Ashraf Coovadia

2005 American Heart Association (AHA) guidelines for cardiopulmonary resuscitation (CPR) and emergency cardiovascular care (ECC) of pediatric and neonatal patients: Pediatric advanced life support

This publication presents the 2005 American Heart Association (AHA) guidelines for cardiopulmonary resuscitation (CPR) and emergency cardiovascular care (ECC) of the pediatric patient and the 2005 American Academy of Pediatrics/AHA guidelines for CPR and ECC of the neonate. The guidelines are based on the evidence evaluation from the 2005 International Consensus Conference on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations, hosted by the American Heart Association in Dallas, Texas, January 23–30, 2005. The “2005 AHA Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care” contain recommendations designed to improve survival from sudden cardiac arrest and acute life-threatening cardiopulmonary problems. The evidence evaluation process that was the basis for these guidelines was accomplished in collaboration with the International Liaison Committee on Resuscitation (ILCOR). The ILCOR process is described in more detail in the “International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations.” The recommendations in the “2005 AHA Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care” confirm the safety and effectiveness of many approaches, acknowledge that other approaches may not be optimal, and recommend new treatments that have undergone evidence evaluation. These new recommendations do not imply that care involving the use of earlier guidelines is unsafe. In addition, it is important to note that these guidelines will not apply to all rescuers and all victims in all situations. The leader of a resuscitation attempt may need to adapt application of the guidelines to unique circumstances. The following are the major pediatric advanced life support changes in the 2005 guidelines: There is further caution about the use of endotracheal tubes. Laryngeal mask airways are acceptable when used by experienced providers. Cuffed endotracheal tubes may be used in infants (except newborns) and children in in-hospital settings provided that cuff inflation pressure is kept <20 cm H2O. Confirmation of tube placement requires clinical assessment and assessment of exhaled carbon dioxide (CO2); esophageal detector devices may be considered for use in children weighing >20 kg who have a perfusing rhythm. Correct placement must be verified when the tube is inserted, during transport, and whenever the patient is moved. During CPR with an advanced airway in place, rescuers will no longer perform “cycles” of CPR. Instead, the rescuer performing chest compressions will perform them continuously at a rate of 100/minute without pauses for ventilation. The rescuer providing ventilation will deliver 8 to 10 breaths per minute (1 breath approximately every 6–8 seconds). Timing of 1 shock, CPR, and drug administration during pulseless arrest has changed and now is identical to that for advanced cardiac life support. Routine use of high-dose epinephrine is not recommended. Lidocaine is de-emphasized, but it can be used for treatment of ventricular fibrillation/pulseless ventricular tachycardia if amiodarone is not available. Induced hypothermia (32–34°C for 12–24 hours) may be considered if the child remains comatose after resuscitation. Indications for the use of inodilators are mentioned in the postresuscitation section. Termination of resuscitative efforts is discussed. It is noted that intact survival has been reported following prolonged resuscitation and absence of spontaneous circulation despite 2 doses of epinephrine. The following are the major neonatal resuscitation changes in the 2005 guidelines: Supplementary oxygen is recommended whenever positive-pressure ventilation is indicated for resuscitation; free-flow oxygen should be administered to infants who are breathing but have central cyanosis. Although the standard approach to resuscitation is to use 100% oxygen, it is reasonable to begin resuscitation with an oxygen concentration of less than 100% or to start with no supplementary oxygen (ie, start with room air). If the clinician begins resuscitation with room air, it is recommended that supplementary oxygen be available to use if there is no appreciable improvement within 90 seconds after birth. In situations where supplementary oxygen is not readily available, positive-pressure ventilation should be administered with room air. Current recommendations no longer advise routine intrapartum oropharyngeal and nasopharyngeal suctioning for infants born to mothers with meconium staining of amniotic fluid. Endotracheal suctioning for infants who are not vigorous should be performed immediately after birth. A self-inflating bag, a flow-inflating bag, or a T-piece (a valved mechanical device designed to regulate pressure and limit flow) can be used to ventilate a newborn. An increase in heart rate is the primary sign of improved ventilation during resuscitation. Exhaled CO2 detection is the recommended primary technique to confirm correct endotracheal tube placement when a prompt increase in heart rate does not occur after intubation. The recommended intravenous (IV) epinephrine dose is 0.01 to 0.03 mg/kg per dose. Higher IV doses are not recommended, and IV administration is the preferred route. Although access is being obtained, administration of a higher dose (up to 0.1 mg/kg) through the endotracheal tube may be considered. It is possible to identify conditions associated with high mortality and poor outcome in which withholding resuscitative efforts may be considered reasonable, particularly when there has been the opportunity for parental agreement. The following guidelines must be interpreted according to current regional outcomes: When gestation, birth weight, or congenital anomalies are associated with almost certain early death and when unacceptably high morbidity is likely among the rare survivors, resuscitation is not indicated. Examples are provided in the guidelines. In conditions associated with a high rate of survival and acceptable morbidity, resuscitation is nearly always indicated. In conditions associated with uncertain prognosis in which survival is borderline, the morbidity rate is relatively high, and the anticipated burden to the child is high, parental desires concerning initiation of resuscitation should be supported. Infants without signs of life (no heartbeat and no respiratory effort) after 10 minutes of resuscitation show either a high mortality rate or severe neurodevelopmental disability. After 10 minutes of continuous and adequate resuscitative efforts, discontinuation of resuscitation may be justified if there are no signs of life.

PMTCT from research to reality — results from a routine service

OBJECTIVES Assessment of the efficacy of a prevention of mother-to-child transmission (PMTCT) programme in a routine service setting in comparison to a research environment. DESIGN Descriptive study over a 13-month period utilising retrospective data obtained from hospital records complemented by prospective data on a sample of patients enrolled in a study to determine an affordable HIV diagnostic protocol for infants. SETTING Routine PMTCT service at Coronation Women and Childrens Hospital (CWCH) situated in Johannesburg and affiliated to the University of the Witwatersrand. SUBJECTS Pregnant women known to be HIV infected who delivered at CWCH from 1 October 2001 to 31 October 2002. OUTCOME MEASURES The HIV transmission rate to infants, which reflects nevirapine (NVP) delivery and infant feeding practices, and follow-up rates of perinatally exposed children. RESULTS Of the 8,221 deliveries, 1,234 (15%) occurred in women known to be HIV infected. HIV transmission rates of 8.7% at 6 weeks and 8.9% at 3 months of age in the study population verifies the high rate of NVP administration and the ability of women to formula-feed their babies and abstain from breast-feeding. More than one-third of infants never return for follow-up and more than 70% are lost to follow-up by 4 months of age. CONCLUSIONS The low HIV transmission rate confirms the efficacy of this routine service PMTCT programme. HIV-infected children are not being identified for medical management as part of PMTCT follow-up. It is imperative that record keeping is improved to facilitate ongoing monitoring.

Effects of highly active antiretroviral therapy duration and regimen on risk for mother-to-child transmission of HIV in Johannesburg South Africa.

Background:Limited information exists about effects of different highly active antiretroviral therapy (HAART) regimens and duration of regimens on mother-to-child transmission (MTCT) of HIV among women in Africa who start treatment for advanced immunosuppression. Methods:Between January 2004 to August 2008, 1142 women were followed at antenatal antiretroviral clinics in Johannesburg. Predictors of MTCT (positive infant HIV DNA polymerase chain reaction at 4-6 weeks) were assessed with multivariate logistic regression. Results:Mean age was 30.2 years (SD = 5.0) and median baseline CD4 count was 161 cells per cubic millimeter (SD = 84.3). HAART duration at time of delivery was a mean 10.7 weeks (SD = 7.4) for the 85% of women who initiated treatment during pregnancy and 93.4 weeks (SD = 37.7) for those who became pregnant on HAART. Overall MTCT rate was 4.9% (43 of 874), with no differences detected between HAART regimens. MTCT rates were lower in women who became pregnant on HAART than those initiating HAART during pregnancy (0.7% versus 5.7%; P = 0.01). In the latter group, each additional week of treatment reduced odds of transmission by 8% (95% confidence interval: 0.87 to 0.99, P = 0.02). Conclusions:Late initiation of HAART is associated with increased risk of MTCT. Strategies are needed to facilitate earlier identification of HIV-infected women.

Polymerase chain reaction for diagnosis of human immunodeficiency virus infection in infancy in low resource settings.

Background: Diagnosis of human immunodeficiency virus (HIV) is essential for accessing treatment. Current HIV diagnostic protocols for infants require adaptation and validation before they can be implemented in the developing world. The timing and type of HIV assays will be dictated by country-specific circumstances and experience from similar settings. The performance of an HIV-1 DNA polymerase chain reaction (PCR) test, and in particular a single test at 6 weeks of age, in diagnosing HIV subtype C infection acquired in utero or peripartum was assessed. Methods: A retrospective review of 1825 Amplicor HIV-1 DNA PCR version 1.5 tests performed between 2000 and 2004 in 2 laboratories in Johannesburg, South Africa on 769 effectively non-breast-fed infants from 3 clinically well characterized cohorts was undertaken. The HIV status of each infant was used as the standard against which the HIV PCR results were compared. Results: The overall sensitivity and specificity of the HIV PCR test were 99.3 and 99.5% respectively. A single test was 98.8% sensitive and 99.4% specific in the 627 infants tested at 6 weeks of age (58 HIV-infected and 569 HIV-uninfected). Repeat testing of all positive HIV PCR tests minimized false positive results. Conclusions: In resource-poor settings where HIV PCR testing in an environment of good laboratory practice is feasible, a single 6-week HIV DNA PCR test can increase identification of HIV-infected children substantially from current levels. Further operational research on how best to implement and monitor such a diagnostic protocol in specific local settings, especially in breast-fed infants, is necessary.

Persistent Minority K103N Mutations among Women Exposed to Single-Dose Nevirapine and Virologic Response to Nonnucleoside Reverse-Transcriptase Inhibitor–Based Therapy

OBJECTIVE We investigated whether there are long-lasting effects of exposure to single-dose nevirapine (sdNVP) treatment on virologic response to nonnucleoside reverse-transcriptase inhibitor (NNRTI)-based therapy among human immunodeficiency virus (HIV)-infected women. METHODS An observational epidemiologic study was conducted in Johannesburg, South Africa. Initial and sustained virologic response to NNRTI-based therapy was compared between 94 HIV-infected women who had received sdNVP 18-36 months earlier and 60 unexposed, HIV-infected women who had been pregnant 12-36 months earlier. Viral load was measured every 4 weeks up to week 24 and then every 12 weeks up to week 78. Time to viral suppression (viral load, <50 copies/mL) and confirmed rebound in the viral load (viral load, >400 copies/mL) were compared. Drug resistance was assessed using K103N allele-specific real-time polymerase chain reaction assay and population sequencing. RESULTS Almost all women (97.5% of sdNVP-exposed women and 91.3% of sdNVP-unexposed women; P = .21) achieved viral suppression by week 24, and similar percentages of sdNVP-exposed and -unexposed women (19.4% and 15.1%, respectively) experienced viral rebound within 78 weeks after treatment (P = .57). K103N was detected with the K103N allele-specific real-time polymerase chain reaction assay among sdNVP-exposed and -unexposed women before treatment; detection was strongly predictive of inadequate viral response: 60.9% of women for whom K103N was detected in either viral RNA or DNA did not experience viral suppression or experienced viral rebound, compared with 15.1% of women for whom K103N was not detected (P < .001). After treatment, the M184V mutation occurred less frequently among sdNVP-exposed women than among sdNVP-unexposed women, but the frequency of NNRTI-associated mutations was similar between these groups of women with inadequate virologic response. CONCLUSIONS Exposure to sdNVP in the prior 18-36 months was not associated with a reduced likelihood of achieving and sustaining viral suppression while receiving NNRTI-based therapy. However, women with minority K103N mutations before treatment had a reduced durability of virologic suppression.

African infants’ CCL3 gene copies influence perinatal HIV transmission in the absence of maternal nevirapine

Background:Individuals with more copies of CCL3L1 (CCR5 ligand) than their population median have been found to be less susceptible to HIV infection. We investigated whether maternal or infant CCL3L1 gene copy numbers are associated with perinatal HIV transmission when single-dose nevirapine is given for prevention. Method:A nested case–control study was undertaken combining data from four cohorts including 849 HIV-infected mothers and their infants followed prospectively in Johannesburg, South Africa. Access to antiretroviral drugs for the prevention of perinatal transmission differed across the cohorts. Maternal and infant CCL3L1 gene copy numbers per diploid genome (pdg) were determined by real-time polymerase chain reaction for 79 out of 83 transmitting pairs (∼10% transmission rate) and 235 randomly selected non-transmitting pairs. Results:Higher numbers of infant, but not maternal, CCL3L1 gene copies were associated with reduced HIV transmission (P = 0.004) overall, but the association was attenuated if mothers took single-dose nevirapine or if the maternal viral load was low. Maternal nevirapine was also associated with reduced spontaneously released CCL3 (P = 0.007) and phytohemagglutinin-stimulated CCL3 (P = 0.005) production in cord blood mononuclear cells from uninfected infants. Conclusion:We observed a strong association between higher infant CCL3L1 gene copies and reduced susceptibility to HIV in the absence of maternal nevirapine. We also observed a reduction in newborn CCL3 production with nevirapine exposure. Taken together, we hypothesize that nevirapine may have direct or indirect effects that partly modify the role of the CCR5 ligand CCL3 in HIV transmission, obscuring the relationship between this genetic marker and perinatal HIV transmission.

Immune reconstitution inflammatory syndrome among HIV-infected South African infants initiating antiretroviral therapy.

Objectives:To determine the incidence, clinical manifestations and risk factors for immune reconstitution inflammatory syndrome (IRIS) in young children initiating highly active antiretroviral therapy (HAART). Design:A prospective cohort of antiretroviral-naïve HIV-infected children less than 24 months of age enrolled in a treatment strategies trial in Johannesburg, South Africa. Methods:Among 169 HIV-infected children initiating HAART, April 2005 to November 2006, the records of 83 children suspected to have IRIS within 6 months of starting treatment were reviewed to determine whether they met criteria for IRIS. Seven were excluded due to incomplete follow-up. Pretreatment and post-treatment characteristics of children with and without IRIS were compared. Results:Overall, 34/162 (21%) children developed IRIS at a median of 16 days (range 7–115 days) post-HAART initiation. Bacille Calmette-Guérin reaction was most common occurring in 24/34 (71%) children, primarily injection site lesions and/or ipsilateral axillary lymphadenitis with abscess. Other IRIS conditions (not mutually exclusive) included Mycobacterium tuberculosis (n = 12), cytomegalovirus pneumonia (n = 1), Streptococcus pneumonia sepsis (n = 1), and severe seborrheic dermatitis (n = 1). Children with IRIS were younger (median age 7 vs. 10 months, P = 0.007) with a lower CD4 cell percentage (median 13.9 vs. 19.2, P = 0.009) at HAART initiation than controls. After 24 weeks on HAART, 62% of IRIS cases vs. 28% of controls had HIV RNA more than 400 copies/ml (P = 0.001), odds ratio = 2.88 (95% confidence interval = 1.14–7.29) after adjusting for baseline factors. Conclusion:Infants and young children with advanced HIV disease initiating HAART are at high risk for developing IRIS, leading to additional morbidity and possibly impairing virologic response to antiretroviral treatment.

Evaluation of Dried Whole Blood Spots Obtained by Heel or Finger Stick as an Alternative to Venous Blood for Diagnosis of Human Immunodeficiency Virus Type 1 Infection in Vertically Exposed Infants in the Routine Diagnostic Laboratory

ABSTRACT The diagnostic accuracy of the Roche Amplicor human immunodeficiency virus type 1 DNA PCR assay (version 1.5) on DNA extracted from pediatric heel prick dried blood spots using Roche MagNA Pure nucleic acid purification technology was evaluated. The methodologies transfer successfully from the labor-intensive research laboratory to the high-throughput automated routine laboratory.

Cutting Edge: Unusual NK Cell Responses to HIV-1 Peptides Are Associated with Protection against Maternal-Infant Transmission of HIV-1

Most infants exposed to HIV-1 in utero and at delivery do not acquire infection. We show that mothers and infants who have CD3-negative cells that respond to HIV-1 peptides are substantially less likely to transmit and acquire infection, respectively. The CD3-negative cells, shown to be NK cells, respond with remarkable specificity and high magnitude to HIV-1 peptides from Env (envelope) and Reg (regulatory) protein regions, as measured by a whole blood intracellular cytokine assay only in the context of HIV-1 infection or exposure. These findings identify an important new measure of protective immunity to HIV-1 that highlights the importance of innate immunity in preventing the establishment of HIV-1 infection.

Integration of antiretroviral treatment within antenatal care in Gauteng Province, South Africa.

Background:Antenatal clinics are a key entry point into HIV treatment and care, together with interventions to reduce mother-to-child transmission (MTCT). Further evaluation is needed of interventions linking antenatal with antiretroviral (ARV) treatment services and effectiveness of triple-ARV regimens for reducing MTCT in resource-constrained settings. Methods:Data were gathered from HIV-infected women attending antenatal care from June 2004 to July 2005 at Coronation Women and Children Hospital, South Africa. After a patient record review, interventions were implemented to strengthen service linkages and integrate ARV treatment within antenatal care. Laboratory investigations were streamlined, including CD4 cell count testing at the first antenatal visit. MTCT risk for women initiating ARV treatment is compared with that of women-infant pairs receiving single-dose nevirapine (sd-NVP). Results:In total, 164 pregnant women initiated ARV treatment and 863 received sd-NVP. After changes to service delivery, time-to-treatment initiation was reduced from a median of 56 days to 37 days (P = 0.041). The risk of MTCT for women receiving ARV treatment (5 [4.3%] of 116 women) was lower than for those given sd-NVP (74 [10.7%] of 692 women; P = 0.032). Conclusions:Strengthening linkages and integrating key components of ARV treatment within antenatal care reduces time-to-treatment initiation. In this setting, among women with a high MTCT risk, triple-ARV regimens are effective in reducing HIV infection in infants.