Case Report
Intravenous immunoglobulin as adjunctive treatment for Fournier’s gangrene Aggressive surgical debridement and broadspectrum antibiotics are the mainstay of treatment for necrotizing fasciitis, of which Fournier’s gangrene is a subtype. Despite such treatments, mortality remains up to 50%, often attributable to the sequelae of septic shock. This case describes the adjunctive use of intravenous immunoglobulin in the treatment of a critically ill septic patient with Fournier’s gangrene, in whom serial debridement and antimicrobial therapy had already been initiated. As demonstrated, the initiation of intravenous immunoglobulin, used to ameliorate the patient’s immune response, correlated with a rapid and sustained decrease in the patient’s requirements for vasopressor support. The patient subsequently made a full recovery and was discharged from hospital. This is the first documented case of intravenous immunoglobulin use in the successful treatment of Fournier’s gangrene.
Discussion Cases of necrotizing fasciitis are common enough that most clinicians will come across it at least once in their careers, yet uncommon enough that familiarity with the condition is unlikely to be achieved (Anaya and Dellinger, 2007). As such, patient recruitment to adequately powered studies assessing the use of intravenous immunoglobulin is difficult (Darenberg et al, 2003). Dr Oliver Sanders, Foundation Year 1 Doctor, Department of Intensive Care, Princess Alexandra Hospital NHS Trust, Harlow CM20 1QX Dr Edward Gilbert-Kawai, Specialty Registrar, Department of Anaesthetics, University College London Hospitals NHS Foundation Trust, London Dr Rajnish Saha, Consultant, Department of Anaesthetics, Princess Alexandra Hospital NHS Trust, Harlow Correspondence to: Dr O Sanders ([email protected])
530
It is postulated that the mechanism of action of intravenous immunoglobulin involves either the inhibition of T-cell
proliferation, or binding the exotoxin produced by some causative agents of necrotizing fasciitis such as group A
CASE REPORT A 70-year-old man was brought into the emergency department following an unexplained syncopal episode, having felt generally unwell for 4 days with 2 days of worsening scrotal pain. He was a known asthmatic and a chronic hypertensive, but was not diabetic. Initial observations demonstrated a heart rate 107 beats per minute, blood pressure 97/54 mmHg, peripheral oxygen saturations 95% on 2 litres/minute via nasal cannula, respiratory rate 18 breaths per minute, and a temperature of 36.8°C. On examination the patient was conscious and oriented, significantly overweight (128 kg, body mass index 39 kg/m²) and in obvious discomfort. The scrotal skin appeared oedematous with a foul-smelling necrotic lesion, 10x6 cm extending posteriorly towards the anus. The lesion was black/green and surrounded by erythema. There was another area of indurating erythematous cutaneous oedema in the left suprapubic area, 5x4 cm, although this was not necrotic on inspection. Under high suspicion of Fournier’s gangrene, an urgent urology review was requested. Bloods taken on arrival were indicative of a severe inflammatory response (C-reactive protein 430 mg/litre, white cell count 20.5x109/ litre, neutrophils 19.0x109/litre), and stage II acute kidney injury (urea 17.5 mmol/litre, creatinine 201 μmol/litre). Venous blood gas showed a metabolic acidosis (pH 7.37) with a raised lactate level (3.71 mmol/litre). Blood cultures were taken, which revealed ‘no growth’. The patient was started on intravenous metronidazole, gentamicin and piperacillin/ tazobactam before surgery. In theatre, he underwent a rapid sequence induction, followed by a nasogastric tube, arterial line and triple lumen central line insertion. The surgical debridement and washout left the patient with three open wounds: one in the sacral area (25x17 cm), one in the perineum (10x6 cm), and one in the left suprapubic area (5x4 cm). All wounds were composed of viable tissue
and were left open at the end of surgery. Intraoperatively, the patient received 7 litres of crystalloid fluid resuscitation, and was subsequently commenced on noradrenaline vasopressor support. Following surgery, the patient was transferred to the intensive care unit, where he remained intubated and ventilated in anticipation of a second procedure. Following microbiology advice, the antibiotics were changed to clindamycin (1.2 g 6-hourly), benzylpenicillin (1.2 g 6-hourly), metronidazole (500 mg 8-hourly) and gentamicin (150 mg 8-hourly), but despite this, the patient’s noradrenaline requirements continued to increase to 0.45 μg/kg/min. After 15 hours on the intensive care unit the haemodynamically unstable patient went back to theatre for further debridement. On his return to intensive care, the patient received 200 g of Octagam human normal immunoglobulin (100 mg/ml) intravenously in an increasing rate infusion, in addition to the aforementioned antibiotics. Intraoperative tissues were cultured, growing Escherichia coli and Proteus mirabilis, sensitive to gentamicin. Within 2 hours of the initiation of intravenous immunoglobulin, the patient’s requirements for noradrenaline support reduced from 0.44 μg/kg/min to 0.29 μg/ kg/min. This prompt decrease in vasopressor support infers a successful response to intravenous immunoglobulin in this septic patient (Figure 1). Noradrenaline requirements continued to decline over the next 6 hours by 65% (0.44→0.14 μg/kg/min), till discontinuation at 27 hours post-intravenous immunoglobulin initiation. The patient required no additional surgical debridement. In total the patient spent 13 days on the intensive care unit, ten of which he was dependent on ventilatory support. The patient was stepped down to a surgical ward and transferred to a regional plastics centre for reconstructive treatment.
© 2017 MA Healthcare Ltd
Introduction
British Journal of Hospital Medicine, September 2017, Vol 78, No 9 © MA Healthcare Ltd. Downloaded from magonlinelibrary.com by 155.198.030.043 on September 14, 2017. Use for licensed purposes only. No other uses without permission. All rights reserved.
Case Report Figure 1. Patient’s vasopressor requirement to maintain mean arterial pressure above 70 mmHg as a function of time.
■■ Early surgical debridement with the use
Intravenous immunoglobulin infusion
0.5
Noradrenaline (µg/min)
0.45
Theatre Start
LEARNING POINTS of several broad-spectrum intravenous antibiotics form the foundation of treatment of necrotizing fasciitis. ■■ A high level of clinical suspicion for
End
necrotizing fasciitis should exist in cases of a clinically septic patient with localized pain in excess of what would be expected based on superficial inspection.
0.4 0.35 0.3
■■ Intravenous immunoglobulin may
0.25
represent a useful adjunctive immunomodulatory therapy in the treatment of necrotizing fasciitis and Fournier’s gangrene.
0.2 0.15 0.1 0.05 0
1 4 7 10 13 16 19 22 25 28 31 34 37 40 43 46 49 52 55 58
© 2017 MA Healthcare Ltd
Time spent on intensive care unit (hours)
streptococci (Sarani et al, 2009; Wang et al, 2015). Binding neutralizes the cytokine- inducing properties of the exotoxin, thereby reducing the systemic inflammatory response (Norrby-Teglund et al, 1998). The evidence supporting the use of intravenous immunoglobulin in the treatment of Gram-negative necrotizing fasciitis is limited, but a meta-analysis has shown an overall reduction in mortality in cases of Gram-negative sepsis when intravenous immunoglobulin was used as an adjunctive treatment (Laupland et al, 2007). Small retrospective studies have shown a survival benefit for the use of intravenous immunoglobulin in streptococcal toxic shock syndrome caused by group A streptococci (Kaul et al, 2009), but randomized controlled trials have not been able to reproduce this finding in necrotizing fasciitis (Darenberg et al, 2003). The majority of the literature supporting the use of intravenous immunoglobulin in necrotizing fasciitis is therefore limited to individual case studies (Raithatha and Bryden, 2012; Koch et al, 2015), but metaanalysis of these data supports its use in critically ill adults with sepsis secondary to necrotizing fasciitis. Notably, there are no published case reports or trial data detailing the use of intravenous immunoglobulin to successfully treat Fournier’s gangrene.
Fournier’s gangrene is frequently polymicrobial in nature with an average of three to four causative agents isolated (Yaghan et al, 2000); both aerobic and anaerobic bacteria have been found, including coliforms, Klebsiella spp., streptococci and staphylococci (Thwaini et al, 2006).
Conclusions This article demonstrates that administration of intravenous immunoglobulin enabled a marked reduction of vasopressor requirements in a critically ill septic patient with Fournier’s gangrene. The therapy was administered alongside the conventional treatment regimen, and as such the authors do not ascribe the therapeutic benefits to the intervention of intravenous immunoglobulin alone. However, further studies should be conducted to assess the efficacy of this treatment as an adjunctive therapy in Fournier’s gangrene and other varieties of necrotizing fasciitis. BJHM Anaya D, Dellinger E (2007) Necrotizing softtissue infection: diagnosis and management. Clin Infect Dis 44(5): 705–710. https://doi. org/10.1086/511638 Darenberg J, Ihendyane N, Sjölin J et al; StreptIg Study Group (2003) Intravenous immunoglobulin G therapy in streptococcal toxic shock syndrome: a European randomized, double-blind, placebo-controlled trial. Clin Infect Dis 37(3): 333–340. https://doi. org/10.1086/376630 Kaul R, McGeer A, Norrby-Teglund A et al;
British Journal of Hospital Medicine, September 2017, Vol 78, No 9
The Canadian Streptococcal Study Group (1999) Intravenous immunoglobulin therapy for streptococcal toxic shock syndrome - a comparative observational study. Clin Infect Dis 28(4): 800–807. https://doi. org/10.1086/515199 Koch C, Hecker A, Grau V, Padberg W, Wolff M, Henrich M (2015) Intravenous immunoglobulin in necrotizing fasciitis – A case report and review of recent literature. Ann Med Surg (Lond) 4(3): 260–263. https://doi.org/10.1016/j. amsu.2015.07.017 Laupland KB, Kirkpatrick AW, Delaney A (2007) 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 35(12): 2686–2692. https://doi.org/10.1097/01. CCM.0000295312.13466.1C Norrby-Teglund A, Basma H, Andersson J, McGeer A, Low DE, Kotb M (1998) Varying titers of neutralizing antibodies to streptococcal superantigens in different preparations of normal polyspecific immunoglobulin G: implications for therapeutic efficacy. Clin Infect Dis 26(3): 631–638. https://doi. org/10.1086/514588 Raithatha A, Bryden D (2012) Use of intravenous immunoglobulin therapy in the treatment of septic shock, in particular severe invasive group A streptococcal disease. Indian J Crit Care Med 16(1): 37–40. https://doi.org/10.4103/09725229.94433 Sarani B, Strong M, Pascual J, Schwab CW (2009) Necrotizing fasciitis: current concepts and review of the literature. J Am Coll Surg 208(2): 279–288. https://doi.org/10.1016/j. jamcollsurg.2008.10.032 Thwaini A, Khan A, Malik A, Cherian J, Barua J, Shergill I, Mammen K (2006) Fourniers gangrene and its emergency management. Postgrad Med J 82(970): 516–519. https://doi.org/10.1136/ pgmj.2005.042069 Wang J, McQuilten ZK, Wood EM, Aubron C (2015) Intravenous immunoglobulin in critically ill adults: when and what is the evidence? J Crit Care 30(3): 652.e9–652.e16. https://doi. org/10.1016/j.jcrc.2015.01.022 Yaghan RJ, Al-Jaberi TM, Bani-Hani I (2000) Fournier’s gangrene. Dis Colon Rectum 43(9): 1300–1308. https://doi.org/10.1007/ BF02237442
531
© MA Healthcare Ltd. Downloaded from magonlinelibrary.com by 155.198.030.043 on September 14, 2017. Use for licensed purposes only. No other uses without permission. All rights reserved.
Intravenous immunoglobulin as adjunctive treatment for Fournier’s gangrene Aggressive surgical debridement and broadspectrum antibiotics are the mainstay of treatment for necrotizing fasciitis, of which Fournier’s gangrene is a subtype. Despite such treatments, mortality remains up to 50%, often attributable to the sequelae of septic shock. This case describes the adjunctive use of intravenous immunoglobulin in the treatment of a critically ill septic patient with Fournier’s gangrene, in whom serial debridement and antimicrobial therapy had already been initiated. As demonstrated, the initiation of intravenous immunoglobulin, used to ameliorate the patient’s immune response, correlated with a rapid and sustained decrease in the patient’s requirements for vasopressor support. The patient subsequently made a full recovery and was discharged from hospital. This is the first documented case of intravenous immunoglobulin use in the successful treatment of Fournier’s gangrene.
Discussion Cases of necrotizing fasciitis are common enough that most clinicians will come across it at least once in their careers, yet uncommon enough that familiarity with the condition is unlikely to be achieved (Anaya and Dellinger, 2007). As such, patient recruitment to adequately powered studies assessing the use of intravenous immunoglobulin is difficult (Darenberg et al, 2003). Dr Oliver Sanders, Foundation Year 1 Doctor, Department of Intensive Care, Princess Alexandra Hospital NHS Trust, Harlow CM20 1QX Dr Edward Gilbert-Kawai, Specialty Registrar, Department of Anaesthetics, University College London Hospitals NHS Foundation Trust, London Dr Rajnish Saha, Consultant, Department of Anaesthetics, Princess Alexandra Hospital NHS Trust, Harlow Correspondence to: Dr O Sanders ([email protected])
530
It is postulated that the mechanism of action of intravenous immunoglobulin involves either the inhibition of T-cell
proliferation, or binding the exotoxin produced by some causative agents of necrotizing fasciitis such as group A
CASE REPORT A 70-year-old man was brought into the emergency department following an unexplained syncopal episode, having felt generally unwell for 4 days with 2 days of worsening scrotal pain. He was a known asthmatic and a chronic hypertensive, but was not diabetic. Initial observations demonstrated a heart rate 107 beats per minute, blood pressure 97/54 mmHg, peripheral oxygen saturations 95% on 2 litres/minute via nasal cannula, respiratory rate 18 breaths per minute, and a temperature of 36.8°C. On examination the patient was conscious and oriented, significantly overweight (128 kg, body mass index 39 kg/m²) and in obvious discomfort. The scrotal skin appeared oedematous with a foul-smelling necrotic lesion, 10x6 cm extending posteriorly towards the anus. The lesion was black/green and surrounded by erythema. There was another area of indurating erythematous cutaneous oedema in the left suprapubic area, 5x4 cm, although this was not necrotic on inspection. Under high suspicion of Fournier’s gangrene, an urgent urology review was requested. Bloods taken on arrival were indicative of a severe inflammatory response (C-reactive protein 430 mg/litre, white cell count 20.5x109/ litre, neutrophils 19.0x109/litre), and stage II acute kidney injury (urea 17.5 mmol/litre, creatinine 201 μmol/litre). Venous blood gas showed a metabolic acidosis (pH 7.37) with a raised lactate level (3.71 mmol/litre). Blood cultures were taken, which revealed ‘no growth’. The patient was started on intravenous metronidazole, gentamicin and piperacillin/ tazobactam before surgery. In theatre, he underwent a rapid sequence induction, followed by a nasogastric tube, arterial line and triple lumen central line insertion. The surgical debridement and washout left the patient with three open wounds: one in the sacral area (25x17 cm), one in the perineum (10x6 cm), and one in the left suprapubic area (5x4 cm). All wounds were composed of viable tissue
and were left open at the end of surgery. Intraoperatively, the patient received 7 litres of crystalloid fluid resuscitation, and was subsequently commenced on noradrenaline vasopressor support. Following surgery, the patient was transferred to the intensive care unit, where he remained intubated and ventilated in anticipation of a second procedure. Following microbiology advice, the antibiotics were changed to clindamycin (1.2 g 6-hourly), benzylpenicillin (1.2 g 6-hourly), metronidazole (500 mg 8-hourly) and gentamicin (150 mg 8-hourly), but despite this, the patient’s noradrenaline requirements continued to increase to 0.45 μg/kg/min. After 15 hours on the intensive care unit the haemodynamically unstable patient went back to theatre for further debridement. On his return to intensive care, the patient received 200 g of Octagam human normal immunoglobulin (100 mg/ml) intravenously in an increasing rate infusion, in addition to the aforementioned antibiotics. Intraoperative tissues were cultured, growing Escherichia coli and Proteus mirabilis, sensitive to gentamicin. Within 2 hours of the initiation of intravenous immunoglobulin, the patient’s requirements for noradrenaline support reduced from 0.44 μg/kg/min to 0.29 μg/ kg/min. This prompt decrease in vasopressor support infers a successful response to intravenous immunoglobulin in this septic patient (Figure 1). Noradrenaline requirements continued to decline over the next 6 hours by 65% (0.44→0.14 μg/kg/min), till discontinuation at 27 hours post-intravenous immunoglobulin initiation. The patient required no additional surgical debridement. In total the patient spent 13 days on the intensive care unit, ten of which he was dependent on ventilatory support. The patient was stepped down to a surgical ward and transferred to a regional plastics centre for reconstructive treatment.
© 2017 MA Healthcare Ltd
Introduction
British Journal of Hospital Medicine, September 2017, Vol 78, No 9 © MA Healthcare Ltd. Downloaded from magonlinelibrary.com by 155.198.030.043 on September 14, 2017. Use for licensed purposes only. No other uses without permission. All rights reserved.
Case Report Figure 1. Patient’s vasopressor requirement to maintain mean arterial pressure above 70 mmHg as a function of time.
■■ Early surgical debridement with the use
Intravenous immunoglobulin infusion
0.5
Noradrenaline (µg/min)
0.45
Theatre Start
LEARNING POINTS of several broad-spectrum intravenous antibiotics form the foundation of treatment of necrotizing fasciitis. ■■ A high level of clinical suspicion for
End
necrotizing fasciitis should exist in cases of a clinically septic patient with localized pain in excess of what would be expected based on superficial inspection.
0.4 0.35 0.3
■■ Intravenous immunoglobulin may
0.25
represent a useful adjunctive immunomodulatory therapy in the treatment of necrotizing fasciitis and Fournier’s gangrene.
0.2 0.15 0.1 0.05 0
1 4 7 10 13 16 19 22 25 28 31 34 37 40 43 46 49 52 55 58
© 2017 MA Healthcare Ltd
Time spent on intensive care unit (hours)
streptococci (Sarani et al, 2009; Wang et al, 2015). Binding neutralizes the cytokine- inducing properties of the exotoxin, thereby reducing the systemic inflammatory response (Norrby-Teglund et al, 1998). The evidence supporting the use of intravenous immunoglobulin in the treatment of Gram-negative necrotizing fasciitis is limited, but a meta-analysis has shown an overall reduction in mortality in cases of Gram-negative sepsis when intravenous immunoglobulin was used as an adjunctive treatment (Laupland et al, 2007). Small retrospective studies have shown a survival benefit for the use of intravenous immunoglobulin in streptococcal toxic shock syndrome caused by group A streptococci (Kaul et al, 2009), but randomized controlled trials have not been able to reproduce this finding in necrotizing fasciitis (Darenberg et al, 2003). The majority of the literature supporting the use of intravenous immunoglobulin in necrotizing fasciitis is therefore limited to individual case studies (Raithatha and Bryden, 2012; Koch et al, 2015), but metaanalysis of these data supports its use in critically ill adults with sepsis secondary to necrotizing fasciitis. Notably, there are no published case reports or trial data detailing the use of intravenous immunoglobulin to successfully treat Fournier’s gangrene.
Fournier’s gangrene is frequently polymicrobial in nature with an average of three to four causative agents isolated (Yaghan et al, 2000); both aerobic and anaerobic bacteria have been found, including coliforms, Klebsiella spp., streptococci and staphylococci (Thwaini et al, 2006).
Conclusions This article demonstrates that administration of intravenous immunoglobulin enabled a marked reduction of vasopressor requirements in a critically ill septic patient with Fournier’s gangrene. The therapy was administered alongside the conventional treatment regimen, and as such the authors do not ascribe the therapeutic benefits to the intervention of intravenous immunoglobulin alone. However, further studies should be conducted to assess the efficacy of this treatment as an adjunctive therapy in Fournier’s gangrene and other varieties of necrotizing fasciitis. BJHM Anaya D, Dellinger E (2007) Necrotizing softtissue infection: diagnosis and management. Clin Infect Dis 44(5): 705–710. https://doi. org/10.1086/511638 Darenberg J, Ihendyane N, Sjölin J et al; StreptIg Study Group (2003) Intravenous immunoglobulin G therapy in streptococcal toxic shock syndrome: a European randomized, double-blind, placebo-controlled trial. Clin Infect Dis 37(3): 333–340. https://doi. org/10.1086/376630 Kaul R, McGeer A, Norrby-Teglund A et al;
British Journal of Hospital Medicine, September 2017, Vol 78, No 9
The Canadian Streptococcal Study Group (1999) Intravenous immunoglobulin therapy for streptococcal toxic shock syndrome - a comparative observational study. Clin Infect Dis 28(4): 800–807. https://doi. org/10.1086/515199 Koch C, Hecker A, Grau V, Padberg W, Wolff M, Henrich M (2015) Intravenous immunoglobulin in necrotizing fasciitis – A case report and review of recent literature. Ann Med Surg (Lond) 4(3): 260–263. https://doi.org/10.1016/j. amsu.2015.07.017 Laupland KB, Kirkpatrick AW, Delaney A (2007) 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 35(12): 2686–2692. https://doi.org/10.1097/01. CCM.0000295312.13466.1C Norrby-Teglund A, Basma H, Andersson J, McGeer A, Low DE, Kotb M (1998) Varying titers of neutralizing antibodies to streptococcal superantigens in different preparations of normal polyspecific immunoglobulin G: implications for therapeutic efficacy. Clin Infect Dis 26(3): 631–638. https://doi. org/10.1086/514588 Raithatha A, Bryden D (2012) Use of intravenous immunoglobulin therapy in the treatment of septic shock, in particular severe invasive group A streptococcal disease. Indian J Crit Care Med 16(1): 37–40. https://doi.org/10.4103/09725229.94433 Sarani B, Strong M, Pascual J, Schwab CW (2009) Necrotizing fasciitis: current concepts and review of the literature. J Am Coll Surg 208(2): 279–288. https://doi.org/10.1016/j. jamcollsurg.2008.10.032 Thwaini A, Khan A, Malik A, Cherian J, Barua J, Shergill I, Mammen K (2006) Fourniers gangrene and its emergency management. Postgrad Med J 82(970): 516–519. https://doi.org/10.1136/ pgmj.2005.042069 Wang J, McQuilten ZK, Wood EM, Aubron C (2015) Intravenous immunoglobulin in critically ill adults: when and what is the evidence? J Crit Care 30(3): 652.e9–652.e16. https://doi. org/10.1016/j.jcrc.2015.01.022 Yaghan RJ, Al-Jaberi TM, Bani-Hani I (2000) Fournier’s gangrene. Dis Colon Rectum 43(9): 1300–1308. https://doi.org/10.1007/ BF02237442
531
© MA Healthcare Ltd. Downloaded from magonlinelibrary.com by 155.198.030.043 on September 14, 2017. Use for licensed purposes only. No other uses without permission. All rights reserved.
