Background

Childhood malnutrition, is the imbalance between nutrient requirement and intake, resulting in cumulative deficits of energy, protein, or micronutrients that may negatively affect growth, development, and other relevant outcomes [1]. Child undernutrition is a major public health problem, especially in many low-income and middle- income countries [2]. Poor nutrition is associated with suboptimal brain development, which negatively affects cognitive development, educational performance and economic productivity in adulthood [3]. The African region and South-East Asia have reported the highest prevalence of undernutrition, with the former accounting for about 39.4% of the stunted, 24.9% of the underweight and 10.3% of the wasted children under-5 years of age [4]. Severe acute malnutrition (SAM) as defined by World Health Organization-United Nations Children’s Fund includes severe wasting and nutritional edema. Severe wasting is defined as weight-for-height below −3 SD or MUAC <115mm [5]. About 25 to 35 million under-five children are living with SAM worldwide [6]. Thirteen Million of these children live in Sub Saharan Africa [6]. Of these 13 Million, I million will die every year [6]. The worst affected parts of Africa are west, central and eastern Africa [6]. In East Africa, Uganda in particular has been reported to have the highest child mortality rates in the world [7]. 40% of these deaths have been attributed to malnutrition as the underlying cause [7].

The World Health Organisation (WHO) has developed management guidelines that if strictly followed, should be able to reduce the mortality to less than 10% [8]. Mortality from SAM has however persistently remained between 10 and 40% in many hospitals in Sub Saharan Africa, despite use of these guidelines [9–13]. This high mortality has been commonly attributed to HIV infection, lack of maternal participation in the feeding program, inadequate care and prescription errors, and over prescription of intravenous therapies and blood transfusion [9, 11, 12, 14–16]. Another study attributed the high mortality in children admitted with SAM to the WHO identified danger signs; lethargy, hypoglycemia and hypothermia as well as bradycardia, capillary refill greater than 2 seconds, weak pulse volume and impaired level of consciousness [10]. Overall, few studies have been done in Uganda to determine the risk factors for mortality in these children. No such study has been done in Western Uganda, yet this region has the highest prevalence of Acute Malnutrition in Uganda [17].

In this study, we aimed at determining the in-hospital mortality rate and its predictors among U5s admitted with SAM on the Pediatric ward at Mbarara Regional Referral Hospital (MRRH), so as to define the most at-risk group of children that need to be triaged for prompt emergency monitoring and treatment during their admission in hospital.

Methods

Data analysis

Results

Participants’ baseline characteristics

We enrolled a total of 122 children with SAM between June 2015 and August 2015.

Of these, 71 (58.2%) were males with a median age [IQR] of 15 months [11–24]. A total of 91 (74.6%) children were less than 24 months. A total of 87 (71.3%) participants had received medical care from a peripheral unit before coming to the Regional Referral Hospital. (See Table 1)

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Table 1. Baseline characteristics of participants.

https://doi.org/10.1371/journal.pone.0234343.t001

The most common symptom at admission was reduced play (97.5%) followed by weight loss (80.3%) and the least frequent symptom was reduced consciousness (3.3%). (See Fig 1)

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Fig 1. Presenting symptoms of the participants at admission.

https://doi.org/10.1371/journal.pone.0234343.g001

On clinical examination, most of the participants enrolled were wasted at presentation (76.2%) while only a small percentage had hypothermia (1.6%). All participants had features of SAM at presentation. Of the 122 participants, 48 (39.3%) had bilateral edema at presentation Fig 2. 97 (79.5%) had comorbidities with 54 (44.3%) of which having one comorbidity while 43 (35.2%) had more than one comorbidity. The commonest comorbidity at admission was Diarrheal illness (41.2%) while the least comorbidity was HIV (7.4%). Other comorbidities at admission included, Pneumonia (26.8%), Malaria (26.8%), severe Anemia (9.3%), severe dehydration (12.7%), and septic shock (11.3%). (See Fig 2)

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Fig 2. Presenting clinical signs of the partcipants at admission.

https://doi.org/10.1371/journal.pone.0234343.g002

A total of 25 (20.5%) participants had a positive malaria test, and only 9 (7.4%) participants had a positive HIV rapid test. Eight (6.6%) participants had hypoglycemia, 72 (59%) had anemia and 38 (31.1%) had a positive blood culture. (See Table 2)

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Table 2. Laboratory parameters of participants at baseline.

https://doi.org/10.1371/journal.pone.0234343.t002

Predictors of in-hospital mortality

At bivariate analysis, under-fives with hypothermia had an 11-fold unadjusted risk of mortality when compared to under-fives who did not have hypothermia. Under-fives who had received intravenous fluid had twice unadjusted risk of mortality when compared to those who had not received intravenous fluid. (See Table 3) Other factors which were significantly associated with mortality on bivariate analysis are shown in Table 3.

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Table 3. Results of bivariate analysis for predictors of in-hospital child mortality in SAM.

https://doi.org/10.1371/journal.pone.0234343.t003

In multivariate analysis, only the administration of IV fluids was significantly associated with mortality. Under-fives who had received intravenous fluid had seven times adjusted risk of mortality when compared to those who had not received intravenous fluids. There was a tendency towards increased risk of mortality for children who had a MUAC of less than 11.5cm and oral sores at examination although it did not reach statistical significance. (See Table 4)

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Table 4. Results of Multivariate analysis for predictors of in-hospital child mortality in SAM.

https://doi.org/10.1371/journal.pone.0234343.t004

Discussion

The proportion of children admitted with SAM who died while in hospital was 10.7%. Those who died in the first 48 hours of admission made up 5.7%. This overall in hospital mortality is lower than what has been reported in previous studies done in Ugandan settings [10, 11, 20]. This was probably because our study enrolled fewer participants compared to what Bachou et al (2006) at Mulago Hospital, Nyeko et al (2016) at Lacor Hospital and Maitland et al (2006) at Kilifi Hospital enrolled in their respective studies [10, 11, 20]. Nevertheless, our results are consistent with the already reported failure of the WHO treatment guidelines in improving outcomes in children with SAM [13]. This failure has been previously attributed to HIV infection, lack of maternal participation in the feeding program, inadequate care and prescription errors, and over prescription of intravenous therapies and blood transfusion [9, 11, 12, 14–16]. Another study also attributed the high mortality in children admitted with SAM to the WHO identified danger signs; lethargy, hypoglycemia and hypothermia as well as bradycardia, capillary refill greater than 2 seconds, weak pulse volume and impaired level of consciousness [10].

We found the administration of IV fluids to be an independent predictor of in-hospital mortality in children 6 months to 5 years with SAM at MRRH. This association has been reported before, with infusion of IV fluids being associated with excess deaths among children hospitalized with severe malnutrition and with these deaths being attributed to possible fluid overload [11, 21]. In our study, a total of 8 out of the 22 participants who received IV fluids died representing a case fatality of 36.4%. All these participants died within three days of receiving IV fluids further affirming a possible contribution of fluid overload to this mortality.

An alternative explanation could be the possibility that IV fluids were administered when it was already too late for the children to survive. According to WHO malnutrition guidelines that our study followed, fluid resuscitation should be given only if all of the following parameters are present; a weak, fast pulse, cold peripheries, a capillary refilling time (CRT) of > 3 seconds plus signs of impaired consciousness [22]. These features would be considered by pediatric life-support providers as constituting a very advanced state of shock, when outcome is generally poor [23]. Indeed a study done in South Africa noted that the WHO guidelines, though relatively simple to implement do not make much difference among severe acute malnutrition cases admitted in critical condition [24]. In our study, most of the patients came to hospital having been ill for more than two weeks with almost half of them having been referred from peripheral health facilities. A total of 40% of the children who received IV fluids during the study had shock at admission. It is possible that these children could have been in shock throughout the duration of their transportation to hospital. Indeed, a study on early goal-directed therapy in treatment of severe sepsis and septic shock demonstrated that for every hour that shock is left uncorrected, there is a doubling of mortality [25] Another big possibility is that the children admitted with SAM with edema could have had hypoalbuminemia. We did not set out to determine the serum albumin levels of these children because of the previously long held view that there was not a causal link between the oedema of malnutrition and the low plasma oncotic pressure induced by hypoalbuminaemia [26].However, a recent Reanalysis of this evidence and a review of the literature has shown that this evidence which, influenced the recommendations for treating children with severe acute malnutrition [22], was a mistaken conclusion and that the oedema is linked to hypoalbuminaemia [27] Malcolm (2015) further noted in his study that children with severe albumin deficiency from any cause continuously ‘struggle’ physiologically to maintain their blood volume by driving hormonal pathways that are normally only called upon in a crisis. They have no mechanisms in reserve; the mildest extra stress can rapidly precipitate severe shock. [27] It is possible that this was happening in the children in our study by the time they were admitted to hospital. Malcolm (2015) further reported that, if such children were treated with just 30 ml/kg over 2 hours of half-strength Darrow's solution with 5% dextrose (hypotonic crystalloid; sodium 61 mmol/l), as recommended by the WHO guidelines they may show a transient improvement as the fluid was delivered, but they would then deteriorate as the water leaked away into the tissues, and would have a high chance of dying [27–31]

Another plausible reason for the high mortality among children who received IV fluids is that there could have been inadequate correction of shock by the type of IV fluids that were prescribed to the children during the study period. This would agree with a study that compared use of half strength Darrow’s solution with use of isotonic solution in children with SAM that reported inadequate correction of shock in all study arms, resulting in a decision to prematurely terminate the trial [23]. On the other hand, Alam et al (2009) in Bangladesh reported that children were able to tolerate up to 100 ml/kg of isotonic fluid given for 6 hours [32]. It’s important to note though, that this study dealt with cholera patients that had significant losses of fluid and not children with SAM. The above findings though would agree with what Raman etal (2014) reported that Marasmic children, whose hypovolaemic shock is caused by an acute loss of salt and water uncomplicated by hypoalbuminaemia, require an intravenous infusion of sufficient isotonic fluid to promptly restore the circulating blood volume [33]. This allows oxygen delivery and perfusion of the organs [33]. They further reported that a rapid 20-ml/kg bolus of an isotonic fluid with glucose, repeated as necessary, would fulfil these logical and physiologically-based criteria [33] this is not what the WHO guidelines recommend. It is also noteworthy that WHO makes no distinction between managing shock in SAM without edema and SAM with edema [27], despite the fact that mortality is linked directly to the degree of oedema [28, 29] and hypoalbuminemia [30, 31]

The WHO recognized danger signs of lethargy, hypothermia and hypoglycemia as well as other clinical signs that pointed to shock, like weak pulse volume, temperature gradient and altered consciousness were not independently associated with mortality as has been reported in other studies [10, 20, 24] nor was age less than twenty four months [35]. This could be because the proportions of patients with these features in the above studies [10, 34, 35] were significantly greater than in our study causing them to register more outcomes than we did. The few numbers of patients in our study with these features (weak pulse volume, temperature gradient and altered consciousness) reduced its power to determine their association with mortality. What is clear though is that although each of them was not able to independently predict mortality, they in combination all point to a septic shock like syndrome that requires IV fluids as part of the management which could explain why administration of IV fluids was independently associated with mortality. We concur with Maitland etal (2009) in Kenya that more research is needed on early identification and better supportive care of sepsis as well as evidence based fluid management strategies [36].

We did not find MUAC to be significantly associated with death as another study found [37] though it predicted death in our children at bivariate analysis. It is possible that it could have been a significant predictor of death had our study had an equally long period like the above study [37] that retrospectively studied records of children with SAM spanning over 8 years.

We did not find HIV infection to be significantly associated with mortality as has been reported other studies [20, 38]. This could be attributed to the fact that half of the children enrolled in the study in South Africa and 28% of the children enrolled in the study at lacor Hospital were HIV positive compared to only 7.4% in our study.

We did not find children with Hyponatremia, Hypokalemia, Hypoglycemia and Bacteremia at admission to be at risk for mortality during admission in hospital as was reported by another study [10]. This could be attributed to the fact that our study had low number of participants and took a short period compared to this study [10] which enrolled almost 8 times the number of participants in our study over a period of two years.

Our study had a number of strengths and limitations. Our study had several methodological advantages. Because it was a cohort study, we were able to assess the temporal relationship between predictors and outcomes. Selection bias was also eliminated because participants were obtained at hospital and selected on the basis of being admitted within a given time period. The nature of the outcome made it impossible that any patient had the outcome at the beginning of the study. The weakness however was that the three months period for the study meant that we had few numbers of children for our study which significantly affected its power. Also, the fact we did not set out from the outset to study levels of creatinine in our study as well as Metabolic acidosis that were found in a study in a similar setting to be associated with late mortality in the under five children [10] could have affected our outcomes. Also the fact that we did not study serum albumin levels in these children yet edema in these children has now been found to cause hypoalbuminemia [27] which is linked to mortality [30, 31] could have affected our outcomes.

Conclusion

The proportion of under five children with SAM who die during admission at Mbarara Regional Referral Hospital is high. Administration of intravenous fluids is a risk factor for mortality, regardless of other clinical and socio demographic factors. There is need to study hypoalbuminemia as a possible cause of severe shock in children with SAM with edema. A randomized controlled clinical trial needs to be conducted in our setting to compare the use of isotonic fluid and hypotonic fluids in management of severely malnourished children with shock. While Administration of intravenous fluids is still the main stay of managing severely malnourished children with shock, there is urgent need to review the present guidance on use of fluids in these children with special emphasis on the parameters presently used to assess children for shock as well as other possible causes of shock. This will help in diagnosing and managing shock in these children when it is still early.

Supporting information

Acknowledgments

We are forever grateful to the Late Prof. Julius Kiwanuka for his mentorship during the design and conducting of the study and the Late Max Irama for the Laboratory work during the study. May their souls rest in peace.

We are deeply grateful to MUST/MGH collaboration and Dr Dana Liza together with the Canadian Pediatric Society for the financial support to TN to do his MMed Program that led to this work and the Makerere University HEPI project for the mentorship in the writing of this paper.