Severe Sepsis in Uganda—
Findings and Future Directions from
the
PRISM-U Study Group
W. Michael Scheld, MD
University of Virginia
May 2008
PRISM-U: Promoting ResourceLimited Interventions for Sepsis
Management in Uganda
Co-Investigators:
Shevin T Jacob (UVA)
Patrick Banura (Masaka Hospital)
Christopher C Moore (UVA)
David Meya (IDI)
Steven J Reynolds (RHSP/NIH)
Pius Opendi (RHSP)
Relana Pinkerton (UVA)
Principal Investigators:
Nathan Kenya-Mugisha (MOH)
Harriet Mayanja-Kizza (Makerere)
W Michael Scheld (UVA)
Outline
Rationale for PRISM-U1
 Data from PRISM-U1
 Future directions with PRISM-U2

Genre: Progressive death metal
Lyrical themes: Human nature, life and death
Discography: The Town of Death, Subjugate the Chaos
RP Wenzel. NEJM 2002; 347 (13): 966-967
Severe sepsis—an important cause
of HIV-associated mortality in Africa?

Increased bacteremia in HIV-infected patients

3 cross sectional studies in Kenya showed that the most
common organisms isolated were:
• non-typhoidal Salmonella
• Streptococcus pneumoniae
• Mycobacterium tuberculosis

High mortality associated with bacteremia in HIV-infected
patients.

Prospective observational study of febrile adult patients
admitted to Mulago Hospital (n=299)
• 24% had bacteremia
• 76% were HIV-infected



Inpatient mortality among bacteremic pts was 28%
Mortality in bacteremic patients likely resulted from severe
sepsis/ septic shock
Sepsis and septic shock were amongst the three most
common causes of mortality in a Ethiopian cohort of HIVinfected patients.
Arthur G, et al. Clin Infect Dis 2001; 33(2): 248-56.
FN Ssali, et al. Journal of Acquired Immune Deficiency Syndromes & Human Retrovirology 1998; 19(5): 484-489.
A Bane, et al. Ethiop Med J. 2003; 41(2): 131-40.
Management of sepsis in
Africa

No prospective studies on the management and outcome of
severely septic patients in SSA

Zambian study showed suboptimal management of
sepsis associated with high mortality.



Retrospective chart review of hospitalized Zambian patients
with fever and hypotension (n=302)
86% (79/92) of hypotensive septic patients received no
intravenous fluid resuscitation
35% in-hospital mortality

Tanzanian study showed increased mortality seen when
empiric antibiotics discordant with sensitivity profiles.

Is there a potential for HIV-associated mortality
reduction through improved sepsis management?
C.Theodosis, et al. Abstract presented at International AIDS Conference, Toronto, 2006.
B Blomberg, et al. BMC Infect Dis 2007; 7:43.
Rounds at Mulago Hospital
Patient Lying on the Floor
PRISM-U, Part 1

Prospective observational study
investigating the management and
outcomes of patients admitted to
medical wards with severe sepsis
Study details


Time frame: July 2006 to November 2006
2 sites



Mulago Hospital
Masaka Regional Referral Hospital
Inclusion


Suspected infection
2 of the following:
• Body temperature >37.5°C or <35.5°C
• Heart rate >90 beats/min
• Respiratory rate >20 breaths/min


Systolic Blood Pressure ≤ 100 mmHg
Exclusion




Age <18yo
Acute cerebrovascular event
GI bleed
Need for triage to surgery or OB/GYN ward
Methods: Ethical approval





University of Virginia Institutional Review
Board
Makerere University Faculty of Medicine
Research Ethics Committee
Mulago Hospital Office of Director
Infectious Disease Institute Scientific
Research Committee
Uganda National Council of Science and
Technology
Results:
Patient characteristics

N: 385 eligible, 382 enrolled





250 patients from Mulago Hospital
132 patients from Masaka Hospital
Sex: 59.2% female
Age: mean, 34 yo (range 18 to 80)
HIV:




Seropositive: 84.9% (320/377)
CD4: median, 52 (range 1-999)
On HAART: 11.9% (38/320)
Unaware of serostatus: 32.5% (104/320)

Mean KPS, admission: 46 (range 10-90)

Fulfilled ≥ 3 SIRS criteria: 83.2%
Most frequent chief complaints:




Fever: 39.2%
Cough: 19.6%
Diarrhea: 11.0%
Results:
Hospital comparisons
Mulago
Masaka
P value
Age, mean
34.34 ± .67
35.56 ± 1.07
.310
Female
59.6%
58.3%
.811
HIV prevalence
85.9% (n=248)
82.9% (n=132)
0.449
CD4, mean
82.24 ± 7.56
(n=212)
146.71 ± 17.95
(n=107)
<0.001
Aware of Status
72.3% (n=212)
57.9% (n=107)
0.013
On HAART
13.1% (n=213)
9.3% (n=107)
.322
Admission KPS
43.24 ± 1.021
52.29 ± 1.399
<0.001
Fulfills ≥ 3 SIRS
criteria*
84.8% (n=250)
80.2% (n=131)
.249
Portable lactate
(mmol/L)*
4.11 ± .31
3.70 ± .22
0.75
+ malaria blood
smear
9.6% (n=250)
20.9% (n=129)
.002
Results: Microbiology


Bacteremia was found in 18.9% of 381
patients.
Most common organisms were:






Mycobacterium tuberculosis (22.1%)*
non-typhoidal Salmonella (17.1%)
Staphylococcus aureus (8.5%)
Streptococcus pneumoniae (5.1%)
Cryptococcus neoformans (4.3%)
Similar findings in 1997 Mulago study by
Ssali et al.
Results: Mycobacterial cultures

22.1% (n=55/249) had mycobacteremia



45.5% (n=25 of 55) had MTB
54.5% (n=30 of 55) had NTM
Are the NTM isolates a true pathogen or
laboratory contamination?



Studies from Uganda and other SSA countries report
MAI to be a rare pathogen in AIDS patients; other
NTM rarely reported
Inpatient mortality increased in patients with MTB
bacteremia compared to patients with negative
mycobacterial cultures (69.6% vs. 44.4%, P=0.024)
No significant differences in mortality between
patients with NTM and negative cultures
(48% vs. 44.4%, P=0.755)
CF Gilks, et al. J Acquir Immune Defic Syndr Hum Retrovirol 1995;8(2):195-8.
DO Okello, et al. J Infect Dis 1990;162(1):208-10.
Combined mortality for patients
with negative mycobacterial, MTB
and NTM cultures
Results: Outcomes

Median length of hospitalization
(days):


Lost to follow-up (after discharge):


6 (range, 1-55)
14.8% (43/290)
Mortality



In-hospital: 23.7% (n=380)
Post discharge, 30-day mortality: 22.3%
(n=248)
Combined (in-hospital + 30-day mortality):
43.0% (n=337)
Results: Clinical predictors


Logistic regression used to assess the
predictive value of SIRS clinical variables,
morbidity assessment scales (eg, KPS and
GCS), and laboratory results for in-hospital
and post discharge mortality.
In-hospital mortality model:
 Significant independent predictors:
• Temperature at 6 hrs post admission (P=0.04)
• Admission KPS (P=0.003)

Post discharge mortality model:
 Significant independent predictors:
• Discharge KPS (P=0.003)
• CD4 count (P=0.006)
Karnofsky Performance Scale




A subset of 72 patients from the Mulago Hospital site
were assessed to determine the utility of portable lactate
testing as a predictor of mortality.
No patients died if their lactate level was ≤ 2.5 mmol/L.
PWBL was positively associated with in-hospital but not
outpatient mortality (P<0.001).
In-hospital mortality was increased in patients with a
PWBL concentration ≥ 4.0 mmol/L vs. < 4.0 mmol/L:


50% vs 7.5%, OR 12.3 [3.5–48.9]; P<0.001
Using multiple logistic regression, standard laboratory
serum lactate results were inconsistent and less
predictive of mortality than were those of PWBL.
Accutrend® portable lactate
machine



Allows point of care
testing
Requires minimal
technical expertise
Requires minimal
sample preparation
or preservation
In-hospital mortality at
different PWBL concentrations
n = 5/5
n = 10/25
n = 3/18
n = 0/22
Results:
Intravenous Fluid Resuscitation

Recommended initial administration of fluid:






53% received at least some IV crystalloid within the first
hour of presentation
28% waited between 1 to 6 hours for fluid
14% of patients received no fluid within the first 6 hours
of presentation.
Within first 6 hours of presentation:




20-40 cc/kg as a fluid challenge
Subsequent fluid challenges every 30 min to 1hour for
refractory hypotension within the first 6 hours
Mean volume of fluid: 671 cc
% receiving > 1L of fluid: 34.5%
% receiving > 2L of fluid: 3.7%
Within first 24 hours of presentation:



Mean volume of fluid: 1075 cc
% receiving > 1L of fluid: 62.7%
% receiving > 2L of fluid: 13.7%
SurvivingSepsisCampaign. http://www.survivingsepsis.org/bundles/individual_changes/treat_hypotension.
Intravenous Fluid Resuscitation:
Hospital Comparison
Fluid
parameter
Mulago
Hospital
Masaka
Hospital
P-value
% receiving ≥
1L in 1st 6 hrs
42.9%
16.8%
<0.001
% receiving ≥
2L in 1st 6 hrs
5.2%
0.8%
0.03
% receiving ≥ 65.1%
1L in 1st 24 hrs
58.6%
0.21
% receiving ≥ 15.6%
2L in 1st 24 hrs
10.2%
0.14
Intravenous Fluid
Resuscitation, cont


No overall survival benefit was observed
across strata of fluid volume.
In patients with any bacteremia (n=71):

Trend towards decreased total mortality in those
receiving ≥ 1L of fluid vs. < 1L of fluid in the first 6 hours
• 36.4% vs. 55.1%, P=0.14

In patients with aerobic bacteremia (n=33):

Decreased mortality at 30 days if given ≥ 1L of fluid vs.
< 1L of fluid in the first 6 hours
• 0% vs. 27.3%, P=0.056

In patients with Gram negative bacteremia
(n=25):

Decreased total mortality in those receiving ≥ 1L of fluid
vs. < 1L of fluid in the first 6 hours
• 20% vs 66.7%, P=0.022
PRISM-U1:
Summary points





Admission for suspected severe sepsis in Uganda is
associated with high mortality and late stage HIV
infection
Microbiology findings similar to other settings in SSA
 Bacteremia-associated in-hospital mortality in Mulago
Hospital has not improved in the last 10 years
(28%33%)
 Chloramphenicol resistance in NTS suggests that it
should be avoided for empiric Gram negative therapy
Important predictors of death after discharge include
KPS at discharge and CD4 count
Management of sepsis in this setting is suboptimal with
respect to fluid resuscitation and antibiotic
administration
Future studies need to be done to evaluate
approaches to managing critically ill patients in
resource constrained settings like Uganda
The next step…




Major constraints to providing optimal sepsis care:
 Lack of skilled health workers—on a 50-bed ward
where the number of patients can approach 100, the
nurse to patient ratio was less than 1:20
 Insufficient fluid supplies—the volume of intravenous
fluids provided to the ward/day was limited to 20 L
There are no current measures in place to decrease the
high mortality (~43%) associated with sepsis
In Uganda, family members accompany patients for the
duration of their hospital stay and are expected to
provide limited assistance for daily patient needs such as
feeding, bathing and toileting.
 91.6% patients in PRISM-U1 accompanied by an
attendant
 Attendants have been used in other settings (eg.
Hospice Africa) to provide care usually attributed to
nurses
Patient attendants may be an untapped resource for
contributing to patient care in busy Ugandan hospitals.
PRISM-U2:
Aims
To determine if early aggressive fluid
resuscitation improves outcomes
among patients with severe sepsis in
Uganda (Jacob, Banura)
 To determine if patient attendants
(Musawos) can assist in early fluid
resuscitation.
 To obtain samples for later testing on
pathogenesis/pathophysiology.

PRISM-U2:
Study Samples
Serum cytokines (Moore)
 Blood 16S rDNA PCR (Fredricks)
 Mycobacterial speciation (Manabe)
 Buccal swabs; SNPs, WGA (Rich,
Concannon)
 HIV clade and tropism (Yuan)
 Point of care microfluidic diagnostics
(Kane)

Discharge
Discharge
Accident &
Emergency Triage
Medicine casualty
consent
Fulfills Inclusion Criteria
Ward 3B
Ward 4A/ 4B/ 4C
Discharge
Portable whole blood
lactate
Death
≤ 2.5 mmol/ L
•Admit to surgery ward
•Admit to OB/GYN ward
Exclude from study
Standard arm
>2.5 mmol/ L
OR Karnofsky ≤ 40
Intervention arm
Provide fluids and
training to
mujanjabi
Karnofsky scale
at
discharge and
30 days
THERAPY:
•Time from arrival to treatment
•Treatment within first 6h? Within first 24?
•Amt of fluid within first 6h? First 24? Overall?
•Which antibacterial/anti-TB/ anti malarial?
Monitor for pulm edema
q 1 hr for first 6 hrs
INITIAL EVAL:
<18 yo, GI bleed,
acute cerebrovascular event
•Chief complaint, other symptoms, duration of illness
•Demographics (age, sex, address,
phone #, referral mode)
•HIV info: knowledge of serostatus, previous OI,
previous HAART, previous OI Rx, WHO clinical stage
•Karnofsky scale on admission
Collect buccal
washings only
LABS/STUDIES:
Mulago Hospital
•WBC, Hb, plts, WBC differential
•Albumin
•HIV test, CD4
•Malaria smear
•Aerobic and Mycobacterial blood cultures
•Buccal washings for genomic DNA
•Tissue banking:
•Cytokine profiles
•HIV chemoreceptor and tropism
•Molec. analysis for rare organisms
OUTCOMES:
•In hospital mortality
•Length of hospitalization
•Out of hospital 30-d survival
Thank you!
Thank you.
PRISM-U2 Methodology:
Enrollment criteria

Inclusion

Patients triaged to the Medical Casualty Units of Mulago Hospital
and Masaka Regional Referral Hospital with:
• Suspected underlying infection
• 2 of the following:
•
•
•
Tachycardia > 90 beats per minute
Tachypnea > 20 bpm
Thermodysregulation (body temperature < 35.5° or > 37.5° C)
• Systolic Blood Pressure ≤ 100 mm Hg
• Accompanied by an attendant

Exclusion

Patients presenting to the Accident and Emergency unit of Mulago
Hospital or Masaka Regional Referral Hospital with:
• < 18 years of age
• History of hypervolemic disease state (i.e., congestive heart failure,
hepatic failure, nephrotic syndrome)
• Signs of fluid overload on physical exam
• Acute cerebrovascular event
• Gastrointestinal bleed
• Need for triage to the Surgical Casualty Unit or Obstetrics and
Gynecology Unit
PRISM-U2 Methodology:
Study details


In PRISM-U1, both portable lactate (PL) concentration
and admission Karnofsky scale were independent
predictors of mortality
After initial screening, patients will be further selected
based on PL testing using a cut-off value of > 2.5 mmol/L
or a Karnofsky score of ≤ 40.

Applying these criteria to our preliminary cohort:
• 95% (39/41) of excluded patients survived
• 50% (28/56) of included patients died

660 severely septic patients will be consecutively enrolled at
Mulago and Masaka Hospitals over 7 months


422 patients will be entered in the intervention arm if they
have either a PL concentration > 2.5 or a Karnofsky
Performance Scale ≤ 40.
The remaining 238 patients will have lactate levels ≤ 2.5
and thus will provide only buccal washing for DNA analysis
in hypothesis 3.
PRISM-U2 Methodology:
Intervention arm
Attendants will be trained by a study team member to
identify when IV fluid bottles are empty.
Once resuscitation begins, attendant will alert the medical
ward study team medical officer (STMO) that the fluid bottle
needs changing.
Bottles of normal saline will be provided for appropriate
early fluid resuscitation within the first 6 hours of
presentation.




All patients will receive enough fluid sufficient for a fluid
challenge of 30 cc/kg in the first 60 minutes and subsequent
fluid challenges for every 60-minute period thereafter.
Role of STMO:





Available on the ward to assist attendants who need help with
their patient.
To assess whether fluid bottles are empty every 30 minutes.
If bottle empty and STMO not alerted by attendant, STMO will
replace fluid bottle and document reason why attendant did
not alert him/her.
To monitor vital signs every hour (including RR, O2 sats, BP)
for the first 6 hours of hospital admission
PRISM U2: Risks

Fluid overload leading to pulmonary edema.






A thorough baseline cardiopulmonary exam will be
performed by the monitoring study team member
All subjects in the intervention arm will have hourly O2
saturation monitoring and repeat cardiopulmonary
exams
If pulmonary edema occurs, chest XRAY, nasal
cannula oxygen and furosemide will be available for
administration if co-investigator assesses that they
are clinically warranted.
Data Safety Monitoring Board (DSMB) in place to
ensure that in-hospital mortality is not higher than
expected
Venipuncture
Risks from Tissue Banking and Genetic
Testing

All samples will be linked and coded in order to
protect from disclosure.
PRISM U2: Benefits




Laboratory and microbiology tests which
otherwise might not be afforded will be
available to patients and their treating physician
as soon as results are available.
Because of the 30-day follow-up contact, ill
patients will be asked to return to the hospital
for evaluation.
Receiving adequate fluid resuscitation has
decreased sepsis mortality in other settings—
May help to decrease the high mortality in this
setting
Results from the study may lead to policy
changes which increase funding for fluids and
health workers—May provide a solution to the
current health care worker crisis contributing to
high sepsis-associated mortality in this setting.
PRISM-U2, Capacity
Building




Providing health workers with algorithms for
the care of critically ill patients
Including a PGY student in the study to
assist with thesis development and train in
laboratory research
Teaching students and interns about sepsis
management
Donating study supplies to respective
hospitals after enrollment is complete
Acknowledgments

PRISM-U Study Team

Mulago Hospital
•
•
•
•

Dr. Angelo Nganizi
Dr. Cassim Kalisa
Dr. Kasozi Kimuli
Mr. Samson Omongot
Masaka Hospital
• Dr. Francis Ssali
• Mr. Patrick Ddikusoka
• Sister Scholastica Sekayiba






Dr. Jackie Mabweijano (head of casualty, Mulago)
Nurses and Red Cross workers of the Mulago and
Masaka Casualty Departments
Ebenezer Labs (Kampala), AID Child (Masaka), and
Uganda Cares (Masaka) for laboratory support
Infectious Diseases Institute
UVA Center for Global Health—Pfizer Initiative for
International Health
Dr. Michael Scheld
Methods: Data collection






Fulfillment of inclusion criteria assessed at A&E
Temperature, heart rate, respiratory rate, and blood
pressure obtained at enrollment and 6 and 24 hours
afterwards.
Followed patients from emergency ward to medical
wards at both sites until discharge or death.
The amount of SIRS criteria fulfilled, IV fluid
resuscitation provided and type of empiric antimicrobial
agents administered in the first 24 hours were
recorded.
Laboratory and culture results provided to primary
medical team to assist in care of patients.
Outcomes measured:



Length of hospitalization
In-hospital mortality
30-day mortality
Methods: Laboratory evaluation




Rapid HIV-1 antibody testing and malaria thick smears
were performed on site at each hospital.
Portable whole blood lactate (PWBL) was performed on
whole blood collected by finger stick.
Mulago:
 Complete blood count (CBC) with differentials
 CD4 counts
 Serum electrolytes
 Cortisol
 Albumin
Masaka:
 CBC with differentials
 CD4 counts
Methods: Microbiology


Mulago:
 Aerobic blood cultures performed at the
Makerere University microbiology lab
 Mycobacterial cultures performed at JCRC
• IS6110 PCR amplification used to further
identify positive AFB smears as MTB complex
or NTM
Masaka:
 Aerobic blood cultures were performed at the
nearby Rakai Health Sciences Program
laboratory
 Mycobacterial cultures not performed at this site.
Results: Empiric antibiotic
administration

Fifty-two different empiric antibiotic
combinations were used by the admitting
doctors caring for the study patients.



Antibiotic regimens included ampicillin, penicillin,
chloramphenicol, ceftriaxone, gentamicin,
metronidazole, TMP-SMX, amoxicillin, ampicillincloxacillin, cefuroxime, and erythromycin.
Availability at any given time was random and
inconsistent.
85.9% of patients received some empiric
antibiotics regimen

No mortality benefit seen in patients receiving any
random empiric regimen compared to patients
receiving no empiric antibiotics
• 23.8% vs 22.6%, P=0.849
Empiric antibiotic
administration, cont


Appropriate antibiotic usage was defined as using an
empiric antibiotic regimen to which the isolate was
found to be sensitive.
Among aerobic cultures where susceptibilities were
tested (n=30),
 Decreased total mortality in patients receiving
appropriate vs. inappropriate empiric antibiotics
• 18.2% vs 50%, P=0.074

Increased survival for discharged patients who
received appropriate therapy vs. inappropriate
therapy
• 100% vs. 69.2%, P=0.066

95% (19/20) of Salmonella isolates were resistant to
chloramphenicol.