2009, 53: 39-45. 10.1111/j.1399-6576.2008.01825.xView ArticlePubMedGoogle Scholar
  17. Martin GS, Mannino DM, Eaton S: The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 2003, 348: 1546-1554. 10.1056/NEJMoa022139View ArticlePubMedGoogle Scholar
  18. Dombrovskiy VY, Martin AA, Sunderram J: Rapid increase in hospitalization and mortality rates for severe sepsis in the United States: a trend analysis from 1993 to 2003. Crit Care Med 2007, 35: 1244-1350. 10.1097/01.CCM.0000261890.41311.E9View ArticlePubMedGoogle Scholar
  19. Friedman G, Silva E, Vincent JL: Has the mortality of septic shock changed with time. Crit Care Med 1998, 26: 2078-2086. 10.1097/00003246-199812000-00045View ArticlePubMedGoogle Scholar
  20. Augus DC, Linde-Zwirble WT, Lidicker J: Epidemiology of sever sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001, 29: 1303-1310. 10.1097/00003246-200107000-00002View ArticleGoogle Scholar
  21. El-Nawawy A, El-Kinany H, Hamdy El-Sayed M: Intravenous polyclonal immunoglobulin administration to sepsis syndrome patients: a prospective study in a pediatric intensive care unit. J Trop Pediatr 2005, 51: 271-278. 10.1093/tropej/fmi011View ArticlePubMedGoogle Scholar
  22. Werdan K, Pilz G, Bujdoso O: Score-based immunoglobulin G therapy of patients with sepsis: the SBITS study. Crit Care Med 2007, 35: 2693-2701. 10.1097/01.CCM.0000295426.37471.79View ArticlePubMedGoogle Scholar
  23. Brocklehurst P, Farrell B, King A, INIS Collaborative Group: Treatment of neonatal sepsis with intravenous immune globulin. N Engl J Med 2011, 365: 1201-1211.View ArticlePubMedGoogle Scholar
  24. The Japanese Society of Intensive Care Medicine, Committee of Sepsis Registry: The Japanese Guidelines for the Management of Sepsis. J Jpn Soc Intensive Care Med 2013, 20: 124-173.View ArticleGoogle Scholar
  25. Masaoka T, Hasegawa H, Takaku F: The efficacy of intravenous immunoglobulin in combination therapy with antibiotics for severe infections. Jpn J Chemother 2000, 48: 199-217.Google Scholar
  26. Aikawa N, Fujishima S, Endo S: Multicenter prospective study of procalcitonin as an indicator of sepsis. J Inf Chemother 2005, 11: 152-159. 10.1007/s10156-005-0388-9View ArticleGoogle Scholar
  27. Assicot M, Gendrel D, Carsin H: High serum procalcitonin concentrations in patients with sepsis and infection. Lancet 1993, 341: 515-518. 10.1016/0140-6736(93)90277-NView ArticlePubMedGoogle Scholar
  28. Negi VS, Elluru S, Siberil S: Intravenous immunoglobulin: an update on the clinical use and mechanism of action. J Clin Immunol 2007, 27: 233-245. 10.1007/s10875-007-9088-9View ArticlePubMedGoogle Scholar
  29. Kimura A, Shibata Y, Nishizawa K: Intravenous immunoglobulin administration for patients with systemic inflammatory response syndrome. J Jpn Soc Emer Med 1997, 7: 307-308.Google Scholar
  30. Jansen TC, van Bommel J, Schoonderbeek FJ, LACTATE study group: Early lactate-guided therapy in intensive care unit patients: a multicenter, open-label, randomized controlled trial. Am J Respir Crit Care Med 2010, 182: 752-761. 10.1164/rccm.200912-1918OCView ArticlePubMedGoogle Scholar
  31. Svenson M, Hansen MB, Bendtzen K: Binding of cytokines to pharmaceutically prepared human immunoglobulin. J Clin Invest 1993, 92: 2533-2539. 10.1172/JCI116862PubMed CentralView ArticlePubMedGoogle Scholar

Copyright

© Hamano et al.; licensee BioMed Central Ltd. 2013

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Advertisement