University of Michigan
Department of Pediatrics
Evidence-Based Pediatrics Web Site

Question

• In mechanically ventilated preterm infants, is 5% albumin more effective than normal saline as volume replacement therapy for the treatment of hypotension?

Clinical Bottom Lines

1. There was no detectable difference in the effectiveness of albumin versus normal saline for the treatment of hypotension in preterm infants in one small study.
2. Normal saline has an advantage of causing less fluid retention in the first 48 hours.
3. Unlike colloids (i.e. albumin), crystalloids (i.e. normal saline) are non-biological products and therefore pose a much lower risk of infection.
4. The cost of albumin is approximately twenty times higher than normal saline.
5. The above findings suggest that the use of normal saline is as effective as albumin in treating hypotension.
6. Albumin was associated with higher weight gain.
7. Adult studies suggest other risks of albumin.
8. More research with a larger sample size and longer duration of follow-up is needed to detect potential differences in mortality including chronic lung disease, intraventricular hemorrhage, patent ductus arteriosus, and necrotizing enterocolitis.

Summary of Key Evidence

1. This was a randomized controlled trial. It was not blinded.¹
2. 63 preterm infants were enrolled with the following inclusion criteria: 1) gestational age < 34 weeks, 2) birth weight < 2kg, 3) mechanically ventilated, 4) presence of hypotension within the first 2 hours of life, and 5) absence of fluid replacement or inotropic support during resuscitation at birth.
3. Exclusion criteria for the study were: 1) infants whose mothers had received anti-hypertensive medication within 24 hours of delivery, 2) infants with severe congenital anomalies, and 3) infants with cyanotic congenital heart disease or with lesions involving the left ventricular outflow tract.
4. Study Design: Arterial blood pressure was monitored from birth continuously through an indwelling arterial catheter or, when this was not available, a blood pressure cuff at 15 minute intervals. Hypotensive infants were randomly assigned into 2 groups. Group 1 was given volume expander in the form of 5% albumin at a dose of 10ml/kg while group 2 received normal saline at a dose of 10ml/kg. Each group received a maximum of 3 doses of volume expander if an infant remained hypotensive >30 min after completion of the previous infusion. Those infants who remained hypotensive after receiving 3 doses of the respective volume expander were started on continuous dopamine at 5mcg/kg/min initially with a maximum dose of 20mcg/kg/min. If an infant remained hypotensive on maximum dopamine, they were given additional volume expander in the form of 5% albumin regardless of group.
5. There was no difference in the key characteristics (gestational age, birth weight, Apgar scores, pretreatment MAP, pretreatment oxygenation status, presence of RDS, or presence of sepsis) of the study infants in each group.
6. No difference was seen in the number of infants requiring inotropic support between the albumin (59%) and the normal saline group (58%).
7. After inotropic support was initiated, the albumin group required more volume expander to maintain normal blood pressure (27.5ml vs. 10ml, p=0.0187).
8. No significant difference in mean arterial pressure or ventilation requirement was measured between the albumin group and the normal saline group.
9. The albumin group had a higher mean percentage weight gain within the first 48 hours of life (5.9% vs. 0.9%).
10. Although the study was likely not powered to detect differences in long-term outcomes, there were no differences seen in mortality and complication rates including chronic lung disease, intraventricular hemorrhage, patent ductus arteriosus, and necrotizing enter colitis between the 2 groups.
11. Disadvantages of this study: 1) The use of albumin in the normal saline group if additional volume expander was required after the first 3 doses - this "treatment contamination" may have reduced the study's ability to detect differences in outcomes such as weight gain, oxygenation status and the development of chronic lung disease. 2) The study included a small sample size. Thus, it was underpowered to demonstrate more modest differences in failure rates between the groups and it was not powered to demonstrate differences in long-term outcomes between the albumin and the normal saline group. 3) The study was not blinded and this may be an additional source of bias.

Additional Comments

• A systematic review of randomized controlled trials of human albumin administration in critically ill adult patients with hypovolemia, burns or hypoalbuminia strongly suggested that albumin increases mortality.²
• Additionally, meta-analysis of studies on fluid resuscitation in adult patients has shown an association between the use of colloids and a higher mortality in patients with capillary leak syndrome and adult respiratory distress syndrome.³
• In another meta-analysis studying morbidity, 9 of 71 trials included were performed in high-risk neonates. The relative risk for morbidity with albumin administration was 0.82% (95% confidence interval of 0.66-1.01). However, only 2 of these 9 RCTs specifically studied the administration of albumin vs NS for the treatment of hypotension. Many of the other 7 were looking at albumin in premature infants with hypoproteinemia/ hypoalbuminemia. In the 2 trials that specifically addressed albumin vs NS for the treatment of hypotension, a total of 74 events occurred in the albumin group vs 61 events in the normal saline group. Therefore, there may be selective situations where albumin may reduce morbidity and others where it is harmful. Further research will need to be done to delineate these clinical situations.⁴
• In sick preterm infants and in older patients with "capillary leak syndrome", the net flow of fluid across the capillary may be independent of the oncotic pressure between intravascular and extra vascular compartments. In these patients plasma protein infused may leak into the interstitial space, resulting in interstitial edema. In infants with RDS, presence of edematous fluid and extravasation of plasma protein into the alveolar space may cause inactivation of surfactant, deterioration in lung mechanics, and inflammatory reactions that may lead to development of chronic lung disease.
• A similar study to the one I chose was done at the University of Michigan in 2003. In this study, 41 infants < 24 hours old were randomized to receive either 5% albumin or normal saline as volume expander for the treatment of hypotension. No difference was seen in response to treatment measured by the need for a second bolus (43% vs. 35%, p=0.444) or the need to go on inotropic support (19% vs. 15%, p=0.697).
  This is another study which concluded that normal saline is as effective as albumin for the treatment of hypotension in the newborn infant.⁵
• Speculative risks with albumin administration in neonates exist based on the results of adult studies. Therefore, additional research with a larger sample size is needed to detect differences in mortality and complication rates including: chronic lung disease, intraventricular hemorrhage, patent ductus arteriosus, and necrotizing enterocolitis.
  

Citation

1. So KW, Fok TF, Ng PC, Wong WW, Cheung, KL. Randomised controlled trial of colloid or crystalloid in hypotensive preterm infants. Arch Dis Child Fetal Neonatal Ed 1997; 76:F43-6.
2. Cochrane Injuries Group Albumin Reviewers. Human albumin administration in critically ill patients: systematic review of randomised controlled trials. BMJ 1998; 317: 235-40.
3. Velanovich V. Crystalloid versus colloid fluid resuscitation: A meta-analysis of mortality. Surgery 1989; 105: 65-71.
4. Vincent JL, Navickis, RJ, Mahlon, MW. Morbidity in hospitalized patients receiving human albumin: A meta-analysis of randomized, controlled trials. Critical Care Medicine 2004; 32 (10): 2029-2038.
5. Oca MJ, Nelson MN, Donn, SM. Randomized trial of normal saline versus 5% albumin for the treatment of neonatal hypotension. Journal of Perinatology 2003; 23: 473-476.
   

CAT Author: Michelle Robida, MD

CAT Appraisers: Alex Kemper, MD

Date appraised: May 31, 2006