Vitamin D deficiency and length of pediatric intensive care unit stay: a prospective observational study

Our data suggests a high prevalence (74 %) of vitamin D deficiency in our study population.
In two recently published studies from India, the prevalence in critically ill children
in general was found to be 40 % 6] and in children with sepsis it was around 50 % 10]. Despite being from a tropical country, the incidence of vitamin D deficiency in
our study is as high as has been reported from temperate countries such as in the
study by Madden et al. 3]. While Madden et al. attributed the high incidence in the critically ill population
in their study to factors such as transcapillary leak, fluid administration, and organ
dysfunction, the high incidence observed in ours could be attributed to the high incidence
of underlying deficiency in the general population as such in addition to the factors
described above in critically ill children. Various factors like duration and timing
of sun exposure, amount of skin exposed, skin pigmentation, dietary and genetic factors
19], 20], have been implicated as possible reasons for the high incidence of vitamin D deficiency
observed in the tropics. However, as most cases in the general population are asymptomatic
therefore, the deficiency may not be clinically relevant. The same cannot be said
for the critically ill population where there are multiple other factors involved
and the physician is only trying to optimize various therapeutic options to decide
what works best for the patient. Therefore, deficiency of any essential nutrient or
element deserves careful consideration.

Though high prevalence of vitamin D deficiency in critically ill adults and children
has been documented, the impact of such deficiency is not yet clear. Few studies have
documented significant association of deficiency with poor outcomes such as longer
duration of ICU stay 4], 21], increased inotropic requirement 5], 11] and higher admission illness severity scores 3], 4]. We chose length of ICU stay as a clinically important outcome for the primary objective
as it was one of the key variables found to be significantly associated with vitamin
D deficiency in the largest prospective study of 326 children published till date
4]. On multivariable regression analysis, a value of less than 50 nmol/L (20 ng/mL)
was independently associated with a PICU stay of an additional 1.92 days (95 % CI:
0.2–3.7; p = 0.03) in this study 4]. In our study too, we observed that the length of ICU stay was longer in children
with ‘vitamin D deficiency’ with a mean difference in PICU stay of 3.5 days (95 %
CI: 0.50–6.53; p = 0.024) as compared to those ‘not deficient’. The association remained significant
even after adjusting for key baseline and clinical variables. In comparison to the
study by Mc Nally et al., the overall duration of stay as well as the difference in
length of stay was greater in our study between ‘deficient’ and ‘not deficient’ children
despite having similar incidence rates as in their study. Differences in patient population
such as medical or surgical patients, age, genetic heterogeneity, underlying nutrition
status and admitting diagnosis could be the possible reasons for the longer duration
of stay as compared to their study. For example, in the study by Mc Nally et al.,
the study population was mostly surgical (70 % of patients) (cardiac or otherwise)
whereas our population was only medical. Medical conditions have a long drawn course
of illness unlike surgical patients in who the recovery is quicker and patients are
shifted out of the ICU once their post-op period is uneventful and they are extubated
4]. The mean duration of mechanical ventilation (intubation) was 3.5 days in their study
compared to 9 days in our study in the deficient children. Even in the other group
it was 2.6 days in their study compared to 8 days in our study. Deficient children
were older as compared to those ‘not deficient’. This could have been due to lack
of exposure to adequate sunlight during school hours or very little exposure owing
to mostly indoor activities in this age group apart from dietary factors. Moreover,
there were large numbers of undernourished children in our study population which
may have contributed to longer diseases course and slower recovery in these children
and therefore prolonged the stay in both groups and in the deficient group much more.
The undernourished children with vitamin D deficiency could have had other micronutrient/essential
nutrient deficiency which were not overtly manifesting but could have contributed
to the illness severity and therefore the slow recovery. The admitting diagnoses were
mostly infections in our study compared to cardiac and non-cardiac surgical cases
in their study. In a previous study from our Institute, we observed that the median
duration of stay in children with infections with or without shock is 5–7 days 22]. Thus, although the duration is longer compared to the study by Mc Nally et al.,
the differences in the patient population, clinical course and outcomes in these two
settings might be contributory.

Vitamin D deficiency is presumed to increase morbidity and mortality by its pleiotropic
effects on various organ system functions and its effects on innate and adaptive immunity
2], 12], 23]. Although a cause and effect relationship has not been clearly established due to
the conflicting evidence available, it is presumed that deficiency of this hormone
may contribute to triggering or aggravating the multi organ dysfunction that occurs
in the critically ill and is responsible for the increased morbidity and mortality
in this population 3], 4], 23]. Although the differences were not statistically significant on univariable analysis,
we observed that children who were vitamin D deficient at admission were more likely
to require mechanical ventilation, inotropes, fluid boluses, have higher organ dysfunction
scores and have prolonged duration of mechanical ventilation. All these factors in
combination might have contributed to the slow recovery in this group of children
thereby prolonging the length of stay in these patients.

There is limited data available in pediatric literature on the effect of vitamin D
deficiency on clinically important outcomes and there is no evidence to support that
outcomes may improve with supplementation. Supplementation of vitamin D in cases of
deficiency is therefore, only subjective and should be based on features of deficiency
(such as due to hypocalcemic seizures, bowed legs, rickets on X-ray) 24] rather than only the serum levels. A large randomized control trial (VITdAL-ICU)
25] in critically ill adults involving vitamin D supplementation showed no significant
difference in length of ICU stay or other outcomes after supplementation with vitamin
D3 against placebo group. Presently, there is no recommendation for routine supplementation
in adults too in view of inconclusive evidence. Therefore, there is a need to generate
further evidence on the role of supplementation in children.

Twenty-five (OH) D being the stable storage form, estimation of its levels in serum
reflects the total body stores and thus is widely accepted parameter for assessment
of vitamin D status. The most commonly and widely used definition of vitamin D deficiency
used to estimate prevalence in several populations around the world has been a cut
off value of 25(OH) D of 20 ng/mL or 50 nmol/L and is also recommended by the American
Academy of Pediatrics (AAP) committee on nutrition 26] and US Endocrine Society 15] for starting therapy in symptomatic cases. Therefore, we used this definition as
has been used in similar previous studies in children 3], 4]. A level of 37.5 nmol/L or 15 ng/mL indicates severe deficiency and may manifest
clinically as rickets and/or histologically as osteomalacia 18], 27], 28]. The number of children with severe deficiency in our study was 62 (61 %). Severe
deficiency like mild-moderate deficiency has been shown to be associated with increased
disease severity, duration of stay as well as mortality in few while no association
has been found in few other studies 29], 30], 31]. Most interventional studies have used 20 ng/mL as the cut off for supplementation
24]. However, it appears that the group of patients to benefit the most would be the
ones with severe deficiency and therefore interventional studies should be planned
targeting this group rather than those with any deficiency.

We anticipated a higher prevalence of vitamin D deficiency in malnourished children
due to poor diet, altered metabolism or reduced environmental ultraviolet exposure.
Although the median 25(OH) D levels were lower in the malnourished group, the prevalence
of vitamin D deficiency was observed to be high in both well-nourished and malnourished
groups. Similar observation has been documented in the study by Mc Nally et al. 4] where the authors observed that, children with higher weight for age were more deficient
than others. The reasons for this observed phenomenon could be the same as described
for deficiency in healthy school children such as lack of exposure to sunlight due
to staying indoors, increased skin pigmentation and unknown genetic factors 7], 9]. The median vitamin D levels were higher in the severely malnourished group as one
child had a level of 54 mmol/L which increased the overall median in this population.
Vitamin D supplementation at some point in time (1 year before enrollment into the
study) was probably responsible for high levels in this child although severely undernourished.

Strengths and limitations

Our study emphasizes higher prevalence of vitamin D deficiency in critically ill children
from a tropical country and its association with longer duration of ICU stay. Well
defined eligibility criteria and prospective data collection are the strengths of
our study. One major limitation is that we did not include a control group of healthy
children. But data on this population is already available from the Indian sub-continent.
The other important limitation is we only had the weight for age Z scores, which is
not the best method to assess underlying nutritional status in children. Low levels
of vitamin D are associated with inflammatory diseases. Whether they are the cause
or the effect of vitamin D deficiency is unclear form the current evidence 32], 33]. Therefore, there is a need to cautiously interpret the results in patients with
inflammatory conditions.