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Three Part Question

In [neonates requiring intravascular volume replacement/resuscitation] is [use of Gelofusine] [efficacious and safe]?

Clinical Scenario

A neonate born at 26 weeks and weighing 930 g underwent laparotomy on day 21 of life for perforation secondary to necrotising enterocolitis (NEC). He required fluid resuscitation during the procedure and Gelofusine was given rather than normal saline or blood products. We reviewed the evidence for the use of Gelofusine for volume replacement in neonates.

Search Strategy

Search literature: PubMed and Medline 1966–2005, EMBASE 1974–2005, Cinahl 1982–2005 using Dialog Data Star, Google Scholar, Proquest journals.
Search terms: "Gelofusine", "Gelatin" and "Synthetic Colloids".
LIMIT to humans and English Language

Search Outcome

2 papers were relevant to neonates/paediatrics

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Osborn et al, 2004	<32 weeks, <1.5 kg, n = 940 Seven randomised controlled trials comparing the effects of early volume expansion with normal saline, fresh frozen plasma, albumin, plasma substitutes or blood compared to no treatment or another form of volume replacement. Only 1 RCT evaluated use of gelatine based plasma substitute with FFP or no treatment	Systematic Review 1a	Gelatin vs no treatment	No significant differences. were found in mortality (RR 1.22, 95% CI 0.86 to 1.72), ultrasound abnormalities and death or severe disability (RR 1.05, 95% CI 0.82 to 1.34)	Highlights possible adverse outcome with gelatine use in neonates, although wide confidence interval suggests study was underpowered in this regard
			Gelatin vs FFP	No significant difference was found in mortality (RR 1.17, 95% CI 0.83 to 1.64) and death or grade 3–4 P/IVH (RR 1.22, 95% CI 0.89 to 1.67) The rate of NEC was significantly higher (RR 4.92, 95% CI 1.44 to 16.80) and sepsis significantly lower (RR 0.57, 95% CI 0.39 to 0.83) in infants who received the gelatin based plasma substitute compared to FFP
Akech et al, 2006	Children n=88 Children admitted with severe falciparum malaria were allocated to receive albumin or Gelofuscine. Primary outcome: resolution of shock Secondary outcome: mortality and neurological sequelae	Controlled Trial - 2a	Resolution of shock or acidosis between the groups	No significant difference	Paediatric age group, not randomised
			Mortality	lower in patients receiving albumin (1/44; 2.3%) than in those treated with Gelofusine (7/44; 16%) by intention to treat (Fisher exact test, p = 0.06), or 1/40 (2.5%) and 4/40 (10%), respectively, for those treated per protocol (p = 0.36) In children with severe malaria, there was a consistent survival benefit of receiving albumin infusion compared to other resuscitation fluids

Comment(s)

Gelofuscine is a synthetic colloid, which, in recent years, has been increasingly used for volume replacement. The advantages of Gelofuscine are that it is less expensive than other synthetic colloids, is readily available and can be stored for long periods without degradation (Saddler, Salmon). The increased usage is also, perhaps, secondary to perceived increased risk associated with albumin infusions and other blood products (Martin, Cook, Alderson). The effects of Gelofuscine or alternative volume expansion in preterm infants have been subjected to a systematic review which included seven randomised controlled trial (RCTs) (Osborn). Out of these only one RCT investigated the use of Gelofusine for volume expansion in neonates. The Northern Neonatal Nursing Initiative (NNNI) Trial Group in this multicentre study compared the effects of prophylactic administration of fresh frozen plasma (FFP), gelatine and glucose on early mortality and morbidity in preterm infants. We did not find any evidence in the literature regarding objective evaluation of the efficacy of Gelofuscine for volume resuscitation/replacement in neonates. With regard to safety, the NNNI trial did not demonstrate any adverse short term outcomes related to Gelofuscine use. Developmental outcome at 2 years was also similar in the three groups (Tin). However, the Cochrane review by Osborn et al noted that Gelofuscine use or no treatment was associated with increased risk of developing NEC (relative risk (RR) 4.92) when compared to FFP. Although no significant differences in mortality or disability were found in this study and a wide confidence interval suggests an underpowered study, this finding warrants further research. In view of the lack of appropriate studies in neonates and to further elucidate our clinical question, we extended our search to studies in the paediatric and adult population. One RCT has compared volume expansion with Gelofusine and albumin in children with severe malaria. Akech et al noted no significant difference in the resolution of shock or acidosis between the two groups, but fatal neurological events were more common in the group receiving Gelofusine. Five RCTs have reported on the use of Gelofusine in adults( Allison, Ritoo 2004 2005, Schortgen, Haisch) (see supplemental table 1 available at http://adc.bmj.com/supplemental). Allison et al compared the use of gelatine and HES for resuscitation in patients with blunt trauma and suggested that Gelofuscine was associated with a worse post-trauma capillary leak. This may be important in newborns with capillary leak syndrome such as sepsis and NEC, but relevance at present is conjectural. Schortgen et al investigated the effects of gelatine and HES on renal function in adults with severe sepsis and suggested that gelatine is safer in terms of renal function. No impairment of haemostasis was noted by Haisch et al following Gelofuscine use in adults undergoing major abdominal surgery. Rittoo et al in an RCT in adults undergoing abdominal aortic aneurysm surgery noted inferior gas exchange and lung compliance and poorer small lung injury score in the Gelofusine group compared to HES. Whether this has any implications in neonates with unstable lung function and in worsening lung damage needs to be elucidated. Adult studies suggest that Gelofuscine has less antigenic properties and thus a lower chance of hypersensitivity reactions. The other potential disadvantages include the possibility of altered haemostasis (Evans , Coats) and proteinuria (Lundsgaard-Hansen, ten Dam). The relevance of these findings to the neonatal population has not been explored. Although Gelofuscine is readily available and cheap, and less monitoring is required during infusions, there is no evidence to support its efficacy for use in volume expansion in neonates. Moreover, considering the potential side effects in preterm neonates, it should be used with caution until further studies are available to prove its safety and efficacy. This is especially pertinent considering the lack of evidence of any potential superiority of various colloids over normal saline for volume replacement (Boluyt).

Editor Comment

CI, confidence interval; FFP, fresh frozen plasma; NEC, necrotising enterocolitis; P/IVH, peri-intraventricular haemorrhage; RCT, randomised controlled trial; RR, relative risk. (see supplemental table 1 available at http://adc.bmj.com/supplemental) for Adult data

Clinical Bottom Line

There is lack of evidence for the efficacy of Gelofuscine for volume resuscitation in neonates. There is insufficient evidence to support or refute the use of Gelofuscine over fresh frozen plasma or dextrose or no fluid therapy in the context of prophylactic volume replacement in neonates. (Grade B) Weak evidence suggests an increased risk of necrotising enterocolitis with the use of Gelofuscine in neonates. (Grade B) Gelofuscine use should be restricted to a clinical trial setting. (Grade A) A large RCT is needed to evaluate the efficacy and safety of Gelofuscine for volume replacement in neonates.

References

1. Osborn DA, Evans N, et al. Early volume expansion for prevention of morbidity and mortality in very preterm infants. Cochrane Database Syst Rev 2004; (2): CD002055.
2. Akech S, Gwer S, Idro R, et al. Volume expansion with albumin compared to Gelofusine in children with severe malaria: results of a controlled trial. PLoS Clin Trials 2006; 1 (5): e21.
3. Saddler JM, Horsey PJ. The new generation gelatins. A review of their history, manufacture and properties. Anaesthesia 1987; 42 (9): 998–1004.
4. Salmon JB, Mythen MG. Pharmacology and physiology of colloids. Blood Rev 1993; 7 (2): 114–20.
5. Martin G. Conflicting clinical trial data lesson from albumin. Crit Care 2005; 9 (6): 649–50.
6. Cook D. Is albumin safe? N Engl J Med 2004; 350 (22): 2294–6.
7. Alderson P, Bunn F, Li Wan Po A, et al. Human albumin solution for resuscitation and volume expansion in critically ill patients. Cochrane Database Syst Rev 2004; (4): CD001208.
8. The Northern Neonatal Nursing Initiative [NNNI] Trial Group. A randomized trial comparing the effect of prophylactic intravenous fresh frozen plasma, gelatin or glucose on early mortality and morbidity in preterm babies. Eur J Paediatrics 1996; 155 (7): 580–8.
9. Tin W, Wariyar U, Hey E, et al. Randomised trial of prophylactic early fresh-frozen plasma or gelatin or glucose in preterm babies: outcome at 2 years. Lancet 1996; 348: 229–32.
10. Allison KP, Gosling P, Jones S, et al. Randomised trial of hydroxyethyl starch versus gelatine for trauma resuscitation. J Trauma 1999; 47 (6): 1114–21.
11. Rittoo D, Gosling P, Burnley S, et al. Randomised study comparing the effects of hydroxyethyl starch solution with Gelofuscine on pulmonary function in patients undergoing abdominal aortic aneurysm surgery. Br J Anaesth 2004; 92 (1): 61–6.
12. Schortgen F, Lacherade J-C, Bruneel F, et al. Effects of hydroxyethylstarch and gelatin on renal function in severe sepsis: a multicentre randomised study. Lancet 2001; 357: 911–16.
13. Haisch G, Boldt J, Krebs C, et al. The influence of intravascular volume therapy with a new hydroxyethyl starch preparation (6% HES 130/0.4) on coagulation in patients undergoing major abdominal surgery. Anesth Analg 2001; 92 (3): 565–71.
14. Rittoo D, Gosling P, Simms MH, et al. The effects of hydroxyethyl starch compared with Gelofuscine on activated endothelium and the systemic inflammatory response following aortic aneurysm repair. Eur J Vasc Endovasc Surg 2005; 30 (5): 520–4.
15. Evans PA, Glenn JR, Heptinstall S, et al. Effects of gelatine-based resuscitation fluids on platelet aggregation. Br J Anaesth 1988; 81 (2): 198–202.
16. Coats TJ, Brazil E, Heron M. The effects of commonly used resuscitation fluids on whole blood coagulation. Emerg Med J 2006; 23 (7): 546–9.
17. Lundsgaard-Hansen P, Tschirren B. Clinical experience with 120000 units of modified fluid gelatin. Dev Biol Stand 1980; 48: 251–6.
18. ten Dam MA, Branten AJ, Klasen IS, et al. The gelatine-derived plasma substitute Gelofuscine causes low-molecular weight proteinuria by decreasing tubular protein reabsorption. J Crit Care 2001; 16 (3): 115–20.
19. Boluyt N, Bollen W, Bos AP, et al. Fluid resuscitation in neonatal and pediatric hypovolemic shock: a Dutch Pediatric Society evidence-based clinical practice guideline. Intensive Care Med 2006; 32 (7): 995–1003.