Iatrogenic Complications in the Neonatal Intensive Care Unit

KC Sekar Department of Pediatrics, Neonatal-Perinatal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

In neonatal medicine, significant iatrogenic events leading With the introduction of novel technologies and approaches in neonatal to severe morbidity and death have been identified and addressed. care and the lack of appropriately designed and well-executed randomized Low incubator temperature leading to death (1930); irradiation clinical trials to investigate the impact of these interventions, iatrogenic causing thyroid cancer, and excess oxygen exposure causing complications have been increasingly seen in the neonatal intensive care retinopathy of prematurity and blindness (1940); excess unit. In addition, increased awareness and the introduction of more synthetic vitamin K, sulfisoxazole and chloramphenicol causing appropriate quality control measures have resulted in higher levels of kernicterus and gray baby syndrome (1950); intrauterine suspicion about and increased recognition of complications associated with exposure to thalidomide causing limb defects (1960); umbilical delivery of care. The incidence of complications also rises with the increased arterial catheter, tolazoline and total parenteral nutrition (TPN) length of hospital stay and level of immaturity. Approximately half of the causing thrombosis, hypotension and essential fatty acid deficiency, iatrogenic complications are related to medication errors. The other respectively (1970); vitamin E and propylene glycol causing complications are due to nosocomial infections, insertion of invasive organ damage, hyperosmolarity and seizures (1980); and catheters, prolonged mechanical ventilation, administration of parenteral mechanical ventilation and systemic corticosteroid administration nutrition solution, skin damage and environmental complications. Adopting causing bronchopulmonary dysplasia (BPD) and affecting newer technologies and preventive measures might decrease these brain growth (1990) have all been reported.3 As extremely complications and improve outcomes. Quality improvement projects low birth weight infants are being treated more frequently targeting areas for improvement are expected to build team spirit and in the neonatal intensive care unit (NICU) for long periods further improve the outcomes. In addition, participation in national of time, new complications are beginning to emerge, such reporting systems will enhance education and provide an opportunity to as skin damage, sensorineural effects of a hostile environment compare outcomes with peer institutions. in the NICU (sound, light) and an increase in nosocomial Journal of Perinatology (2010) 30, S51–S56; doi:10.1038/jp.2010.102 infections. Keywords: iatrogenic; medication errors; quality improvement In the landmark Institute of Medicine report, ‘To Err is Human,’ it was estimated that 44 000 to 98 000 people die of preventable medical errors in the United States.4 Indeed, medical errors in the hospital exceeded deaths from such feared threats Introduction as motor vehicle accidents, breast cancer and AIDS. This report The medical term ‘iatrogenic’ refers to a condition that is due also classified the types of errors into four different categories: to the action of a physician or a therapy the doctor prescribed. diagnostic, treatment, preventive and miscellaneous (the latter is An iatrogenic disease may be inadvertently caused by a physician mainly related to failures of communication, equipment and or a surgeon, or a medical or surgical treatment, or a diagnostic systems). In addition, a national strategy for improvement was procedure. For example, puerperal fever (childbirth fever) was suggested, establishing a national focus, identifying and learning an iatrogenic infection before the days of antisepsis as it was from errors, raising performance standards and implementing caused by the soiled hands and instruments of the physician safety systems in health care. assisting with the delivery. If, in the course of a procedure, Neonatal medicine remains a fertile ground for iatrogenic an artery is cut and bleeds, that is an iatrogenic accident.1,2 errors because of the rapid development in technology over the last two decades, inadequate randomized trials, medical errors and Correspondence: Dr KC Sekar, Department of Pediatrics, Oklahoma University Health lack of structured across-the-board follow-up, factors responsible Sciences Center, Children’s Hospital, 1200 Everett Drive, 7th Floor, North Pavilion, for what one author calls an ‘iatroepidemic’.3 These preventable Oklahoma City, OK 73104, USA. E-mail: [email protected] mistakes could be classified as errors of execution (slips and This paper resulted from the Evidence vs Experience in Neonatal Practices conference, lapses), errors of planning (mistakes), active errors (care giver) 19 to 20 June 2009, sponsored by Dey, LP. and latent errors (issues with design and system). A list of serious Iatrogenic complications in the NICU KC Sekar S52 reportable events has been published, which consists mainly of and include the following: prescription; order communications; environmental events resulting in death and criminal events such product labeling, packaging and nomenclature; compounding; as assault causing significant harm to the patient.5 dispensing; distribution; administration; education; monitoring and use.11 The National Coordinating Council for Medication Error Reporting and Prevention categorizes the errors from ‘No Error’ Incidence of iatrogenic events in the NICU (Category A) to ‘Error Resulting in Death’ (Category I).11 In a The Harvard Medical Practice Study and the Health Cost and review of the literature, the highest rate of medication error Utilization Project Study have estimated that between 1.2 and 1.4% reported in the NICU was 5.5 medication errors per 100 of the neonates admitted to the hospital have been affected by prescriptions. The error rates varied widely due to the different medical errors by discharge.6,7 This is suspected to be an methodologies used to define medication errors, making underestimation as this was a retrospective study and it was based comparison difficult among the studies.12 A voluntary Internet- on the International Classification of Diseases-9 codes. It is also based reporting system for medical errors was evaluated by the generally accepted that there is a trend of underreporting of Vermont Oxford Network.13 Health professionals from 54 member iatrogenic events unless there is significant harm to the patient. hospitals received access to a secure Internet site for anonymous Therefore, voluntary, nonpunitive systems are thought to yield the reporting of errors, near-miss errors and adverse events. The most best estimate of iatrogenic events. One such prospective cohort frequent event reported (47%) was medication error, including study in neonates admitted to the NICU reported the incidence of nutritional agents and blood products. The most frequent iatrogenic events at 25.6 per 1000 patient days. In this population, contributing factors were failure to follow policy or protocol (47%), 8.8 events per 1000 patient days were preventable and 7.6 events inattention (27%), communication errors (22%), errors in per 1000 patient days were severe.8 Serious iatrogenic events were documentation (13%), distraction (12%), inexperience (10%), found to be less frequently preventable than minor events. It was labeling error (10%) and poor team work (9%). Serious patient also noted in this study that the commonly reported preventable harm was reported in 2% of the patients.13 This study confirms iatrogenic complications included nosocomial infections, adverse the effectiveness of a nonpunitive, voluntary reporting system and drug events, and respiratory, vascular and skin complications. In a that of learning and implementing protocols to enhance patient prospective observational study of iatrogenic events in the NICU, safety. The MEDMARX reporting system of the United States the prevalence rate was 18.0 per 100 hospitalized days.9 In this Pharmacopeia is an Internet-accessible anonymous medication study, 7.9% of the incidence was classified as life threatening and reporting system designed to allow hospitals and health-care 45.1% as harmful. Among the preventable errors, 26.9% were systems to systematically collect, analyze and report medication medication errors. The rate of iatrogenic events was much higher errors.11 The experience of the MEDMARX reporting system reveals at gestational ages of 24 to 27 weeks (57%) compared with that most of the medication errors occur during administration term gestation (3%). In addition, increased length of stay was (37%), followed by documentation (26%), dispensing (21%), independently associated with more iatrogenic events.9 A recent prescribing (15%) and monitoring (1%). Approximately two-thirds thorough review of the literature focusing on the incidence and of the errors reported reached the patient, with relatively few types of errors in neonatal intensive care could not find a causing harm. In this analysis, performance deficits and failure to systematic review or randomized controlled trial on the topic. This follow procedure or protocol were consistently identified as the review also found that the error rate was much higher in studies cause for error. In addition, distraction and workload increases using voluntary reporting than in those based on mandatory were often cited as contributing factors. The recent examples of reporting, reinforcing again the importance of the creation of a celebrity’s twins receiving an overdose of heparin and three a nonpunitive, voluntary reporting system. Among the errors other premature babies dying as a result of heparin overdose reported in the various studies reviewed, medication errors were were determined to be system problems that are preventable.3,14 the most frequent error type.10 Although these cases with heparin use are extreme examples, more A brief review of major iatrogenic events encountered in the errors occur with the use of common medications in the NICU, such NICU follows below. as antibiotics and parenteral nutrition. The top four medication errors in an NICU in the United States involved the administration of narcotics, parenteral nutrition, vasopressive agents and antibiotics.15 Medication errors In the NICU, physicians’ ordering errors were commonly noted due A medication error is any preventable event that may cause or to incorrect patient weight, dose or units. In addition, mistakes in lead to inappropriate medication use or potential harm while diluting medications, administration errors and documentation the medication is in the control of the health-care professional, discrepancies were also noted.12 Medication errors are also a frequent patient or consumer. Such events may be related to professional cause of adverse drug events. Fortunately, adverse drug events are of practice, health-care products, and/or procedures and systems, low incidence in the in-patient pediatric population compared with

Journal of Perinatology Iatrogenic complications in the NICU KC Sekar S53 adults (2.3 vs 6.5%).16 The general processes for detecting adverse enterococcus. In addition, S. aureus, Klebsiella species, drug events are well established, including classifying the events and Pseudomonas and Enterobacter, as well as fungal and viral the safety measures to be undertaken in response to the occurrence. infections, have all been reported. However, CONS appears to be the These are routinely monitored in US hospitals these days. predominant nosocomial infection accounting for 40% of all the Several strategies have been implemented to minimize infections in neonates.25,26 Symptoms of CONS infections are medication errors. Computerized physician order entry (CPOE) usually subtle and rarely cause death, except in extremely low birth has been shown to reduce medication errors from 3.2 to 0.6 per weight infants. In contrast, Gram-negative nosocomial sepsis 1000 patient days, with improved physician satisfaction.17,18 frequently presents with rapid deterioration, shock and death However, CPOE may also create new types of errors such as within 48 h.27 Risk factors for CONS infections include the use of the selection of an incorrect product. Standard medication invasive central venous catheters, parenteral nutrition solutions concentration, smart pumps and unit-dose medication distribution and intravenous lipid infusions, and frequent venipuncture and can potentially reduce medication errors. Larsen et al.19 showed heel sticks. The colonizing organisms in the skin become invasive a reduction in errors from 3.5 to 1.4 of 1000 cases using smart and cause bloodstream infections. In addition, practice-related risk pumps. An important component of minimizing medication errors factors, such as the use of corticosteroids, H2 receptor blockers and in the nursery is to have full-time dedicated clinical pharmacists heparin, also increase the risk of nosocomial infections.28,29 in the NICU. The clinical pharmacist can review medication Numerous other environmental factors might also contribute to orders daily, recommend changes in medication therapy, provide nosocomial infections, including equipment in the NICU, sinks, pharmacokinetic monitoring, medication information, staff siblings, toys, hand lotions and so on. As each individual unit is education and patient counseling, and help in discharge planning. different, bacterial surveillance and antibiotic resistance should be Having such professionals involved has also been shown to be routinely monitored. In general, better practices for prevention cost saving primarily because of close drug monitoring and of nosocomial infections should be practiced, starting with discontinuation of medications when they are no longer enforcing strict hand washing, offering better nutritional support, necessary.20–22 Finally, implementing CPOE can be very promoting breast milk feeding, practicing proper skin care, challenging in the pediatric population and in particular to the minimizing the use of vascular access, avoiding prolonged neonatal population. This is due to the lack of evidence-based data intubations if possible, instituting developmentally supportive care, on pharmacotherapy and the need for frequent updating of and establishing sound policies and procedures for central line patient’s weight as most dose determination in neonates is weight care and blood draws for laboratory studies. Finally, antibiotic dependent.11 The development of such software may not be cost- usage should be carefully monitored to decrease the risk of effective. Therefore, only a few studies have looked at its impact emergence of resistant strains of organisms.25–27 in the NICU. A retrospective review in the neonatal population showed dramatic results when a commercially available software program was successfully adjusted to accommodate NICU needs, Complications from invasive lines minimizing medication turn-around time and errors for selected Complications from peripheral and invasive lines (umbilical drugs.23 arterial catheter, umbilical venous catheter and peripherally inserted central catheters) have been frequently reported in the NICU. These lines are often essential and thus unavoidable for Nosocomial infections monitoring and nutritional support in extremely premature Nosocomial infections are deﬁned as those that occur beyond 48 h infants. However, they can cause thrombophlebitis, infections, after birth and are caused by pathogens that are not maternally inﬁltrations, thromboembolism, bleeding, pneumothorax, brachial derived. There are more than two million nosocomial infections plexus injury, and pleural and pericardial effusions. Clinical signs and 48 000 catheter-related bloodstream infections in children and of venous obstructions include renal vein thrombosis with enlarged adults in the United States. It is estimated that B17 000 deaths kidneys and hematuria, edema, cyanosis of the legs, superior vena occur in the United States from catheter-related infections alone.24 cava thrombosis presenting with edema of the head, neck and chest Nosocomial infections prolong hospital stays and add to the cost (superior vena cava syndrome), and adrenal hemorrhagic necrosis of care in the NICU. Approximately half of the nosocomial among others. Clinical signs of arterial thrombosis include infections are resistant to routine antibiotics, making this a serious congestive cardiac failure, decreased femoral pulses, decreased problem in today’s NICUs. Over the last several decades the temperature in the extremities, pulmonary hypertension, most common organisms causing nosocomial infections have respiratory distress and necrotizing enterocolitis.30,31 Pericardial changed from Staphylococcus aureus in the 1950s to effusion should be suspected when there is sudden cardiovascular predominantly coagulase-negative staphylococci (CONS), collapse in a neonate with a central venous catheter in place. methicillin-resistant S. aureus and vancomycin-resistant Immediate pericardiocentesis and avoidance of resuscitation through

Journal of Perinatology Iatrogenic complications in the NICU KC Sekar S54 the central line are the immediate life-saving measures, followed by imbalance, fluid overload, hypertriglyceridemia, hypo- and appropriate studies to determine and then adjust the position of the hyperglycemia, and catheter-related complications.3 Cholestasis central line as appropriate. Increasingly, radial arterial lines are and hyperalimentation-associated hepatitis are generally seen if the being used in the NICU. The radial artery is the major blood- infant is on TPN for more than 2 weeks. Hyperalimentation- supplying vessel to the thumb and index finger. Although collateral associated hepatitis can be halted and then reversed with early vessels might establish circulation if the radial artery is obstructed by introduction of initially low-volume gastrointestinal feedings and a thrombus, this may not always be the case in extremely premature with advancing on gastrointestinal feedings to full feedings as soon infants. Preventive measures to minimize catheter complications as possible so that TPN can be decreased and discontinued include practicing strict aseptic precautions during insertions, accordingly.37,38 appropriately verifying the position of the catheter tip, ensuring the central line remains in unchanged and secured position daily, using appropriate low-dose heparin in the fluids administered through the Miscellaneous complications line, monitoring signs for occlusion or malfunction, avoiding Discussion of the numerous other complications seen in the NICU, infusing blood or medications through arterial lines or such as skin complications, environmental complications, trauma, percutaneously inserted central lines if possible, and removing the necrotizing enterocolitis and so on, are beyond the scope of this lines immediately once their use is deemed no longer necessary.32 article. However, a comprehensive review of these complications has been published recently.39

Complications of mechanical ventilation Several papers have been published describing the complications Quality improvement in the NICU associated with mechanical ventilation. It is well known that One of the best ways to improve quality and prevent complications prolonged mechanical ventilation is associated with the is to establish ongoing quality improvement projects involving development of BPD. Other complications of mechanical multidisciplinary teams. An excellent review of how hospitals ventilation include air-leak syndromes (pneumothorax, achieve and sustain improvements over time was performed with pneumomediastinum, pneumopericardium, pulmonary interstitial actual case studies sponsored by the Commonwealth Fund.40 The emphysema), complications associated with endotracheal quality improvement sequence generally involves triggering events, intubations (malpositioning, trauma to the vocal cords, larynx, which then lead to structural changes in the organization (quality and esophagus, development of subglottic stenosis and palatal improvement (QI) committees, nurse empowerment, nurturing grove) and ventilator-associated pneumonias.3 So far, no mode of champions), problem identiﬁcation and solving (tracking mechanical ventilation using an endotracheal tube has been measures, QI teams, root-cause analysis, accountability), practice shown to prevent BPD. However, the use of nasal continuous changes (new protocols, clinical guidelines, pathways) and, in the positive airway pressure immediately after delivery or intubation for end, improved outcomes (reduced errors, complications and surfactant administration followed by quick extubation to nasal mortality, higher satisfaction and commitment to change). The continuous positive airway pressure has been associated with a entire process reﬂects the establishment of a ‘Culture of Quality’ reduced incidence of BPD.33–35 Recently, nasal intermittent over time.40 Several successful applications of this approach have positive pressure ventilation (NIPPV) has been introduced and been published. One such project in a small NICU reinforced the shown to reduce the need for mechanical ventilation and possibly usefulness of infection control standards after establishing protocols the incidence of BPD.36 Thus, it appears that the use of less- and frequent audits. Compliance with infection control standards invasive ventilation modalities and protocols to extubate babies improved from a median range of 70 to 95% within 6 months.41 In to nasal continuous positive airway pressure or NIPPV whenever our own NICU, a QI project entitled ‘Targeted oxygen saturation for possible may decrease the iatrogenicity of respiratory support in premature infants’ reduced the incidence of chronic lung disease the NICU. and retinopathy of prematurity requiring surgical intervention when a lower oxygen saturation threshold was adopted from 90 to 99% to 85 to 93%.42 In another QI project, there was a reduction in Complications associated with parenteral nutrition the incidence of ventilator-associated pneumonia (VAP) after the Over the last two decades, TPN has become sophisticated with a introduction of VAP bundle prevention.43 Such projects involve the balanced mixture of macro- and micronutrients. The addition of entire nursery staff and also build team spirit. intravenous lipid infusion has enabled clinicians to administer There are now several national organizations that monitor essential fatty acids and additional calories in extremely premature patient outcomes. The hospital QI Committee is vital in identifying infants. However, prolonged TPN administration is associated with areas for improvement, establishing protocols, overseeing these complications such as infection, cholestasis, rickets, electrolyte projects, transferring information for data gathering, and

Journal of Perinatology Iatrogenic complications in the NICU KC Sekar S55

Hospital Regional Q A Committee

Create a “Culture of quality” Local 1. Identify Physician and nurse Q I Projects “Champions” 2. Establish a multi disciplinary VON (NIC/Q 2007) team “Four Key Habits” 3. Identify areas for improvement – QI Projects Change 4. Create “clinical practice Evidence Based Practice guidelines” Collaborative Learning 5. Education and inclusion of Systems Thinking personnel 6. Objective data gathering tools 7. Share information quarterly National

National Organizations National incident reporting - JC - systems - FDA - SES - AHRQ - NNIS - MEDMARX - ASHP - - AAP MERP NPO & Private foundations - SRS - VON, NICHD - NPSF - IHI - Leapfrog

Figure 1 Relationship between local quality improvement projects, hospital QI committees, national reporting organizations and surveillance systems. AAP, American Academy of Pediatrics; AHRQ, Agency for Health Care Research and Quality; ASHP, Academy for State Health Policy; FDA, Food and Drug Administration; IHI, Institute for Health Care Improvement; JC, Joint Commission; MEDMARX, national database for medication errors; MERP, medication errors reporting program; NICHD, National Institute for Child Health and Development; NIQ, Quality Improvement Collaborative; NNIS, national nosocomial infection surveillance system; NPO, non-proﬁt organization; NPSF, National Patient Safety Foundation; QI, quality improvement projects; SES, sentinel event system; SRS, state reporting systems; VON, Vermont Oxford Network (adapted and modiﬁed from Ramachandrappa and Jain3).

implementing strategies toward improving outcomes. For neonatal Conflict of interest care, the Vermont Oxford Network has established an NIC/Q KC Sekar was a member of the speaker’s bureau and a consultant initiative with four key habits for improvement: habits for change, for Dey, LP. evidence-based practice, collaborative learning and systems thinking.44 In addition, there are national incidence-reporting systems, nonprofit foundations, and national organizations such as The Joint Commission and Food and Drug Administration that References closely monitor quality issues. The Joint Commission recently 1 Online Medical Dictionary and glossary with medical definitions; http://www.medterms.com. published patient safety goals for 2009, which provide a template 2 Jain L, Vidyasagar D. Iatrogenic disorders in modern neonatology. Clin Perinatol 1989; for all hospitals to follow. Key elements of the QI projects, reporting 16(1): 255–273. 3 Ramachandrappa A, Jain L. Iatrogenic disorders in modern neonatology: a focus on systems, and the relationship between these organizations are safety and quality of care. Clin Perinatol 2008; 35(1): 1–34. shown in Figure 1. 4 Kohn L, Corrigan J, Donaldson M. To Err is Human: Building a Safer Health System. Institute of Medicine; National Academy Press: Washington, DC, 2000. 5 Leape L. Reporting of adverse events. N Engl J Med 2002; 347: 1633–1638. Conclusions 6 Brennan TA, Leape LL, Laird NM, Hebert L, Localio AR, Lawthers AG et al. Incidence of Iatrogenic complications in the NICU consist predominantly of adverse events and negligence in hospitalized patients. NEnglJMed1991; 324:370–376. 7 Leape LL, Brennan TA, Laird NM, Lawthers AG, Localio AR, Barnes BA et al. The nature medication errors. Every effort should be made to minimize these of adverse events in hospitalized patients. New Engl J Med 1991; 324: 377–384. errors through proper education and the use of technology. Proper 8 Ligi I, Arnaud F, Jouve E, Tardieu S, Sambuc R, Simeoni U. Iatrogenic events application of CPOE and training will prevent errors from order in admitted neonates: a prospective cohort study. Lancet 2008; 371(9610): 404–410. entry, preparation and administration. A culture of quality should 9 Kugelman A, Inbar-Sanado E, Shinwell ES, Makhoul IR, Leshem M, Zangen S et al. be developed and system change should be implemented. Local QI Iatrogenesis in neonatal intensive care units: observational and interventional, prospective, multicenter study. Pediatrics 2008; 122(3): 550–555. projects in the NICU involving multidisciplinary teams, education 10 Snijders C, van Lingen RA, Molendijk A, Fetter WP. Incidents and errors in neonatal and frequent auditing will minimize errors, enhance patient safety intensive care: a review of the literature. Arch Dis Child Fetal Neonatal Ed 2007; and improve outcomes. 92(5): F391–F398.

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