Fluid Bolus Increases Mortality in Children with Severe Febrile Illness and Impaired Perfusion in Low-Resource Settings

DynaMed Weekly Update - Volume 6, Issue 27

Early fluid resuscitation is recommended for hemodynamic support in critically ill children (Crit Care Med 2008 Jan;36(1):296), but there has been little evidence to guide the type, timing and volume of fluids to use, especially in children who are not severely hypotensive or dehydrated. The FEAST trial evaluated the use of fluid boluses (saline or albumin) in severely ill children in Uganda, Kenya and Tanzania. A total of 3,141 children (57% positive for malaria parasitemia) without severe hypotension (moderate hypotension in 6%, dehydration in 7%) were randomized to 1 of 3 fluid bolus strategies for initial fluid resuscitation: 0.9% saline solution 20 mL/kg IV over 1 hour vs. 5% albumin solution 20 mL/kg IV over 1 hour vs. no bolus (the initial bolus in the saline and albumin groups was increased to 40 mL/kg after a trial protocol amendment). All children had severe febrile illness, impaired consciousness and/or respiratory distress, and impaired perfusion. Children were excluded for severe malnutrition, gastroenteritis, noninfectious causes of shock, or contraindication to fluid expansion.

At 48 hours, mortality was increased for both saline (10.5%, p = 0.01, NNH 31) and albumin (10.6%, p = 0.008, NNH 30) compared to placebo (7.3%) (level 1 [likely reliable] evidence). There were no significant differences in the rates of pulmonary edema or increased intracranial pressure. Mortality was also increased in the saline and albumin groups at 4 months (14.6% vs. 15.2% vs. 11.1%, p = 0.01), with an NNH of 30 for saline and 28 for albumin. There were no significant differences between saline and albumin, and subgroup analyses did not find any subgroup demonstrating benefit for fluid bolus. An additional group of 29 severely hypotensive children, for whom it was considered unethical to withhold fluids, were randomized to saline vs. albumin and showed no significant differences in mortality between the 2 bolus strategies (69% vs. 56%) (N Engl J Med 2011 Jun 30;364(26):2483).

This trial has immediate implications for care in low-resource settings, but also raises questions about the standard practice of fluid resuscitation in other settings where benefits have yet to be proven.

For more information, see the Fever without apparent source in children aged 3-36 months and Sepsis treatment in children topics in DynaMed.


Varenicline May Be Associated with Small Increased Risk of Cardiovascular and Psychiatric Adverse Events

The FDA recently announced a labeling change for the smoking cessation aid varenicline (Chantix) concerning cardiovascular risks (FDA MedWatch 2011 Jun 16). The concern arose largely from a trial in which 714 patients with stable cardiovascular disease were randomized to varenicline vs. placebo for 12 weeks. Cardiovascular events were reported in 7% of the varenicline group vs. 5.6% of controls, but this difference was not statistically significant (Circulation 2010 Jan 19;121(2):221). The FDA has asked the drug manufacturer to provide a meta-analysis of their safety data for varenicline.

In the meantime, independent investigators reported a systematic review of 14 randomized trials (including the trial above) evaluating the cardiovascular risks of varenicline. The other 13 trials (7,502 patients) all had much lower incidence of cardiovascular events (pooled rates 0.593% vs. 0.237%), though the definition of cardiovascular outcomes varied across studies (level 2 [mid-level] evidence). In meta-analysis of these 13 trials, varenicline was associated with significantly increased risk (odds ratio 2.54, 95% CI 1.26-5.12), but the number-needed-to-harm (NNH) was very high, ranging from 103 to 1,627 (CMAJ 2011 Jul 4 early online).

More concerning than these cardiovascular events may be the risk for psychiatric adverse events. The FDA previously required a Boxed Warning to indicate increased risk of serious neuropsychiatric symptoms including changes in behavior, hostility, agitation, depressed mood, suicidal thoughts and behavior, and attempted suicide (FDA MedWatch 2009 Jul 1). Evidence for the risk of neuropsychiatric events has largely come from case reports, and there have been hundreds of cases reported to the FDA, including 272 cases of completed suicide (ISMP QuarterWatch 2011 May 19;2010(Q3):14 PDF). However, quantifying this risk is uncertain, and the specific association with varenicline is unclear. A cohort study in 2009 with 80,660 patients found similar rates of self-harm among users of varenicline, bupropion and nicotine replacement products (level 2 [mid-level] evidence) (BMJ 2009 Oct 1;339:b3805).

The risks of these potential adverse events must be weighed against the mortality benefit associated with smoking cessation (JAMA 2008 May 7;299(17):2037) and the demonstrated efficacy of varenicline as a cessation aid. In the trial cited by the FDA for cardiovascular risk, the varenicline group had significantly higher rates of confirmed continuous abstinence than the placebo group from 9 weeks to 1 year (19.2% vs. 7.2%, p< 0.0001, NNT 9) (level 1 [likely reliable] evidence). Also, in a Cochrane review, varenicline was associated with higher rates of continuous abstinence compared to placebo (NNT 6-9 at 24 weeks in analysis of 10 trials with 4,443 patients) (level 1 [likely reliable] evidence). The most common adverse events were nausea, headache, and insomnia (Cochrane Database Syst Rev 2011 Feb 16;(2):CD006103).

For more information, see the Varenicline topic in DynaMed.