A subset of patients from the 2008 Vasopressin and Septic Shock Trial (VASST) trial had invasive haemodynamic monitoring measurements from pulmonary artery catheters. These data have now been analysed, revealing that vasopressin was associated with a lower heart rate compared with norepinephrine (noradrenaline) alone, without significant difference in cardiac index or stroke volume index. However, there was significantly greater use of inotropic drugs in the vasopressin group compared with the norepinephrine group.
Tachycardia and high quantities of catecholamine infusion are both associated with mortality in sepsis. The authors discuss:
“The idea of decatecholaminization, reducing both endogenous and exogenous adrenergic stimulation, is now believed to be an important treatment strategy, and the use of beta-blockers in septic shock is being considered. The early use of vasopressin or speciﬁc V1a receptor agonists in early septic shock may be another possible treatment.”
This interesting post-hoc analysis may help further define the patients in whom vasopressin is to be considered, by those clinicians who are using it in septic shock. For those that aren’t, I wouldn’t worry about it.
The cardiopulmonary effects of vasopressin compared with norepinephrine in septic shock
Chest. 2012 Sep;142(3):593-605
BACKGROUND: Vasopressin is known to be an effective vasopressor in the treatment of septic shock, but uncertainty remains about its effect on other hemodynamic parameters.
METHODS: We examined the cardiopulmonary effects of vasopressin compared with norepinephrine in 779 adult patients with septic shock recruited to the Vasopressin and Septic Shock Trial. More detailed cardiac output data were analyzed for a subset of 241 patients managed with a pulmonary artery catheter, and data were collected for the first 96 h after randomization. We compared the effects of vasopressin vs norepinephrine in all patients and according to severity of shock (< 15 or ≥ 15 μg/min of norepinephrine) and cardiac output at baseline.
RESULTS: Equal BPs were maintained in both treatment groups, with a significant reduction in norepinephrine requirements in the patients treated with vasopressin. The major hemodynamic difference between the two groups was a significant reduction in heart rate in the patients treated with vasopressin (P < .0001), and this was most pronounced in the less severe shock stratum (treatment × shock stratum interaction, P =.03). There were no other major cardiopulmonary differences between treatment groups, including no difference in cardiac index or stroke volume index between patients treated with vasopressin and those treated with norepinephrine. There was significantly greater use of inotropic drugs in the vasopressin group than in the norepinephrine group.
CONCLUSIONS: Vasopressin treatment in septic shock is associated with a significant reduction in heart rate but no change in cardiac output or other measures of perfusion.
Inpatient paediatric teams can be scornful when bronchodilators are given by ED staff to wheezing infants, correctly referring to the lack of evidence of clinical benefit(1). There is however a persisting meme out there I’ve heard on a number of occasions that ‘young infants don’t have the receptors so inhaled beta agonists will never work.’ I’d love to know where this comes from.
Apparently, beta 2-receptors are present from the 16th gestational week(2). Pulmonary function testing of ventilated, very-low-birth-weight babies has shown that some consistently responded to beta-agonists whereas others did not(3). A newly published study reports that a quarter of mechanically ventilated infants with bronchiolitis were responders to inhaled albuterol, defined as a reduction in respiratory system resistance more than 30% below baseline(4).
In summary: beta-agonist bronchodilators have not been shown to improve clinical outcomes in wheezing infants. However some infants with some wheezing disorders will show a response in terms of pulmonary function. The receptors are there, and in life-threatening presentations bronchodilators should certainly be considered.
1. Short acting beta agonists for recurrent wheeze in children under 2 years of age
Cochrane Database Syst Rev. 2002;(3):CD002873
BACKGROUND: Wheeze is a common symptom in infancy and is a common cause for both primary care consultations and hospital admission. Beta2-adrenoceptor agonists (b2-agonists) are the most frequently used as bronchodilator but their efficacy is questionable.
OBJECTIVES: To determine the effectiveness of b2-agonist for the treatment of infants with recurrent and persistent wheeze.
SEARCH STRATEGY: Relevant trials were identified using the Cochrane Airways Group database (CENTRAL), Medline and Pubmed. The database search used the following terms: Wheeze or asthma and Infant or Child and Short acting beta-agonist or Salbutamol (variants), Albuterol, Terbutaline (variants), Orciprenaline, Fenoterol
SELECTION CRITERIA: Randomised controlled trials comparing the effect of b2-agonist against placebo in children under 2 years of age who had had two or more previous episodes of wheeze, not related to another form of chronic lung disease.
DATA COLLECTION AND ANALYSIS: Eight studies met the criteria for inclusion in this meta-analysis. The studies investigated patients in three settings: at home (3 studies), in hospital (2 studies) and in the pulmonary function laboratory (3 studies). The main outcome measure was change in respiratory rate except for community based studies where symptom scores were used.
MAIN RESULTS: The studies were markedly heterogeneous and between study comparisons were limited. Improvement in respiratory rate, symptom score and oxygen saturation were noted in one study in the emergency department following two salbutamol nebulisers but this had no impact on hospital admission. There was a reduction in bronchial reactivity following salbutamol. There was no significant benefit from taking regular inhaled salbutamol on symptom scores recorded at home.
REVIEWER’S CONCLUSIONS: There is no clear benefit of using b2-agonists in the management of recurrent wheeze in the first two years of life although there is conflicting evidence. At present, further studies should only be performed if the patient group can be clearly defined and there is a suitable outcome parameter capable of measuring a response.
2. The beta-2-agonists in asthma in infants and young children
Arch Pediatr. 2002 Aug;9 Suppl 3:384s-389s
Beta 2-agonists, by inducing a fast and long relaxation of the bronchial smooth muscle, are considered as the more potent bronchodilators. beta 2-receptors are present from the 16th gestational week, explaining a possible bronchial response in the youngest children. beta 2-agonists do not induce any bronchodilator response in healthy children. Short-acting beta 2-agonists (salbutamol or albuterol, terbutaline) are indicated for asthma attacks, as needed in chronic asthma, and for prevention of symptoms during effort. They are safe and secure. The more efficient route of administration in preschool children is pressurized metered-dose inhaler used with a spacer device. Therefore, whatever the route of inhalation chosen (inhalation, injection, or continuous nebulization in acute asthma attack), more specified indications and doses are needed in young children. Long-acting beta 2-agonists (formoterol, salmeterol) are not authorized in France in children under 4 to 5 years of age depending on the drug used. Because of new oral formulations and recent considerations about their use in asthma attack, instead of short-acting beta 2-agonists, their indication in preschool asthmatic children might be reconsidered.
3. Use of a beta-agonist in ventilated, very-low-birth-weight babies: a longitudinal evaluation
Dev Pharmacol Ther. 1990;15(2):61-7
To determine if there is a specific postnatal (PNA) or postconceptional age (PCA) at which ventilated preterm infants respond to beta-agonists, we evaluated 15 infants with a mean gestational age of 26.5 +/- 1.5 weeks and mean birth weight of 0.89 +/- 0.23 kg who required mechanical ventilation at 10 days of age. Weekly pulmonary function testing (PFT) was performed before and 1 h after administration of albuterol. Taking the group as a whole, as well as individual babies, regression analysis showed no relationship between positive response and either PNA or PCA. Evaluation of individual infants, however, showed that some consistently responded to beta-agonists whereas others did not. We recommend individual PFT to identify those infants who will benefit from use of beta-agonists.
4. Pulmonary mechanics following albuterol therapy in mechanically ventilated infants with bronchiolitis
J Asthma. 2012 Sep;49(7):688-96
BACKGROUND AND AIMS: Bronchiolitis is a common cause of critical illness in infants. Inhaled β(2)-agonist bronchodilators are frequently used as part of treatment, despite unproven effectiveness. The purpose of this study was to describe the physiologic response to these medications in infants intubated and mechanically ventilated for bronchiolitis.
MATERIALS AND METHODS: We conducted a prospective trial of albuterol treatment in infants intubated and mechanically ventilated for bronchiolitis. Before and for 30 minutes following inhaled albuterol treatment, sequential assessments of pulmonary mechanics were determined using the interrupter technique on repeated consecutive breaths.
RESULTS: Fifty-four infants were enrolled. The median age was 44 days (25-75%; interquartile range (IQR) 29-74 days), mean hospital length of stay (LOS) was 18.3 ± 13.3 days, mean ICU LOS was 11.3 ± 6.4 days, and mean duration of mechanical ventilation was 8.5 ± 3.5 days. Fifty percent (n = 27) of the infants were male, 81% (n = 44) had public insurance, 80% (n = 41) were Caucasian, and 39% (n = 21) were Hispanic. Fourteen of the 54 (26%) had reduction in respiratory system resistance (Rrs) that was more than 30% below baseline, and were defined as responders to albuterol. Response to albuterol was not associated with demographic factors or hospitalization outcomes such as LOS or duration of mechanical ventilation. However, increased Rrs, prematurity, and non-Hispanic ethnicity were associated with increased LOS.
CONCLUSIONS: In this population of mechanically ventilated infants with bronchiolitis, relatively few had a reduction in pulmonary resistance in response to inhaled albuterol therapy. This response was not associated with improvements in outcomes.
Prescribing in the critically ill patient can be a challenge due to a number of factors impacting on pharmacology:
- variable enteral absorption and interaction with enteral feed
- less protein binding in hypoalbuminaemic states
- extravascular volume expansion with fluid loading and capillary leak can alter the volume of distribution
- altered hepatic metabolism of drugs
- impaired renal excretion
- accumulation of toxic metabolites
- removal by renal replacement therapy
- interaction with other drugs
There’s another factor to bear in mind, though, which has been recently highlighted in the context of antibiotic prescription: that of Augmented Renal Clearance (ARC).
Some ICU patients have supraphysiologic renal function. Several studies have demonstrated significant numbers of ICU patients with higher than normal creatinine clearance. This is thought to be due to varying combinations of the following factors:
- Low systemic vascular resistance and increased cardiac output leading to increased renal blood flow
- Above factors enhanced by aggressive fluid and vasoactive therapy in pursuit of haemodynamic targets
- These lead to increase delivery of solute to the kidneys and increased clearance
This can have implications for prescribing: the serum creatinine will not identify these patients, but it is possible that ARC will result in less effective therapy for a given dose of a renally-excreted drug, for example beta-lactam antibiotics.
An editorial by critical care physician Dr Andrew Shorr highlights the inadequacy of basing prescribing recommendations on data from the ex-vivo interaction between drug and pathogen:
‘To believe that all patients will respond in the same fashion and with the same trajectory is to become handcuffed by the median response noted in clinical trials……….The central fallacy of the bug-drug approach is that it misses the key role of the host.’
Sub-therapeutic initial β-lactam concentrations in select critically ill patients: association between augmented renal clearance and low trough drug concentrations
Chest. 2011 Dec 22. [Epub ahead of print] Free Full Text
Antibiotics in the critically ill: the bug, drug, host triad
Chest. 2012 Jul 1;142(1):8-10 Free Full Text