This present work is a retrospective study performed in two distinct ICUs. The medical ICU of the Saint-Louis University Hospital, Paris, France, is a 12-bed medical unit that admits 850 patients per year, of whom about one-third have hematologic malignancies. The nephrology ICU of the Tenon University Hospital, Paris, France is a 17-bed medical unit that admits 900 patients per year. The study was approved by the ethical committee of the “Société de reanimation de langue française” (n°18-34).
Patients
We included all adult patients admitted in ICU with severe HCM from January 2007 through February 2017. We defined severe HCM by a total calcemia above 12 mg/dL (3 mmol/L) [13, 14]. When needed, calcemia was corrected by serum albumin level, and in default of, by total protein levels.
Definitions
Definition and staging of AKI were defined according to the 2012 KDIGO (Kidney Disease: Improving Global Outcomes) guideline [15]. Decisions regarding the initiation, discontinuation, and modalities of renal replacement therapy (RRT) were made by senior nephrologists based on the guidelines from Bellomo and Ronco [16].
Etiologies of HCM were retrospectively subdivided in four groups: (1) hematologic malignancies; (2) solid tumors; (3) endocrinopathies; (4) other causes, including iatrogenic, granulomatosis, and unknown causes. We sought for etiological investigations including the testing of PTH or 1–25(OH) Vit D during the hospital stay.
Based on known complications of HCM [1, 17], we classified HCM manifestations in four entities: (1) renal manifestations, including polyuria and acute kidney injury; (2) cardiovascular manifestations, including de novo arterial hypertension and any EKG manifestations; (3) neurological manifestations, including seizures and mental status alteration; and (4) digestive manifestations, such as acute pancreatitis, digestive occlusion, or constipation.
We used the Glasgow scale score [18] for evaluation of mental status at admission.
Bisphosphonate safety was assessed on creatinine variation 3 months after admission in ICU.
Patient’s characteristics
Demographic parameters, medical history, presenting symptoms, and treatments were collected. All laboratory data were recorded at admission. Serum creatinine level was recorded 3 months before ICU admission when possible, at ICU admission, ICU discharge, hospital discharge, 3 and 6 months after ICU and at last follow-up. Sequential Organ Failure Assessment (SOFA) and Simplified Acute Physiology Score (SAPS II) parameters were collected on day 1 [19, 20]. ECOG/WHO performance status [21], and Charlson comorbidity index [22] were evaluated based on precedent medical records.
Serum PTH level were measured using a radio-immunologic assay (CIS-Bio-Radio-ImmunoAnalysis®) with a normal range between 8 and 76 ng/L. Serum 25-dihydroxyvitamin D was measured using a radio-immunologic method (Diasorin®) that recognized both 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3. An excess of 25-dihydroxyvitamin D was arbitrary defined by a level above 100 ng/mL. Serum 1,25-dihydroxyvitamin D was measured using a radio-immunologic method (Diasorin®) with reference values ranging from 20 to 60 pg/mL. Plasma phosphate was measured using colorimetry (phosphomolybdate assay) and serum ionized calcium, using a specific electrode.
Vital status at ICU discharge, hospital discharge, and last follow-up were determined from medical records and the outpatient clinic electronic database.
Treatment
All patients received the standard of care. The period and duration of renal replacement therapy were collected. Bisphosphonate treatment dose and duration were recorded. Type and daily volume of hydration, corticosteroid treatment, use of salmon calcitonin, furosemide in hypocalcemic purpose, and calcimimetic were collected.
Statistical analyses
Patients’ characteristics at ICU admission are described as median and interquartile range (IQR) for quantitative variables and frequencies and percentages for qualitative variables. Distribution of baseline variables, life-supporting treatments, and specific treatments of HCM were compared between patients alive or not at leaving the ICU using the Wilcoxon test for quantitative variables, and Fisher’s test for qualitative variables.
Cumulative incidence of mortality in ICU and hospital was estimated, taking ICU or hospital discharge as competing risk. Univariate analysis for complications was performed in logistic regression to identify factors associated with complications. For mortality risk in ICU, univariate analysis with logistic regression was adjusted on SAPSII scale score and Charlson morbidity index. Multivariate models were adjusted on age, SAPSII for mortality, pre-existing cardiopathy for cardiovascular complications, CKD for AKI stage 3, and variables that were significant at 0.15 level.
The endpoint of treatment analysis was the diminution of total calcemia below 3 mmol/L (12 mg/dL) between day 0 and day 5. Univariate analyses were performed in Cox proportional hazards regression models. Final multivariate model was adjusted on etiologies and significant treatments at 0.15 levels. Patients with stage V-CKD were excluded from this analysis. All tests were two sided with a 5% type I error. All calculations were performed with the R software (version 3.4.4)®.