despite developing therapeutic strategies and new antibiotic regimens , mortality of sepsis and septic shock has actually remained at a level of about 3550% . novel anti - inflammatory treatment regimens such as anti - tumor necrosis factor , anti - platelet - activating factor , anti - interleukin-1 , anti - endotoxin , anti - bradykinin , inhibitors of nitric oxide synthase and steroids have also yielded disappointing results until now . systemic inflammatory response syndrome and sepsis are diseases of the immune system rather than simple effects of a causative agent . an immunotherapeutic approach that acts through neutralization of endotoxin and various bacterial products by passive administration of intravenous immunoglobulin ( ivig ) seems to be promising in clinical practice , rather than target one mediator of the inflammatory cascade . besides the effect of immunoglobulin substitution in a case of deficiency , several other mechanisms , such as neutralizing endotoxins and exotoxins , scavenging active complement components , as well as lipopolysaccharides , stimulating opsonic and bactericidal activity in serum , reducing pro - inflammatory mediators , and increasing anti - inflammatory mediators , it has been previously shown that commercial ivigg products contained antibodies against gram - negative and gram - positive bacteria , often encountered in the intensive care unit . in a recent study , trautmann et al .   showed that antibodies against lipopolysaccharides of escherichia coli , pseudomonas aeruginosa and klebsiella spp . are much more concentrated in human igm fraction . in this prospective , randomized controlled study , we aimed to evaluate the effect of igm - enriched immunoglobulin treatment on progression of organ failure and septic shock in patients with severe sepsis . after approval by the faculty ethics committee , patients with severe sepsis ( temperature > 38c or < 36c , heart rate > 90 beats / min , respiratory rate > 20/min or paco2 < 32 mmhg , white blood cell count > 12,000/mm or < 4000/mm , documented infection and dysfunction of an organ or hypotension ) were enrolled in the study . patients were randomly allocated to the study groups according to the numerical order of a computer - generated randomization list . patients in the study group ( n = 21 ) received ivig preparation in addition to standard sepsis therapy . polyclonal ivig treatment ( pentaglobin , biotest pharma gmbh , dreieich , germany ) was started on the day of diagnosis of severe sepsis : 5 ml / kg per day pentaglobin ( 38 g / l igg , 6 g / l igm and 6 g / l iga ) was infused intravenously over a period of 6 hours and repeated for 3 consecutive days . patients in the control group ( n = 18 ) received standard sepsis therapy , but no immunoglobulin administration . electrocardiogram , invasive arterial blood pressure and central venous pressure were monitored continuously ( horizon xl ; mennen medical , rehovot , israel ) . the aim was to achieve a central venous pressure of 812 mmhg . dopamine , dobutamine , epinephrine and/or norepinephrine were used to treat hypoperfusion that was unresponsive to volume resuscitation . oliguria and fluid overload were treated by hemofiltration , if adequate urine flow could not be obtained by medical therapy . septic shock was diagnosed when severe sepsis was associated with hypotension ( systolic blood pressure < 90 mmhg or a reduction of > 40 mmhg from baseline , in the absence of other cause for hypotension ) despite adequate fluid resuscitation . blood samples for procalcitonin ( pct ) measurements were taken daily for 8 days following study admission . samples were obtained from an arterial catheter every morning and the samples were processed by the same person in the laboratory of the medical biology department . pct was determined with an immunoluminometric assay , allowing quantitative measurement of a wide range of pct concentrations ( b.r.a.h.m.s . severity of critical illness was assessed by obtaining daily acute physiological and chronic health evaluation score ( apache ii ) . sequential organ failure assessment ( sofa ) score was used to assess the development of organ failure , and in an attempt to describe the degree of organ failure over time in individual septic patients . duration of mechanical ventilation , length of stay in the intensive care unit , septic shock incidence and 28-day mortality rate were also recorded . appropriate microbial samples were obtained before prescribing any prophylactic and pre - emptive medication , and if this was not possible then the probable causative agents were considered and therapy was administered accordingly . all isolated bacteria were identified and antimicrobial susceptibilities of isolates were determined by the disk diffusion method described in nccls m2-a6 and m100-s8 . in these patients with sepsis , all samples , especially blood cultures , should be obtained as soon as possible and before any changes are made in antimicrobial therapy . data are presented as mean  sd or median ( range ) for data that were not normally distributed . demographic and outcome data were examined on the basis of intention - to - treat analysis . mortality rate , septic shock incidence and gender were compared using fisher 's exact test . the mann pct values , sofa and apache ii scores were not normally distributed ; these were analyzed with friedman analysis of variance on ranks . in case of statistical significance after approval by the faculty ethics committee , patients with severe sepsis ( temperature > 38c or < 36c , heart rate > 90 beats / min , respiratory rate > 20/min or paco2 < 32 mmhg , white blood cell count > 12,000/mm or < 4000/mm , documented infection and dysfunction of an organ or hypotension ) were enrolled in the study . patients were randomly allocated to the study groups according to the numerical order of a computer - generated randomization list . patients in the study group ( n = 21 ) received ivig preparation in addition to standard sepsis therapy . polyclonal ivig treatment ( pentaglobin , biotest pharma gmbh , dreieich , germany ) was started on the day of diagnosis of severe sepsis : 5 ml / kg per day pentaglobin ( 38 g / l igg , 6 g / l igm and 6 g / l iga ) was infused intravenously over a period of 6 hours and repeated for 3 consecutive days . patients in the control group ( n = 18 ) received standard sepsis therapy , but no immunoglobulin administration . electrocardiogram , invasive arterial blood pressure and central venous pressure were monitored continuously ( horizon xl ; mennen medical , rehovot , israel ) . dopamine , dobutamine , epinephrine and/or norepinephrine were used to treat hypoperfusion that was unresponsive to volume resuscitation . oliguria and fluid overload were treated by hemofiltration , if adequate urine flow could not be obtained by medical therapy . septic shock was diagnosed when severe sepsis was associated with hypotension ( systolic blood pressure < 90 mmhg or a reduction of > 40 mmhg from baseline , in the absence of other cause for hypotension ) despite adequate fluid resuscitation . blood samples for procalcitonin ( pct ) measurements were taken daily for 8 days following study admission . samples were obtained from an arterial catheter every morning and the samples were processed by the same person in the laboratory of the medical biology department . pct was determined with an immunoluminometric assay , allowing quantitative measurement of a wide range of pct concentrations ( b.r.a.h.m.s . severity of critical illness was assessed by obtaining daily acute physiological and chronic health evaluation score ( apache ii ) . sequential organ failure assessment ( sofa ) score was used to assess the development of organ failure , and in an attempt to describe the degree of organ failure over time in individual septic patients . duration of mechanical ventilation , length of stay in the intensive care unit , septic shock incidence and 28-day mortality rate were also recorded . appropriate microbial samples were obtained before prescribing any prophylactic and pre - emptive medication , and if this was not possible then the probable causative agents were considered and therapy was administered accordingly . all isolated bacteria were identified and antimicrobial susceptibilities of isolates were determined by the disk diffusion method described in nccls m2-a6 and m100-s8 . in these patients with sepsis , all samples , especially blood cultures , should be obtained as soon as possible and before any changes are made in antimicrobial therapy . data are presented as mean  sd or median ( range ) for data that were not normally distributed . demographic and outcome data were examined on the basis of intention - to - treat analysis . mortality rate , septic shock incidence and gender were compared using fisher 's exact test . the mann pct values , sofa and apache ii scores were not normally distributed ; these were analyzed with friedman analysis of variance on ranks . in case of statistical significance three patients from the control group were excluded because of technical problems during laboratory analysis . demographic data and clinical characteristics of the patients are presented in table 1 . thirteen patients ( 72% ) in the control group and 14 patients ( 67% ) in the pentaglobin group had sepsis resulting from infection with gram - negative microorganisms . mortality rates of those sub - groups of patients were 23% in the control group and 14% in the pentaglobin group ( p = 0.6 ) . pct levels showed a statistically significant decrease in the pentaglobin group ( p < 0.001 ) ; however , an improvement in sofa scores could not be demonstrated . pct levels and sofa scores did not change significantly in the control group ( table 3 ) . daily pct levels and sofa scores of both groups are shown in figs 1 and 2 . procalcitonin plasma concentrations of patients in pentaglobin and control groups . indicated are median ( inner line ) , 25/75 percentiles ( box ) and 10/90 percentiles ( whisker ) obtained during an 8-day observation period . p < 0.05 , p < 0.01 when compared to day 1 . sequential organ failure assessment ( sofa ) scores of patients in pentaglobin and control groups . indicated are median ( inner line ) , 25/75 percentiles ( box ) and 10/90 percentiles ( whisker ) obtained during an 8-day observation period . apache ii scores showed a statistically significant decrease in the pentaglobin and control groups ( p < 0.001 in both groups ) . pct levels , sofa and apache ii scores did not demonstrate statistically significant differences between the groups on each evaluation day . duration of mechanical ventilation , length of intensive care stay , septic shock incidence and 28-day mortality rate were found to be similar between the groups ( table 4 ) . in the present study , the use of igm - enriched and iga - enriched igg preparation in addition to standard sepsis therapy could not produce an improvement in any of the outcome measures of patients with severe sepsis . the only encouraging observation was the reduction in pct levels obtained with pentaglobin administration . in the previous studies specific igm and igg antibodies against lipopolysaccharides of escherichia coli strains , klebsiella pneumoniae , pseudomonas aeruginosa , -haemolysin of staphylococcus aureus , and against surface proteins of oxacillin - resistant s. aureus and vancomycin - resistant streptococci were detected in pentaglobin solution . when using in vitro cell cultures , pentaglobin preparation produced the highest inhibition of tumor necrosis factor  release when added to the medium with lipopolysaccharide . rieben et al .   showed that igm enrichment of ivig preparations leads to an enhanced complement - inhibitory capacity both in vitro and in vivo as compared with pure ivigg . monoclonal ( igg ) and polyclonal ( iggma ) immunoglobulin solutions have previously been applied to different groups of intensive care patients . both igg and iggma have been used prophylactically in high - risk patients after cardiac surgery and resulted in an improvement in infectious morbidity and in a reduction in mortality rate . however , consistent reductions in mortality could not be demonstrated in placebo - controlled trials performed in sepsis or septic shock . igg was applied to 653 sepsis patients having an apache ii score higher than 20 ; a moderate improvement was obtained in severity of sepsis , but the mortality rate could not be reduced . used igg solution in patients with severe sepsis and obtained reductions in hospitalization and number of days on antibiotics , as well as in the number of positive cultures ; however , the mortality rate ( 75% control versus 58% ivigg ) was unchanged . ( 41% control versus 46% ivigg , iviggma ) and vogel   ( 44% control versus 24% iviggma ) were also not able to demonstrate reductions in mortality rate by iggma application to different intensive care patients with sepsis . on the other hand , impressive improvement in outcome for septic patients was reported in certain investigations using ivig preparations . in a study performed by dominioni et al . , the mortality rate was reduced by administration of the igg solution from 67% to 38% in postoperative septic patients having a sepsis score higher than 20 . reported a statistically significant decrease in the apache ii score beyond the fifth day after inclusion , as well as a decrease in the 6-week mortality rate ( 1/27 in the pentaglobin group versus 9/28 in the control group ) in septic shock patients receiving pentaglobin treatment . serum concentrations of endotoxin - equivalent were also found to be decreased significantly within 24 hours after inclusion of the patients in the study in patients treated with pentaglobin . the cochrane group analyzed 23 controlled clinical studies published between 1966 and 1999 and found that sepsis - related mortality was significantly reduced only in patients who received polyclonal ivig in contrast to treatment with monoclonal antibodies and anti - cytokines in sepsis and septic shock . our results could not make a clear - cut contribution to the conflicting data obtained from trials studying the effects of the different types of immunoglobulin preparations in septic patients . as well as the use of different antibiotics , other treatment strategies , such as the use of catecholamines , corticosteroids or hemofiltration have the potential to interact with the immune system and , therefore , with the response of the patients . if we examine possible explanations for inconsistency of the literature , the dosage and application schedule as well as the timing of immunomodulatory therapy should also be taken into consideration . almost all investigators applied a total amount of approximately 1 l pentaglobin 5% during 3 consecutive days in previous studies . the stage of the disease at which immunoglobulin substitution was performed might be an important determinant of the response of the patients . the most striking data about the beneficial effects of polyclonal immunoglobulin were presented by schedel et al .   in septic shock patients . dominioni et al . , also reported impressive mortality reduction with the igg preparation in septic patients with a sepsis score higher than 20 . it is now well known that systemic inflammatory response syndrome is the result of the imbalance between proinflammatory and anti - inflammatory forces . the compensatory anti - inflammatory response is assumed to lead to an increased susceptibility to infection or anergy , whereas systemic overflow of the proinflammatory system may lead to apoptosis , organ dysfunction , and thus septic shock . the anti - inflammatory potential of pentaglobin may not show clear benefits , or may even be harmful , in cases or at disease stages in which proinflammatory forces are not dominant . according to this paradigm , a more precise understanding of the laboratory and clinical information of the immune status of patients will help with administering the right drug at the right time for the right patient . it was suggested that a single therapeutic method of immunoglobulin substitution in the therapy of this complex syndrome might accomplish the goal of improvement in morbidity , instead of expecting a magic approach to reducing the mortality rate in sepsis . in this study , the sofa score was used to describe the damage to the different organ systems , as well as the impact of the therapy on the progression of organ dysfunction . with regard to the sofa scores , which did not demonstrate an improvement in organ morbidity throughout the 8-day follow - up period , pct is a pro - hormone that shows elevated plasma levels in severe bacterial , fungal and parasitic infections , as well as in sepsis and multiorgan failure . it has been used not only in the diagnosis of sepsis but also in treatment of the clinical course of the disease . in contrast to the control group , this marker demonstrated a consistent decline in patients treated with pentaglobin preparation . however , the decline in pct levels did not correspond with the clinical course of severe sepsis , which was reflected in unchanged sofa scores throughout the study . the evaluation of serial apache ii scores also did not demonstrate a difference between the pentaglobin and control groups . in our study there are some limitations that should be noted . restricting the investigation period to only 8 days we suggest that extending the duration of data collection might allow the change in pct levels to be accompanied by an improvement of the severity of organ dysfunction . the increase in pct levels on days 68 could possibly reflect a septic relapse in some of the patients in the control group . because cytokine levels were not measured in the present study , we could not comment on the possible role of pentaglobin in the prevention of a similar relapse in the treatment group . increasing the number of patients could confirm a change in the severity of organ dysfunction , the incidence of septic shock and mortality rate as a result of using pentaglobin . apache ii , acute physiological and chronic health evaluation ; f / m , female / male ; gcs , glasgow coma scale ; sofa , sequential organ failure assessment . pentaglobin group ( n = 21 ) ; control group ( n = 21 ) . cns , central nervous system ; mrsa , methicillin - resistant staphylococcus aureus ; e. coli , escherichia coli ; k. pneumoniae , klebsiella pneumoniae ; p. aeruginosa , pseudomonas aeruginosa ; s. maltophilia , stenotrophomonas maltophilia . procalcitonin levels , sofa and apache ii scores values are expressed as median ( range ) . anova , analysis of variance ; apache ii , acute physiological and chronic health evaluation ; pct , procalcitonin ; sofa , sequential organ failure assessment . pentaglobin group ( n = 21 ) ; control group ( n = 21 ) . in conclusion , our data could not demonstrate any beneficial effects of the polyclonal immunoglobulin preparation pentaglobin on organ morbidity , septic shock incidence and mortality rate in patients with severe sepsis . we believe that further investigations should focus on laboratory and clinical measures to identify and monitor patients who might benefit from specific immunomodulatory therapies . the aim of this prospective study is to evaluate the effect of igm - enriched immunoglobulin treatment on progression of organ failure and septic shock in patients with severe sepsis . reduction in pct levels observed with pentaglobin   administration was a striking observation of the study . serial sofa and apache ii scores did not reveal significant differences between the groups . the decline in pct levels did not correspond with the clinical course of severe sepsis in the pentaglobin group . present data could not demonstrate any beneficial effects of polyclonal immunoglobulin preparation on organ morbidity , septic shock incidence and mortality rate in patients with severe sepsis . apache ii = acute physiological and chronic health evaluation ii ; ivig = intravenous immunoglobulin ; pct = procalcitonin ; sofa = sequential organ failure assessment .
introductionin this prospective , randomized controlled study , we aimed to evaluate the effect of igm - enriched immunoglobulin treatment on progression of organ failure and septic shock in patients with severe sepsis.materials and methodsforty - two patients with severe sepsis were enrolled in the study . 
 patients in the study group ( n = 21 ) received an intravenous immunoglobulin preparation ( pentaglobin ) in addition to standard therapy . 
 pentaglobin therapy was commenced on the day of diagnosis of severe sepsis : 5 ml / kg per day pentaglobin ( 38 g / l igg , 6 g / l igm , and 6 g / l iga ) was infused over 6 hours and repeated for 3 consecutive days . 
 patients in the control group ( n = 18 ) received standard sepsis therapy , but no immunoglobulin administration . 
 blood samples for procalcitonin ( pct ) measurements were taken daily for 8 days . 
 severity of critical illness and development of organ failure were assessed by obtaining daily acute physiological and chronic health evaluation ( apache ) ii and sequential organ failure assessment ( sofa ) scores.results and discussionprocalcitonin levels showed a statistically significant decrease in the pentaglobin group ( p < 0.001 ) ; however , an improvement in sofa scores could not be demonstrated . 
 procalcitonin levels and sofa scores did not change significantly in the control group . 
 septic shock incidence ( 38% versus 57% ) and 28-day mortality rate ( 23.8% versus 33.3% ) were found to be similar between the pentaglobin and control groups . 
 the evaluation of serial apache ii scores did not demonstrate a difference between pentaglobin and control groups either.conclusionpresent data could not demonstrate any beneficial effects of polyclonal immunoglobulin preparation pentaglobin on organ morbidity , septic shock incidence and mortality rate in patients with severe sepsis .