Diagnostic aid quickly and reliably identifies respiratory pathogens in critically ill children

16th January 2023

A molecular diagnostic aid provides reliable and fast respiratory pathogen identification in mechanically ventilated children with pneumonia

A diagnostic aid based on polymerase chain reactions (PCR), that uses a 52-pathogen custom array card, has been found to provide both rapid (compared to blood culture) and reliable information on respiratory infections in critically ill, mechanically ventilated children, according to a study by UK researchers.

Respiratory tract infections are responsible for a large number of admissions to paediatric intensive care units. Moreover, an intensive care unit is unique environment and for which clinicians often make decisions to use antibiotics with some degree of diagnostic uncertainty. This was clearly illustrated in one study of paediatric intensive care unit children, where despite most critically children receiving antimicrobial therapy, infection was often not microbiologically confirmed. While in many cases, respiratory infections are viral in nature, it is necessary to utilise methods such as quantitative PCR, as a diagnostic aid to identify the presenting pathogens. In fact, a recent study in adults found that multiplex bacterial PCR examination of bronchoalveolar lavage, reduced the duration of inappropriate antibiotic therapy of patients admitted to hospital with pneumonia and who were at risk of Gram-negative infection. In the current study, researchers made use of the TaqMan Array Card (TAC) as a diagnostic aid which is a microfluidic quantitative PCR system comprising of 384 wells containing pre-aliquoted customised primer and probe combinations. The aid has been previously shown to be of value in supporting ventilator-associated pneumonia (VAP) diagnosis in adults. Nevertheless, it has not been examined in critically ill children and therefore, the aim of the present study was to assess the utility of TAC to identify bacterial and fungal respiratory pathogens in critically ill children with suspected community acquired pneumonia or VAP. The study recruited children ≤ 18 years of age and if they were mechanically ventilated and had commenced or were commencing antimicrobial therapy for a lower respiratory tract infection. The researchers determined the sensitivity and specificity of TAC to detect bacterial and fungal pathogens causing lower respiratory tract infections and the time to a result provided by TAC compared to standard microbiology cultures. Secondary objectives included a description of the micro-organisms detected by TAC but not by microbiology culture as well as the impact of TAC on antimicrobial decision-making.

Diagnostic aid and outcomes

A total of 100 children with a median age of 1.2 years (58% male) were included in the study and of whom, 80 had suspected community acquired pneumonia and the remainder, hospital acquired pneumonia.

Bacteria were detected more frequently on TAC compared to microbiology cultures (57% vs 18%, p < 0.001)) and In addition, TAC also identified more fungi (17% vs 2%, p < 0.001).

For the detection of bacterial and fungal species, TAC had a sensitivity of 89.5% (95% CI 66.9 – 98.7) and a specificity of 97.9% (95% CI 97.2 – 98.5). The median time to obtain a result for the diagnostic aid was 25.8 hours compared to 110.4 hours for microbiological cultures and overall, TAC was significantly quicker for both positive and negative results (p < 0.001).

Finally, consultants reported a change of prescription in 47% of cases based upon TAC results. Antimicrobial therapy duration was reduced or stopped in 26% of children, extended in16% and the spectrum of treatment was broadened in 17% of cases and reduced in 17%.

The authors concluded that as a diagnostic aid, TAC can be used to reliably detect pathogens quicker than routine culture in critically ill children with suspected lower respiratory tract infections and called for future studies to incorporate antimicrobial decision support and economic analysis.

Citation
Clark JA et al. The rapid detection of respiratory pathogens in critically ill children. Crit Care, 2023

Higher acetylcholinesterase activity associated with delirium during critical illness

12th December 2022

A higher cholinesterase activity in critically ill patients increases the risk of delirium but does not lead to cognitive impairment over time

Increased acetylcholinesterase activity in critically ill patients is associated with an increased risk of being delirious but this does lead to subsequent cognitive impairment following discharge from hospital according to the findings of a prospective study by US researchers.

Delirium is defined as a disturbance of consciousness and cognition that develops over a short period of time (hours to days) and fluctuates over time. Furthermore, it is a common manifestation of acute brain dysfunction in critically ill patients with prevalence as high as 75%. However, more troublesome is the finding from a meta-analysis of 24 studies, which showed how delirium was significantly associated with long-term cognitive decline in both surgical and nonsurgical patients. The causes of delirium remain uncertain although several pro-inflammatory markers have been found to be elevated in critical ill patients with delirium. A widely held hypothesis has proposed that this inflammatory response seen in critically ill patients is regulated by the cholinergic system, resulting from a deficit of acetylcholine (ACh). The cholinesterase enzyme, acetylcholinesterase (AChE), is found primarily found in synapses and red blood cell membranes and cleaves ACh in the synaptic cleft, terminating the transmission of a stimulus. Although the primary neurotransmitter of the cholinergic system is acetylcholine, this cannot be measured directly in clinical settings but the activity of two enzymes, AChE and butyrylcholinesterase (BChE) can be assessed with a decreased activity of the latter, seen in patients with systemic inflammation.

Researchers therefore set out to establish whether there was an association between acute brain dysfunction (i.e., delirium and coma) during critical illness and the activity of these two enzymes as well as if enzyme activity levels were predictive of long-term cognitive impairment, disability, and health-related quality of life in survivors of critical illness. Blood samples were taken on days 1 (study enrolment), 3, 5 and 7 while in the hospital to measure the activity of both enzymes. In addition, patients were assessed for delirium and/or coma twice daily until discharged from the intensive care unit IICU) and then once daily after ICU discharge.

Cholinesterase activity, delirium and cognitive impairment

A total of 272 patients with a median age of 56 (56% male) and a median Sequential Organ Failure Assessment score at enrolment of 8, were included in the analysis. Overall, 15% of the cohort died within the hospital and 23% within 90 days of enrolment.

Measurement showed that a higher AChE enzyme activity level was associated with a higher odd of delirious status on the same day (p = 0.045), but not comatose mental status (p = 0.13). When examining delirium, patients with AChE activity at the 75th percentile compared to those with values at the 25th percentile example, had 64% increased odds of developing delirium (odds ratio, OR = 1.64, 95% CI 1.11 – 2.43, p = 0.045). However, when AChE levels were normalised per gram of haemoglobin (since AChE is found in synapses and on red blood cell membranes), this relationship was no longer significant (OR = 1.20, 95% CI 0.95 – 1.52, P = 0.21).

A further finding was how patients in the 75^th percentile of BChE activity, had 44% higher odds of having more days alive without delirium or coma, i.e., indicating less brain dysfunction (OR = 1.44, 95% CI 1.06 – 1.94, p = 0.05). Finally, there was no significant association between any of the cholinesterase enzymes with cognitive impairment, disability, or quality of life after discharge.

The authors concluded that plasma cholinesterase activity was predictive of acute brain dysfunction during critical illness but not long-term impairments. They suggested that future studies need to examine whether cholinergic modulation in selected patients identified by plasma cholinesterase activity, could reduce acute brain dysfunction.

Citation
Hughes CG et al. Association between cholinesterase activity and critical illness brain dysfunction. Crit Care 202

Review finds vitamin D administration linked to favourable outcomes in critical care patients

16th September 2022

Vitamin D administration produces significantly reduces mortality, intensive care stay and mechanical ventilation in critical care patients

Vitamin D administration to critical care patients leads to a significant reduction in mortality, the length of stay in critical care and the need for mechanical ventilation according to the findings of a systematic review and meta-analysis by European and Canadian researchers.

Except for rare circumstances such as the complete absence of UV radiation, the human body can synthesise vitamin D. Whilst the vitamin is known to play a role in the regulation of calcium and phosphate levels in circulation, the active metabolite of vitamin D, calcitriol, has been found in vitro to up-regulate different anti-inflammatory pathways. Furthermore, as dysregulated host immune responses to infection often occur, leading to sepsis, multiple organ failure, and death, vitamin D deficiency appears to be associated with an increased susceptibility of sepsis. In fact, a 2020 meta-analysis suggested that severe vitamin D deficiency may be independently associated with increased mortality in adult patients with sepsis. Nevertheless, based on the currently available evidence, it seems that correction of a deficiency, through high dose vitamin D administration to critically ill patients does not reduce hospital length of stay, hospital mortality, or 6-month mortality compared to placebo, unless patients had severe deficiency of the vitamin. Despite this, one small trial in 36 patients with COVID-19, did find that high dose (300,000 IU) vitamin D administration to intensive care patients, decreased the length of stay and duration of mechanical ventilation. 

Given this uncertainty, for the present study, researchers undertook a systematic review and meta-analysis of clinical outcomes in critically ill patients given vitamin D. They focused on randomised trials that included adults treated within an intensive care unit and for whom vitamin D administration or its metabolite, was provided via either an enteral or parenteral route. Studies were also required to have a comparator group who received standard care and which reported on the outcomes of interest, i.e., mortality, length of intensive care unit (ICU) and hospital stay or the duration of mechanical ventilation. The primary outcome of interest was overall mortality, whereas secondary outcomes were hospital and ICU length of stay and the duration of mechanical ventilation.

Vitamin D administration and critical care outcomes

A total of 16 studies with 2449 patients were included in the analysis. Only 12 studies included vitamin D deficient patients (i.e., < 30 ng/mL) whereas the remaining 4 studies did not specify a threshold.

In terms of mortality, vitamin D administration was associated with a 22% reduced risk of death compared to placebo (risk ratio, RR = 0.78, 95% CI 0.62 – 0.97, p = 0.03). With respect to ICU length of stay, vitamin D supplementation lead to a mean difference in length of stay (compared to placebo) of 3.13 days (95% CI -5.36 to – 0.89, p = 0.006). Based on 7 studies, the length of hospital stay was no different to placebo. Finally, vitamin D administration was significantly associated with a reduction in the number days for which patients required mechanical ventilation (mean difference = -5.07 days, 95% CI -7.42 to -2.73, p < 0.0001). There was also an important effect of the route of administration, with parenteral having a more significant effect on mortality compared to the enteral route.

The authors concluded that vitamin D administration may be associated with a lower mortality among critically ill patients. However, they added that since several smaller and inconsistent studies with an inherent risk of bias were included, larger and more definitive trials were needed to support the findings regarding the type of supplementation and specific populations that achieve the greatest benefit.

Citation
Menger J et al. Administration of vitamin D and its metabolites in critically ill adult patients: an updated systematic review with meta-analysis of randomized controlled trials Crit Care 2022