Z. A. BHUTTA AND K.

YUSUF

Neonatal Sepsis in Karachi: Factors Determining

Outcome and Mortality
by Zulfiqar Ahmed Bhutta and Kamran Yusuf
Department of Paediatrics, The Aga Khan University Medical Centre, Stadium Road, P.O. Box 3500,
Karachi 74800, Pakistan

Summary
Neonatal sepsis is a major cause of morbidity and mortality among newborns in the developing world. In
a consecutive cohort of 292 infants with culture proven neonatal sepsis, the mortality was 68 (22 per
cent). We analysed the association of predisposing factors, clinical, and laboratory characteristics of the
infected newboms with mortality by univariate methods and logistic regression analysis. Comparatively
higher rates of mortality were seen among home-delivered newborn infants and those referred from
other maternity facilities. The mortality was significantly higher among infants weighing < 1500 g and
those with birth asphyxia (/ ) <0.05). The overall mortality was higher for gram negative infections and
the highest case fatality rates were seen in infections with Pseudomonas species (52 per cent) and
Streptococcus pneumonia* (100 per cent). Several clinical features suggestive of septicaemk shock and
metabolic derangement were associated with significantly increase risk of death. Of these, the logistic
regression model identified hypotensive shock (odds ratio 3.6) and acute renal failure (odds ratio 11.2) as
significant factors associated with risk of death. Our data suggest that delayed presentation and
recognition of neonatal sepsis is associated with rapid development of multiorgan dysfunction and
increased risk of mortality.

Introduction presentation, and that prompt identification of risk

More than 14 million children under 5 years of age,
die annually in the third world.1 It is recognized that
much of this mortality occurs during the neonatal
period and infections account for upto 70 per cent of
these deaths.2 Although neonatal tetanus accounts
for a large proportion of neonatal mortality, there is
growing evidence from several large community-
based surveys that other bacterial infections and
septicemia. are responsible for a significant number
of deaths Bartlett et al. in a longitudinal survey of a
cohort of newborns in Guatemala during infancy,
clearly identified that infectious diseases accounted
for 92 per cent of all lethal or potentially lethal
episodes during this period.3 In a similar, but longer
follow-up study of a cohort of 1441 newborns from a
community around Lahore (Pakistan), Jalil et al.
documented that 38 per cent of all first week deaths
were related to infective disorders.4 Several other
studies of hospitalised newborns from developing
countries have identified mortality rates ranging from
12 to 30 per cent.5"7 In a retrospective analysis of 55
consecutive newborn infants with culture proven
sepsis from Karachi, we found an overall mortality
rate of 42 per cent, with a higher mortality among
late-onset and nosocomial infections.8
It is possible that wide differences in mortality
rates between different series, could be in part
attributable to varying clinical and bacteriological
factors for mortality may help identify specific high-
risk categories of infected newborns for more
aggressive or alternative therapy. This is supported
by the contention that many infected newborn
infants die with sterile blood cultures, due to the
pathophysiological changes induced by the infection
and multiorgan dysfunction.9 Few studies have,
however, addressed the specific issues related to
differing mortality rates among infected newborns
on comparable antibiotic regimen in developing
countries.
We have maintained a database of newborn
infections at the Aga Khan University Medical
Centre (AKUMQ in Karachi (Pakistan) since 1989.
We analysed the outcome of neonatal sepsis from a
consecutive group of newborn infants between 1989
and 1994, in relation to predisposing factors, and
various clinical and bacteriological aspects of infec-
tions.
Materials and Methods
The AKUMC is a 400-bed hospital and the only
tertiary referral facility of its kind in Karachi, a city
of 10 million. The newborn unit at AKUMC caters
for a mixture of high-risk in-born obstetric patients
and also referrals from other facilities. The Unit
provides a high standard of newborn care with

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 Z. A BHUTTA AND K. YUSUF

constant qualified neonatal nursing a n d medical Admissions (n) Mortality (%)

200
supervision. T h e Unit has the capacity to provide
30
assisted ventilation t o upto five babies simultaneously
and receives approximately 400 admissions annually.
20
All newborns admitted or referred to the Unit with 100

I
suspected sepsis have a blood culture obtained and
plated according to standard bacteriological proce- 50
dures.8 Cerebrospinal fluid, urine, and other body
fluid cultures are obtained as required. Ancillary 0
HOME OUTSIDE HOSPITALS AKUMC
radiological and laboratory investigations including a Place ol birth
complete blood picture, electrolytes, serum creati-
nine, calcium, and glucose are obtained in all cases, i Admissions
•Mortalty
and repeated as clinically required. Since early 1988,
in view of the large proportion of multi-drug resistant
organisms among the common organisms isolated FIG. 1. The relationship of place of birth and
from infected newborns, our antibiotic regime has mortality. • P<0.05 cf AKUMC births.
consisted of a combination of cefotaxime (100 mg/
kg/day) and amikacin (15 mg/kg/day) in all cases of
suspected sepsis, until culture and sensitivity results
intrauterine growth retardation. Overall 133 (46 per
are available and the dose and frequency are adjusted
cent) of the cohort were low birth weight. Survival
accordingly. In some cases alternative antibiotics or
was associated with a higher birth weight and
combinations are chosen as specifically indicated.
maturity. Table 2 describes the mortality for the
Most babies are nursed in intensive care incubators
cohort according to different birthweight categories,
with constant monitoring until stable. Blood pro-
with the highest mortality in the very low birth
ducts, colloids, and inotropic support are provided as
weight category. The mean duration of therapy
required. Clinical, laboratory, and bacteriological
among the non-survivors was 5 days, and despite
profiles of all newborns are recorded at admission
initiation of antibiotic and supportive therapy, 38 (59
and during the course of the illness using on-line
per cent) succumbed within 72 h of development of
interactive mainframe computer data-base (Medi-
sepsis.
tech). Since 1989 a specific database of newborns
with culture proven sepsis has been maintained, Tables 3 and 4 describe the clinical and laboratory
which is periodically reviewed and follow-up data parameters at presentation and initiation of therapy
recorded. This paper will describe the results from the for the two groups of newborns. A number of clinical
first 292 cases of newborn sepsis thus recorded until and laboratory features differentiated survivors from
April 1994. non-survivors. Although a large proportion of both
groups of infants had evidence of severe sepsis, non-
Data on outcome was analysed for comparison of survivors had greater likelihood of multi-organ
dichotomous variables by univariate methods and for failure and nearly half had evidence of renal failure
continuous variables by analysis of variance using with hyperkalemia at presentation. Several of these
EPI-INFO (Version 6.0). In addition, a comparison infants were hyperglycaemic at admission, with
of outcome controlling for several variables was done severe metabolic and respiratory acidosis. Nearly a
by logistic regression using the statistical package
EGRET. Significance was set at P<0.05.

TABLE 1
Results General characteristics of newborns with sepsis
A total of 292 consecutive newborn infants were
Survivors Non-survivors
registered during this period, of which 189 (65 per
cent) were referred from outside facilities. The overall Number 227 65
mortality for the cohort was 65 (22 per cent), of these Sen ratio (M:F) 150:77 45:20
47 (72 per cent) were outborn. Figure 1 indicates the Age at admission (days) 6.5 ±6.6 7.9 ±8.6
relative mortality rate for the cohort according to Gestational age (weeks) 37.6 ±3.1 36.2±4.3"
place of birth. The highest mortality rate (33 per cent) Birth weight (g) 2669 ±759 2286±861"*
was seen in the subgroup of infants delivered at home Duration of therapy (d) 11.0±3.4 5.0±5.1"*
(w= 18) and subsequently brought to the emergency Born at AKUH 85 (37%) 18 (28%)
services. Birth asphyxia 70(31%) 31 (48%)*
Congenital malformation 35 (15%) 12 (19%)
Table 1 indicates the general characteristics of the Intra-uterine growth 53 (23%) 22 (34%)
two groups of infants according to their respective retardation
outcomes. There were no significant differences
between the two groups according to the degree of * /><0.05;'

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 Z. A. BHUTTA AND K. YUSUF

TABLE 2
Birthweight specific mortality

Birthweight categories
(g) Number Survivors Non-survivors

sJlOOO 5(1.7%) 2 (40%) 3 (60%)

1001-1500 28 (9.6%) 16 (57%) 12 (43%)
1501-2000 44(15.1%) 33 (75%) 11 (25%)
2001-2500 61 (20.9%) 43 (71%) 18 (29%)
>2500 154 (52.7%) 133 (86%) 21 (14%)

TABLE 3
third of all infants, including 85 per cent of non-
Clinical features and outcome survivors required assisted ventilation during the
course of their illness.
Clinical features Survivors Non-survivors No specific association of pathogens with mortal-
ity was seen for the majority of the organisms
Hypothermia 70(31%) 45 (69%)"* isolated (Table 5). The commonest pathogens, i.e.
Hyperthermia 58 (26%) 14 (22%) Klebsiella species and Staphylococcus aureus were
Respiratory distress 137 (60%) 59 (91%)** equally distributed between the two groups. Some of
Respiratory failure 46 (20%) 55 (85%)** the most severe and refractory forms of septic shock
Seizures 45 (20%) 21 (32%)* were seen in the three infants with Streptococcus
Hypotension 80 (35%) 56 (86%)** pneumoniae sepsis. The next highest cause-specific
Ileus 27 (12%) 27 (42%)**
Generalized bleeding 28 (12%) 31 (48%)" mortality was seen with Pseudomonas species, but
Oligo/anuria 34(15%) 33 (51%)" these constituted only 8 per cent of the total isolates.
Cardiac failure 20 (9%) 37 (57%)** No difference between the general antimicrobial
Jaundice 110(49%) 24 (37%) sensitivity patterns was found between the survivors
and non-survivors.
*/><0.05;*" P<Q.0O0\. Table 6 details the results of logistic regression

TABLE 4
Comparison of laboratory features at presentation according to survival

Laboratory features Survivors Non-survivors

Anaemia 61 (27%) 38 (59%)"*
(Hb <12g/dl)
Leucopenia 77 (34%) 27 (42%)
(WCC <4 x 109/l)
Leucocytosis 61 (27%) 23 (35%)
(WCC >20 x 109/l)
Thrombocytopenia 92(41%) 43 (66%)***
(Platelets <100 x 1012/l)
Increased FDPs 22 (10%) 13 (20%)
(>20mcg/l)
Acidosis 123 (54%) 51 (79%)"*
Hyponatraemia 70(31%) 30 (46%)*
Hypernatraemia 9 (4%) 9 (14%)**
Hyperkalaemia 58 (26%) 25 (39%)*
Hypokalaemia 20 (9%) 13 (20%)*
Hyperglycaemia 38(17%) 25 (39%)"*
Hypoglycaemia 33 (15%) 12(19%)
Hypocalcaemia 99 (44%) 30 (46%)
* /><0.05; ** P<0.0\; " * /><0.0001.

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 Z- A. BHUTTA AMD K YUSUF

TABLE 5
Organism specific mortality
Organism Survivors Non-survivors Overall
Klebsiella species 53 (23%) 18 (28%) 25°/<
Staphylococcus aureui 34(15%) 7(11%) 17°/(
Enlerobacter 22 (10%) 6 (9%) 21°/c
Staphylococcus epidermidis 22 (10%) 5 (8%) 19 0 /
Escherichia coli 20 (9%) 4 (6%) \l°/i
Pseudomonas species 11(5%) 12(19%) 52°/c
Streptococcus species 18 (8%) 1 (2%) 5°/t
Salmonella species 12 (5%) 4 (6%) 25°/c
Enterococcui 14 (6%) 1 (2%) 7°/c
Group B Streptococcus 6 (3%) -
Cilrobacter 5 (2%) 1 (2%) 17°/<
Serratia marcescens 4 (2%) 1 (2%) 20°/c
Streptococcus pneumoniae - 3 (5%) 100°/<
Others 6 (3%) 1 (2%)

analysis for mortality against a number of risk
factors. The strongest association of mortality with
sepsis was found for newborn infants presenting
with hypotensive shock, and respiratory or renal
failure.
Discussion
Our experience at AKUMC is rather unique for the
developing world, as it is understandably rare to
find adequate facilities for detailed serial haemato-
logical and biochemical monitoring in sick new-
borns. Lack of respiratory support facilities also
doom many sick septic newborns with respiratory
failure to almost certain death. Thus, it is difficult to
compare data on outcome of sepsis with western
series where such therapy is standard. We believe
that being the only tertiary referral neonatal centre
in Karachi, our experience represents a rather severe
spectrum of sepsis. Roughly a third of all septic
newborns were ill enough to require ventilatory
assistance, and 48 (16 per cent) of the newborns
thus supported survived. It is gratifying to note that
despite a similar spectrum of organisms and patient
population, there has been an improvement in
survival rates in comparison to our previous
experience.8 The 34 per cent mortality among
infants weighing <2.0 kg at birth, is much lower
than the 60 per cent among this birthweisht
category reported by Mathur et al. from India.
It has been stated that the magnitude and duration
of the inflammatory response to bacteria, rather than
the direct effects of bacteria themselves, determine
the expression and outcome of sepsis." We entirely
concur with this view and believe that the inexorable
course of events in several of our patients despite the
institution of antibiotic and supportive' therapy, is
indicative of a multiple organ failure and systemic

TABLE 6
Logistic regression analysis of risk factors for mortality
Standard 95% Confidence
P Coefficient error Odds intervals
Birth weight <1000 g 1.26 1.55 3.33 0.15-74.39
Weight 1000 g-2500 g 0.76 0.63 2.16 0.63-7.44
Asphyxia 0.22 0.18 1.22 0.85-1.73
Shock 1.29 0.5 3.59 1.34-9.62
Renal failure 2.43 0.49 11.23 4.34-29.05
Seizures 0.33 0.48 1.43 0.56-3.66
Hypothermia 0.32 0.42 1.37 0.60-3.13
Anaemia 0.76 0.44 2.13 0.89-5.09
Hyperkalaemia 0.67 0.44 1.76 0.72-4.29
Hypokalaemia 1.08 0.6 2.78 0.85-9.02
Hyperglycaemia 0.37 0.45 1.34 0.54-3.35
Respiratory failure 1.85 0.44 8.43 3.30-24.54

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 Z. A. BHUTTA AND K. YUSUF
inflammatory response syndrome.12'13 Several recent
studies highlighting a close correlation between
cytokine elevation and mortality14'15 point out the
need for better therapeutic alternatives. Notwith-
standing the potential for these interventions for
improving the outcome of neonatal sepsis in the
developed world, the need for developing countries is
clearly to improve basic newborn care and prevent
such infections in the first place. Unlike developed
countries, our problem is clearly still with relatively
larger, viable, and mature newborn infants, with
infections which are preventable.
Nearly a third of our cohort of infants had
evidence of birth asphyxia and the proportion of
asphyxia was significantly higher among those who
died. A close association between asphyxia and sepsis
has been identified.14'15 A significant impairment in
neutrophil function has been demonstrated in rats
exposed to ,an asphyxial insult.16 It is not surprising
that the acute insult of asphyxia is compounded by
concomitant sepsis in a newborn, resulting in higher
mortality. Several studies have highlighted the
importance of temperature instability in the newborn
as markers of infection.17"19 Given the close associa-
tion between post-delivery care and neonatal tem-
perature,20 it is possible that hypothermia and
asphyxia reflect an overall poor attention to im-
mediate newborn care in these infants. However, 36
per cent of infants delivered at AKUMC and nursed
with close attention to thermoregulation, also devel-
oped hypothermia with sepsis. In several cases the
sepsis was of early-onset. There is some recent
evidence to indicate that the temperature response
to endotoxin may be dose and postnatal age
dependent.21 It is possible that hypothermia may
indicate a more severe bacterial infection, and our
evidence would tend to support this.
None of the other hematological parameters,
including leucocyte counts identified newborn infants
with a higher risk of dying. This is different from the
experience of Squire et al.22 who described higher
rates of leucopenia and neutropenia among newborn
infants dying with sepsis. A refractory hypercoagul-
able state has been described in septic newborn
infants at a higher risk of dying.23 Contrary to the
observations of Alamelu et al., we found a close
correlation between clinical bleeding and abnormal-
ities of the coagulation profile. While there was no
significant difference in bleeding complications there-
after, infants subsequently dying had higher rate of
thrombocytopenia and overt bleeding at admission.
However, there was no significant difference in the
overall plasma or platelet concentrate requirements
for the two groups. We did not perform cranial
ultrasounds in all infants and are therefore unable to
comment on the prevalence rates of intraventricular
hemorrhage in the two groups.25
Endotoxaemia and sepsis has been shown to
produce hypoglycaemia by an inhibition of gluco-
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neogenesis,26 lactic acidosis and increased glucose
requirements.27 In the newborn period, poor feeding
or inadequate caloric intake is likely to produce
hypoglycaemia.28 The hyperglycaemia and hyperna-
traemia seen in several of these infants probably
reflected the administration of inappropriate intra-
venous dextrose and saline containing fluids to
several infants prior to their transfer to AKUMC,
with little attention to blood sugar status. However,
hyperglycaemia was also observed in 18 per cent of
newborns with early-onset sepsis born at AKUMC,
and may reflect greater adrenergic activity and stress
hormone release in these infants. While the initial
concerns about the effect of hyperglycaemia on the-
post-asphyxial brain do not seem to be true for the
newborn period,29 it is probably best to avoid
hyperglycaemia in neonatal sepsis.
Our data provides strong evidence that the clinical
status at admission or diagnosis was the most
important determinant of outcome of neonatal
sepsis. Babies delivered at home, where there was
an understandable delay in recognition of problems
and referral, had a two-fold higher mortality than
hospital born infants. It is disconcerting to note that
the spectrum of organisms isolated from these home
delivered infants was similar to the predominantly
gram negative Enterobacteriacae isolated from hos-
pital born infants, indicating that these organisms
abound in the community in Pakistan. This conten-
tion is supported by the high proportion of fatal early
neonatal septicemic episodes documented by Jalil et
al. in their community-based study from Lahore.4
While a higher mortality rate was identified in low
birth weight infants, the impact of birth weight on
mortality due to sepsis was lower than that reported
from western literature on infected newborn in-
fants.30"33 This is also consonant with the findings
of Victora et al. from Brazil.34
In summary, therefore, our experience in Karachi
provides evidence that neonatal sepsis in developing
countries is frequently seen as fulminant septic shock
with multi-organ failure. With meticulous intensive
care it is possible to save many of these infants, but in
a significant proportion, the disorder is refractory to
currently available therapeutic regimen with an
inexorable downhill course. While newer therapeutic
strategies for treating sepsis may hold some pro-
mise3 the only effective long-term strategies for most
of the developing world are therefore preventive.
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