Sex: U
Vaccine: DTAP, HEP, HIBV, IPV, PPV
Symptoms: Apnoea, Extubation, Intubation
Clinical narrative: It was reported in a literature article that "There were 2 infants who required intubation during the postimmunization period, 1 of whom was intubated during the first 24 hours after receipt of HBV vaccine, DTaP vaccine (mfr unknown), IPV (mfr unknown), PedvaxHIB (mfr. unknown) and PNEUMOVAX 23 manufacturer unknown and was extubated during the 48- to 72-hour postimmunization period.  The other infant was intubated during the 24- to 48-hour period after administration of IPV (third set of vaccines) and was extubated within the next time period.  Neither of those infants experienced cardiorespiratory events during the 24 hours before immunization or experienced any other cardiorespiratory events after extubation.  Immunization of preterm infants is recommended for all infants after the chronological age of 2 months.  Immunization of preterm infants has been generally considered safe, effective, and particularly necessary, however, because premature infants are at high risk from vaccine-preventable disease.  Of concern, however, have been observations that premature infants immunized while in the NICU seem to experience either an increase in or a resurgence of apnea after vaccination.  A number of studies have investigated the incidence of apnea after immunization in the NICU.  An early retrospective study observed that 20% of premature infants developed apnea after immunization with the DTP vaccine.  Subsequent studies reported an incidence of 12% after administration of the DTP vaccine, 3 incidences of 17% to 20% after administration of the DTP vaccine in combination with Hib, and abnormalities in cardiorespiratory signs for 30% of patients after administration of the DTP vaccine, Hib vaccine, IPV, and HBV vaccine.  Most apneic events have been reported as mild, although one study reported 4 cases of severe apnea after immunization with the DTP and Hib vaccines.  Studies with the DTaP vaccine reported similar incidences of postimmunization apnea.  In general, studies have found a number of factors to be associated with postimmunization apnea, including age and weight at immunization, gestational age, and history of mechanical ventilation or chronic lung disease.  More-recent studies have suggested that the greatest risk of postimmunization apnea is among patients with preexisting cardiorespiratory events.  his study, we report on the characteristics of immunized NICU infants, with special emphasis on factors associated with postimmunization apnea among those vaccinated NICU patients.  " The initial subject cohort consisted of all infants identified in a state who were born between January 1, 1997, and December 31, 2003.  We chose a hospital stay of 53 days because we wished to study infants who both received vaccines at day 56 or later (corresponding to the time of their 2-month vaccines) and had chart data available for the 72 hours preceding immunization, to meet the criteria for a separate immunization safety study.  Because multiple vaccines were sometimes divided and administered over the course of 2 days, a set of vaccines consisted of 1 to 5 vaccines administered over the course of 48 hours.  We conducted detailed chart abstraction for our subjects for 3 periods, beginning 24 hours before immunization with the first vaccine in a given set (preimmunization) and continuing through two 24-hour periods (0-24 hours and 24-48 hours) after administration of the last vaccine in the set.  We obtained baseline information on age, birth weight, gestational age, vaccination status, from the Neonatal Minimum Data Set. "  "To evaluate apnea after discharge from the NICU, we examined hospital and emergency department visits for apnea diagnoses captured within the electronic medical record during the 2 weeks after hospital discharge.  We excluded diagnoses of apnea listed in the electronic medical record in conjunction with an identifiable cause (eg, Streptococcus pneumonia infection).  During the 7-year study period (1997-2003), the vaccines administered in the NICU included polio vaccines (IPV and oral poliovirus vaccine), diphtheria/tetanus/pertussis vaccine (either DTP or DTaP vaccine), Hib vaccine, HBV vaccine, Streptococcus pneumoniae vaccine (pneumococcal conjugate vaccine), and trivalent influenza vaccine.  Because new vaccines such as pneumococcal conjugate vaccine were introduced during this period, infants born in the later years might have received additional vaccines not available earlier.  Infants born earlier in the study period might have received the combination DTP/Hib or DTaP/Hib vaccines, whereas those born later might have received DTaP/IPV/HBV vaccine (Pediarix, GlaxoSmithKline Biologicals, To be consistent with previous studies and to enable future comparisons, we define apnea as a cessation of respiration for 20 seconds, bradycardia as a decrease in heart rate to 100 beats per minute for a period of 20 seconds, and desaturation as a decrease in the oxygen saturation to 88%, as measured with pulse oximetry.  We further categorized cardiorespiratory events as benign, moderate, or severe, on the basis of the need for intervention and the type of respiratory support.  We considered cardiorespiratory episodes as benign when the resolution was spontaneous or the infant self-recovered, moderate when the infants responded to tactile stimulation and/or low-flow oxygen administration (blow by), and severe when bag-mask ventilation, chest compressions, ventilation/intubation, epinephrine administration, or chemical or electrical resuscitation was required.  In addition, we regarded bradycardia as moderate in severity if the heart rate decreased to <40 beats per minute (regardless of duration), even if spontaneous recovery occurred.  Similarly, we deemed a desaturation event as moderate if the pulse oximeter reading decreased to <60%, even with spontaneous recovery.  Infants with completed chart abstractions consisted of 259 boys (52.1%) and 237 girls (47.7%) (1 infant's gender was not specified) and included 456 infants (91.8%) with gestational age of <31 weeks.  The mean corrected gestational age at receipt of the first immunization was 36.8 weeks, with a mean weight of 2134 g.  At receipt of the first vaccine series, 106 infants (21%) were receiving caffeine as a cardiorespiratory stimulant and 242 infants (49%) were receiving some form of supplemental oxygen.  All 497 immunized infants received 1 set of vaccines, with 63 (12.7%) of 497 infants receiving 2 sets, 15 (3%) of 497 receiving 3 sets, and 5 (1%) of 497 receiving 4 sets.  Seventy-three infants (14.7%) received only the HBV vaccine during their first set of vaccines.  The remaining 424 infants (85.3%) received 1 of the following vaccines, either with or without the HBV vaccine, as part of their first set of vaccines: DTP vaccine, DTaP vaccine, IPV, oral poliovirus vaccine, Hib vaccine, or pneumococcal conjugate vaccine.  A total of 342 infants (68.8%) received the first set of vaccines on the same day, 120 infants (24.1%) over 2 days, 34 infants (6.8%) over 3 days, and 1 infant over 4 days.  During the 24 hours before receipt of the first set of vaccines, 27 infants had 1 episode of apnea; during the 48 hours after the first set of vaccines, 65 infants had 1 episode of apnea.  All episodes of preimmunization apnea occurred in infants who were born at <31 weeks of gestation.  There were 2 infants who required intubation during the postimmunization period, 1 of whom was intubated during the first 24 hours after receipt of HBV vaccine, DTaP vaccine, IPV, Hib vaccine, and pneumococcal conjugate vaccine and was extubated during the 48- to 72-hour postimmunization period.  The other infant was intubated during the 24- to 48-hour period after administration of IPV (third set of vaccines) and was extubated within the next time period.  Neither of those infants experienced cardiorespiratory events during the 24 hours before immunization or experienced any other cardiorespiratory events after extubation.  We sought to compare the preimmunization characteristics of infants with postimmunization apnea with those of infants without postimmunization apnea.  We limited this analysis to infants with gestational age of <31 weeks because 95% of the episodes of postimmunization apnea (62 of 65 episodes) occurred among infants born at <31 weeks of gestation.  Bivariate analysis revealed that postimmunization apnea was markedly associated with the presence of preimmunization apnea (P <.0001), although desaturation and/or bradycardia without apnea was not significantly related."  "We investigated whether the number of apneic episodes during the 24 hours before immunization predicted postimmunization apnea by evaluating the 24 infants who had moderate preimmunization apnea (representing 92% of infants with preimmunization apnea).  Eight of the 16 infants with 1 moderate episode of preimmunization apnea had postimmunization apnea, whereas all 8 infants with >1 episode of preimmunization apnea had postimmunization apnea (P = .02), which suggests that infants with >1 episode of apnea are more likely than those with a single episode to have postimmunization apnea.  "Although preimmunization apnea was the most important predictor of postimmunization apnea, it was of interest to identify predictors of postimmunization apnea among infants who were free of apnea in the 24 hours before immunization.  Of the 49 infants who met these criteria, 1 infant immunized 1 day before discharge was apneic at home 3 days after discharge, requiring emergency bag-mask ventilation and subsequent readmission to the hospital.  Another infant immunized 1 day before discharge was readmitted 8 days after discharge with an admission diagnosis of apnea.  No other infants in this group had emergency department visits for apnea.  By comparison, 448 infants were discharged >48 hours after vaccination, of whom 4 (immunized 6-27 days before discharge) were readmitted to the hospital with a diagnosis of apnea within 2 weeks after discharge; an additional 4 infants (immunized 5-34 days before discharge) were seen in the emergency department with apnea but were not admitted.  "We observed more episodes of apnea during the 48-hour postimmunization time period than during the 24 hours before immunization, with the number of infants with apnea increasing from 27 to 65.  Although this study captured preimmunization cardiorespiratory events only for the 24-hour period before immunization, this time frame is consistent with other studies.  Because caffeine is used as a treatment for apnea of prematurity, one might expect that caffeine administration could be used to distinguish infants at risk for developing postimmunization apnea.  However, caffeine treatment at the time of immunization did not predict postimmunization apnea in the multivariate model.  Similarly, neither bivariate nor multivariate analyses identified preimmunization bradycardia and/or desaturation as a risk factor for postimmunization apnea.  The finding is somewhat unexpected, because apnea, bradycardia, and desaturation frequently occur in conjunction with each other in premature infants, and infants with cardiorespiratory symptoms before immunization have been noted to have a five- to eightfold greater risk of developing postimmunization events.  Unlike t.  In clinical practice, however, infants who are symptomatic with apnea just before immunization are likely to be already undergoing cardiorespiratory monitoring and to remain in the hospital after immunization because of their clinical condition.  In contrast, infants without apnea immediately before immunization may be more likely to be assessed as being in clinically stable condition and to be discharged soon after immunization.  Although additional studies will be needed to determine whether infants with these predictors are at greater risk for hospital readmission because of apnea, this observation, together with the findings from the current study, suggests that cardiorespiratory monitoring after immunization of infants with risk factors, regardless of he presence of preimmunization apnea, should be considered.  An important consideration in this study is that the apnea observed in the postimmunization period may not reflect an adverse response to immunization but may be attributable to normal variations in apnea occurrence in this NICU population.  Clinicians may not have vaccinated infants perceived to be at risk for a vaccine-related adverse event until the infants were without apnea for a period of time.  This bias, similar to the healthy vaccinee phenomenon, would result in a healthier preimmunization population, compared with a similar, unvaccinated, NICU population.  Although we think that the postimmunization apnea we observed did not result exclusively from this bias, because there were 27 infants with symptoms of apnea (including 4 infants with severe apnea) before the first immunization, this study was unable to assess this confounder, which may be important because preimmunization data were collected for only 24 hours before vaccination.  An additional study limitation is that apneic events that occurred between administration of the first and last vaccines in a given set were not captured.  Although we assumed that many clinicians would wait for a period of time before completing a set of immunizations for an infant with temporally related severe apnea, it is possible that this study underestimated the true incidence of postimmunization benign and moderate apneic events for infants who received vaccines spread over a period of time.  Furthermore, this study limited postimmunization analysis to the 48 hours after vaccination, because of the increasing proportion of infants being discharged from the hospital in the days after immunization.   Finally, this study was based on data recorded by nurses, whose thresholds for labeling an event as "apnea" or "bradycardia" might vary, even with specified internal nursery protocols.  Although it is true that some variation in accuracy is to be expected from such documentation, it is also true that neonatologists rely on these data when they perform their daily rounds, and basing analyses on such data is reasonable.  Future advances in the understanding of apnea of prematurity may permit a more-accurate and more-nuanced reexamination of findings from this and other studies. "  ""Previous studies suggested with postimmunization apnea is associated with administration of both whole-cell2, 3, 5, 6, 8 and acellular4, 7 pertussis vaccines.  Because of its retrospective design, the current study evaluated postimmunization apnea after.  This finding suggests that postimmunization apnea in susceptible premature infants may be related to a general inflammatory response, rather than the response to particular vaccine antigens.  In support of this idea, previously demonstrated a temporal relationship between vaccination of premature infants and increases in interleukin-6 and C-reactive protein levels.  The findings from this study reveal that most important risk factor for developing postimmunization apnea is the presence of apnea within the previous 24 hours.  It is not known whether apnea occurring >24 hours before immunization is a risk factor but, for infants without apnea during the 24 hours before vaccination, more severe illness at birth, younger age, and lower weight are important predictors of postimmunization apnea.  The results from this study support a recommendation for monitoring susceptible infants for 48 hours after immunization in the NICU. "  Upon internal review apnea requiring intubation was determined to be an other important medical event.  A copy of the published article is attached to further document the patients experience.