Assessment of phosphatemia at admission to the intensive care unit to predict mechanical ventilation among patients with acute exacerbation of chronic obstructive pulmonary disease: a retrospective cohort study

Introduction

Severe acute exacerbation of chronic obstructive pulmonary disease (COPD) is a common cause of admission to the intensive care unit (ICU). It is associated with significant morbidity, mortality, and economic burden (1,2). First line management in ICU consists of the treatment of the triggering factor, if identified, and implementation of non-invasive ventilation (NIV) (2-5). Acute respiratory failure related to COPD exacerbation is a consequence of lung dynamic hyperinflation and increased work of breathing (6). It leads to a higher oxygen and energetic consumption of respiratory muscles that could override the aerobic production of adenosine tri phosphate (ATP) into mitochondria. As a major compound of ATP, phosphate (Ph) could be a simple marker of the intracellular energetic pool (7,8). At the bedside, only plasmatic Ph is easily available. Some studies showed that a low plasmatic Ph concentration is associated with a decreased diaphragmatic contractility (9) and invasive mechanical ventilation (MV) weaning failure (10-12). Dysphosphatemia is a frequent finding in ICU particularly among patient suffering from COPD with a prevalence of hypophosphatemia up to 21.5% (7). Until now, clinical implication of plasmatic Ph concentration at ICU admission (T0-Ph) on respiratory outcomes during acute respiratory failure related to COPD remains unclear. We hypothesize that hypophosphatemia (i.e., below 0.80 mmol/L) at admission to ICU is associated with worse respiratory outcomes. So, the aim of the present study is to investigate the association between T0-Ph and the need for invasive MV among patients with severe acute exacerbation of COPD. We present this article in accordance with the STROBE reporting checklist (available at https://atm.amegroups.com/article/view/10.21037/atm-23-1650/rc).

Methods

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This single-center, observational, retrospective study was approved by the ethics committee of the French Intensive Care Society (No. #20-12) and registered at the French National Institute for Health Data (#MR 2516271119). According to French law, all patients included were informed to the use of their medical data for the study purpose and their right to refusal to participate at any time. Informed consent was sought from the patients upon recovery of competency, in compliance with French law. The 28-bed ICU is in a university-affiliated tertiary hospital in the Paris area with 800 medical and surgical beds.

Patients

We screened all consecutive patients admitted to our ICU between May 2015 and December 2018 with COPD as a confirmed or strongly suspected comorbidity [patient over 40 years old reporting chronic respiratory symptoms due to chronic bronchitis according to Global Initiative for Obstructive Lung Disease (GOLD) criteria (1) and a history of smoking for more than 5 years]. Only patients over 40 years of age admitted for a severe acute exacerbation of COPD were included. COPD was defined according to GOLD criteria (1).

Exclusion criteria were the use of invasive MV before admission to the ICU, patients without T0-Ph plasma measurement, patients deceased in ICU with a decision of do not intubate or do not resuscitate, patients with a specific contraindication of NIV (surgery, deformity or facial trauma, or digestive intolerance with uncontrollable vomiting making NIV impossible), known asthma according to the Global Initiative for Asthma definition (13).

Definition

Severe acute exacerbation of COPD

Severe acute exacerbation of COPD was defined by the presence of acute respiratory failure (clinical signs of excessive muscle activity, polypnea ≥30 breaths/min, or the use of accessory respiratory muscles) and/or hypercapnic acidosis [pH ≤7.35 and carbon dioxide tension (PaCO₂) >45 mmHg], and the need for ICU admission.

Pneumonia

Pneumonia was defined as the presence of at least two of the following criteria: auscultatory crackles, purulent sputum or tracheal suction (for intubated patients), fever >38 ℃, and biological inflammatory syndrome; associated with a new radiological infiltrate (chest X-ray or computed tomography scan).

Bronchitis

Bronchitis was defined as the presence of dyspnoea or cough with purulent expectorations or tracheal suction (for intubated patients) without a new radiological infiltrate.

Phosphatemia

Plasmatic Ph reference value according to our laboratory was 0.80 to 1.15 mmol/L (2.48–3.56 mg/dL).

Patient management

Ventilatory support

According to international guidelines for patients with severe acute exacerbation of COPD, NIV was used as first-line therapy for signs of respiratory failure with respiratory acidosis, e.g., pH ≤7.35 and hypercapnia with PaCO₂ ≥45 mmHg (14). Intermittent NIV was pursued for 24 hours period until clinical improvement with progressive weaning. The formal indications for invasive MV were standardized: (I) NIV failure (neurological worsening with persistent hypercapnic acidosis; respiratory and hypercapnic acidosis worsening; refractory hypoxemia under NIV); (II) cardiac arrhythmias leading to circulatory failure; (III) shock requiring a vasopressor; (IV) cardiopulmonary arrest.

Screening for respiratory tract infection

A search for bacteria with standard methods and for viruses with sensitive methods (i.e., polymerase chain reaction) was performed in all patients admitted for a severe acute exacerbation of COPD in case of suspected respiratory infection according to the standards of care in our ICU at admission.

Plasmatic Ph sample and management

Blood Ph was sampled at ICU admission in our routine practice. In case of abnormal results (i.e., below 0.80 mmol/L or above 1.15 mmol/L) a second sample was performed between 12 and 24 hours later. For patients with T0-Ph below 0.80 mmol/L, an intravenous infusion of Ph was initiated (Phocytan^TM 0.66 mmol/mL, Aguettant, France).

Data collection

All collected data were obtained retrospectively from medical records into a standardized electronic file, secured and anonymized (Excel, Microsoft^©, Redmond, WA, USA). Data collection included age; gender; chronic comorbidities; COPD assessment, triggering factor for the exacerbation; performance status; Simplified Acute Physiology Score II (SAPS II); clinical parameters, neurologic impairment and Glasgow Coma Scale (GCS) at ICU admission; laboratory tests (including electrolytes blood sample, phosphatemia at ICU admission and during the first 24 hours after admission, arterial blood gas); type and duration of ventilatory assistance (oxygen administration, NIV, invasive MV); time from ICU admission to intubation, length of stay in the ICU and in-hospital, and mortality in the ICU. Missing data are reported in the results tables.

Statistical analysis

No specific sample size calculation was made. We include patients from May 2015 as it corresponds to the time of implementation of informatized medical records and prescriptions in the ICU. Quantitative parameters were described as median [interquartile range (IQR)] and qualitative parameters as number (percentage). We compared categorical variables using Fisher’s exact test, continuous variables using the Wilcoxon rank-sum test, and ordered categorical variables using Chi-squared and Kruskal-Wallis tests. We performed logistic regression to identify factors associated with the need for MV. Continuous variables were checked for log-linearity. Non-log-linear variables were transformed into dummy variables according to their inflexion point or median value. The following continuous variables were transformed into binary variables: pH with a cut-off value of 7.33, phosphatemia with a cut-off value of 1.11 mmol/L, and GCS with a cut-off value of 15. Non-collinear variables that yielded P values smaller than 0.001 by univariate analysis or that were clinically relevant were considered for inclusion into a multivariable model. Stepwise model selection guided by the Akaike Information Criterion was performed. The Hosmer-Lemeshow goodness-of-fit test and area under the receiver operating characteristics curve estimated by the C-statistic were computed on the final models. Associations of factors with the need for MV during the ICU stay are reported as odds ratios (ORs) with their 95% confidence intervals (CIs). All tests were two sided, and P values <0.05 were considered significant. The analyses were performed using the R statistical programme, version 4.1.0 (R Foundation for Statistical Computing, Vienna, Austria; http://www.R-project.org).

Results

Patient’s characteristics

Figure 1 is the patient flowchart and Table 1 reports patient characteristics at ICU admission. One hundred and ninety-eight patients were included, of whom 132 (66.7%) were men. The median age was 70 [IQR, 61–77] years; the median SAPS II was 38 [IQR, 31–45]. Nine (4.5%) patients died in the ICU. Among the 167 (84%) patients with available lung spirometry data, 80 (40.4%) had a GOLD classification COPD stage 4, 40 (20.2%) stage 3, 35 (17.7%) stage 2, and 12 (6.1%) stage 1. The main final etiology of exacerbation of COPD was pneumonia in 68 (34.3%), bronchitis in 26 (13.1%), and acute cardiogenic pulmonary oedema in 32 (16.2%) patients. In 29 (14.6%) patients, no trigger was identified. Other causes for exacerbation are described in Table 1.

Figure 1 Patients flow chart. ICU, intensive care unit; COPD, chronic obstructive pulmonary disease; T0-Ph, plasmatic phosphate concentration at ICU admission; MV, mechanical ventilation.

Laboratory findings at admission, patient management and outcomes

Laboratory findings at ICU admission, patient management and outcomes are reported in Table 2. pH was significantly lower and PaCO₂ was higher in patient requiring invasive MV (7.30 vs. 7.34, P=0.0006 and 64 vs. 57 mmHg, respectively, P=0.041) whereas plasmatic bicarbonate concentration was not. Among the 198 patients included, 134 (67.7%) were under NIV and 64 (32.3%) under oxygen therapy at ICU admission. During ICU stay, 33 (16.7%) patients required invasive MV. Median duration of NIV and invasive MV were 3 [IQR, 1–4] and 7 [IQR, 3–13] days respectively. The median time between admission and initiation of invasive MV was 5 [IQR, 2–12] hours. The median length of stay in the ICU for the non-intubated and intubated patients was 5 [IQR, 3–7] and 13 [IQR, 7–19] days, respectively.

Factors associated with the need for invasive MV

Univariate analysis is reported in Table 3. T0-Ph was significantly higher among patient requiring invasive MV compared to those who did not [1.23 (IQR, 1.07–1.41) and 1.09 (IQR, 0.91–1.27) mmol/L; P=0.005]. A T0-Ph >1.11 mmol/L was associated with the need for invasive MV (OR =2.25; 95% CI: 1.14–4.41; P=0.019) whereas T0-Ph <0.80 mmol/L was not (OR =2.38; 95% CI: 0.54–21.9; P=0.38). Other factors were pneumonia (OR =5.66; 95% CI: 2.79–11.5; P=0.0001) and pH <7.33 at ICU admission (OR =2.77; 95% CI: 1.41–5.44; P=0.003).

Table 4 reports the multivariate analysis of factor associated with the need for invasive MV. Pneumonia (OR =6.42; 95% CI: 2.78–15.96; P<0.0001) and previous history of intubation (OR =3.33; 95% CI: 0.97–11.19; P=0.05) were independently associated with the need for invasive MV, whereas T0-Ph was not (OR =1.75; 95% CI: 0.72–4.44; P=0.22).

Variation of phosphatemia after ICU admission according to the ventilatory support

Plasmatic Ph sample at 24 hours was available for 87.9% (29/33) patients that required invasive MV and for 74.5% (123/165) patients who did not. At 24 hours, plasmatic Ph concentration was significantly lower among patients requiring invasive MV as compared to others [0.91 (IQR, 0.7–1.10) and 1.04 (IQR, 0.85–1.21) mmol/L, respectively; P=0.01]. The variation of Ph at 24 hours was significantly lower among non-intubated patients as compared to intubated patients [−0.04 (IQR, −0.225, 0.15) and −0.42 (IQR, −0.53, 0.18) mmol/L, respectively; P=0.0001]. Ph supplementation was administered to eight patients that required MV and in 30 (18.2%) patients in others. The median volume of Ph supplementation (Phocytan^TM 0.66 mmol/mL) was 25 [IQR, 17.5–40] and 30 [IQR, 20–40] mL in patients requiring MV and those not respectively.

Discussion

We aimed to investigate the association between T0-Ph and ventilatory outcomes among patients admitted to the ICU for severe acute exacerbation of COPD. Hypophosphatemia (i.e., T0-Ph <0.80 mmol/L) was not associated with the need for invasive MV. At the contrary, our results showed that T0-Ph was significantly higher in patient requiring invasive MV during ICU stay. However, by multivariate analysis, we found no significant association between T0-Ph and the need for invasive MV. Patients’ characteristics included in our cohort, predominantly men, median age of 70 years old, with pneumonia as main trigger of COPD exacerbation were similar to those of previous large studies on this population (15-18). The rate of patient requiring invasive MV (17%, 33/198) and the median duration of invasive MV (5 days) were similar to other studies (18,19). As compared to previous studies of populations with similar baseline characteristics, we report a lower mortality rate in our study (4.5%) (15,17). This difference could be related to differences in selection criteria for ICU admission and inclusion in the study as only non-intubated patients at ICU admission were included.

Hypophosphatemia is a frequent finding and associated with worse outcomes in ICU (20,21). In a previous study, Aubier et al. measured the transdiaphragmatic pressure at different plasmatic Ph concentration in eight patients receiving invasive MV for acute respiratory failure related to COPD within the 12 hours after admission to ICU. They found a decrease transdiaphragmatic pressure correlated with the level of hypophosphatemia. After Ph supplementation a recovery of the diaphragmatic contractility was observed (9). Similarly, Gravelyn et al. measured the muscular strength in 23 patients recruited from medical and surgical center. Plasmatic Ph level was assessed daily during a 30 days study-period and ranked into normal or hypophosphatemia group (Ph level below 0.80 mmol/L). They found that hypophosphatemia was associated with increased muscular weakness (22). Others clinical studies reported that hypophosphatemia was associated with weaning failure of invasive MV (10-12). In a single-center, prospective study including 100 patients admitted to the ICU, Talakoub et al. found a significant association between plasmatic Ph level at ICU admission and the duration of invasive MV with a Ph level of 1.10 (±0.13) and 0.93 (±0.10) mmol/L in patients receiving invasive MV for less than 5 days and for more than 5 days respectively (P<0.001) (12). Another prospective study including 66 patients showed that the plasmatic Ph concentration was significantly lower among patient who failed their invasive MV weaning trials [relative risk (RR) =1.18; 95% CI: 1.06–1.32; P=0.01] (10). A retrospective study including 67 patients also found that a low plasmatic Ph concentration was associated with an increased risk of invasive MV weaning failure (11). Whereas, hypophosphatemia seems to be frequently associated with worse respiratory outcomes in the literature, our results showed that T0-Ph was higher in patient requiring invasive MV during their stay in. However, it could be explained by several adaptive physiological mechanisms. The increased work of breathing observed in case of severe acute exacerbation of COPD leads to a higher metabolic demand in respiratory muscles (23). Among the most severe patients, ATP synthesis becomes insufficient reflected by a rapid decrease in intracellular ATP and phosphocreatine level. Inorganic Ph and adenosine di-phosphate resulting from the degradation of ATP increase proportionally (24). Patients also develop intracellular acidosis resulting from the increase of both PaCO₂ and lactate production (25,26). This excess of intracellular acid load has to be scavenged and inorganic Ph (acid-basis couple: HPO₄²⁻/H₂PO₄⁻) has been identified to be an important intracellular buffer system (27,28). Because the respiratory system is compromised during severe acute exacerbation it cannot maintain pH between physiological values. The pH regulation system depends on renal response through reabsorption of sodium cation and excretion of chloride anion (to increase the strong ion difference) and organic acids. A previous physiological study showed that metabolic and respiratory acidosis both increase plasmatic Ph concentration and phosphaturia presumably to enhance titratable acids excretion (28). A transient high plasmatic Ph concentration could result from a higher intracellular inorganic Ph production and acid load. It could therefore reflect the severity of the intracellular energetic crisis. Our results are consistent with this physiological hypothesis: Plasmatic Ph concentration was higher in patient who required invasive MV and decreased abruptly after its initiation (−0.42 mmol/L at 24 hours). As in our study, Laaban et al. also found that plasmatic Ph concentration decreased significantly after initiation of invasive MV in patients with COPD (29). It is presumably linked to the correction of the respiratory acidosis and the resting of the respiratory muscle that led to a shift of Ph into the intracellular space, to restore cellular ATP and phosphocreatine supplies through the stimulation of the glycolysis and the production of sugar Ph (30). Lactate level at admission was similar in both group of patients suggesting that the anaerobic metabolism was not predominant in the patients needing invasive MV. However, we only report lactate at admission and not its variation over the time particularly the first 24 hours thus limiting the meaning of this single value as a marker of the anaerobic metabolism.

Our preliminary findings were not confirmed in the multivariate analysis. One plausible explanation is that plasmatic Ph is a dependent variable influenced by numerous factors encountered in ICU such as drugs administration, ventilation modalities, renal excretion and acid base status. A well-designed prospective study is needed to confirm or infirm our hypothesis.

In multivariate analysis, pneumonia and previous history of intubation was associated with the need for invasive MV. These findings are consistent with previous studies, in which pneumonia is one of the main risk factors of intubation in COPD patients (31,32).

Several limitations of our study must be acknowledged. First, this is a single-center retrospective study; thus, the interpretation and generalization of the results are limited but the characteristics of our patients are similar to those of previous large studies. Second, the limited sample size (198 patients) does not allow highlighting all potential risk factors. For 31 (16%) patients lung spirometry data were not available, and COPD was presumed according to the definition used in the method section. Third, important data such as phosphaturia was not monitored, it would have been helpful to determine in which proportion acid load was eliminated through the Ph buffer between the two groups of patients. Most of the patients received additional therapy such as corticosteroids or beta-2 bronchodilators which stimulates renal Ph excretion and could disturb physiological Ph homeostasis. Data regarding the time between admission from emergency ward and ICU was not available, some therapeutics initiated before ICU admission could have influenced plasmatic Ph value. Fourth, the plasmatic Ph concentration is easily available at the bedside, but clinical meaning of T0-Ph remained undetermined. It could reflect the severity of the exacerbation, the consequences of respiratory acidosis, a compensatory mechanism triggered by the intracellular acidosis, or all at the same time.

Further clinical studies with close monitoring of plasmatic Ph concentration and phosphaturia would be helpful to determine the relevance of this biological marker as a predictive factor of invasive MV. In the meantime, it is costless to consider that a high T0-Ph value, could be a warning signal among others, in COPD patients admitted to ICU for acute respiratory failure.

Conclusions

Among patient admitted to the ICU for severe acute exacerbation of COPD, T0-Ph was significantly higher in patients requiring invasive MV as compared to the group of non-intubated patients. However, T0-Ph was not associated with the need for invasive MV in multivariate analysis. Larger multicentric and prospective studies are needed to better investigate the association between T0-Ph and respiratory outcomes.

Acknowledgments

The authors acknowledged the support by the French public funding agency Délégation à la Recherche Clinique et à l’Innovation (DRCI), Le Chesnay, France.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://atm.amegroups.com/article/view/10.21037/atm-23-1650/rc

Data Sharing Statement: Available at https://atm.amegroups.com/article/view/10.21037/atm-23-1650/dss

Peer Review File: Available at https://atm.amegroups.com/article/view/10.21037/atm-23-1650/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-23-1650/coif). A.F. reports honoraria by Fisher & Paykel for a lecture during French Society of emergency medicine (SFMU) Congress 2022, outside the submitted work. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This single-center, observational, retrospective study was approved by the ethics committee of the French Intensive Care Society (No. #20-12) and registered at the French National Institute for Health Data (#MR 2516271119). Informed consent was sought from the patients upon recovery of competency, in compliance with French law.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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