Perioperative apnea in infants with hypertrophic pyloric stenosis: A systematic review

Abstract Background Infantile hypertrophic pyloric stenosis (IHPS) leads to excessive vomiting and metabolic alkalosis, which may subsequently cause apnea. Although it is generally assumed that metabolic derangements should be corrected prior to surgery to prevent apnea, the exact incidence of perioperative apneas in infants with IHPS and the association with metabolic alkalosis are unknown. We performed this systematic review to assess the incidence of apnea in infants with IHPS and to verify the possible association between apnea and metabolic alkalosis. Methods We searched MEDLINE, Embase, and Cochrane library to identify studies regarding infants with metabolic alkalosis, respiratory problems, and hypertrophic pyloric stenosis. We conducted a descriptive synthesis of the findings of the included studies. Results Thirteen studies were included for analysis. Six studies described preoperative apnea, three studies described postoperative apnea, and four studies described both. All studies were of low quality or had other research questions. We found an incidence of 27% of preoperative and 0.2%‐16% of postoperative apnea, respectively. None of the studies examined the association between apnea and metabolic alkalosis in infants with IHPS. Conclusions Infants with IHPS may have a risk to develop perioperative apnea. However, the incidence rates should be interpreted with caution because of the low quality and quantity of the studies. Therefore, further studies are required to determine the incidence of perioperative apnea in infants with IHPS. The precise underlying mechanism of apnea in these infants is still unknown, and the role of metabolic alkalosis should be further evaluated.


| INTRODUC TI ON
Infantile hypertrophic pylorus stenosis (IHPS), the most common cause of gastric outlet obstruction in infants, is caused by hypertrophy of the distal muscular aperture of the stomach. 1,2 The incidence of IHPS is 2-5 per 1000 live births. 1,[3][4][5] The condition typically develops between the third and twelfth week after birth and is characterized by nonbilious, projectile vomiting. 4 Vomiting causes loss of fluid as well as hydrogen, chloride, and potassium ions, resulting in hypochloremic hypokalemic metabolic alkalosis. 3,6 Due to fluid loss, most infants are dehydrated and may develop volume depletion and reduced glomerular filtration rate.
Thus, the usual ability of the kidney to maintain a normal pH by bicarbonate excretion is impeded by chloride depletion and bicarbonate overload. Furthermore, in the distal tubule potassium is conserved at the expense of excreted hydrogen leading to increased metabolic alkalosis. 7,8 Besides renal compensation, the body is also able to compensate metabolic alkalosis by retaining carbon dioxide through hypoventilation. [7][8][9] Normally, respiratory compensation is limited by decreased partial pressure of oxygen in the blood which activates the peripheral chemoreceptors and stimulates the ventilation rate. 6,10,11 However, conflicting evidence exists demonstrating the occurrence of hypoventilation in reaction to metabolic alkalosis. 12,13 Furthermore, in young infants PaCO 2 is the primary stimulus for ventilation via its influence on the pH of the cerebrospinal fluid, affecting the central chemoreceptors. 6 Therefore, infants with IHPS may develop central apneas due to severe metabolic alkalosis.
Little is known about the incidence of perioperative apnea in infants with IHPS. Only a few case reports have been described. 7,9,14,15 Yet, timing of surgery is classically based on the correction of hypovolemia and metabolic derangements to prevent hypotension and respiratory complications, respectively. However, it is unknown to which extent this is necessary. Furthermore, the clinical consequences of the association between metabolic alkalosis and apnea remain unclear. If infants with IHPS have an increased risk of developing perioperative apnea, it may be necessary to monitor them to be able to identify apnea timely and to prevent further deterioration. In order to assess the incidence of apnea in infants with IHPS and to verify the possible association between apnea and metabolic alkalosis, we performed a systematic review.

| Protocol
A literature review was conducted according to the Preferred Reported Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, to examine all cases of apnea with metabolic alkalosis in infants with IHPS. 16 The protocol was registered at PROSPERO (2018, CRD42018116707).

| Literature search
We performed a search in PubMed, EMBASE (Ovid), and the Cochrane Library. The reference lists of the included articles were examined for additional publications, and key journals were hand searched. The search was conducted in September 2018 and repeated in May 2019. Keywords were pyloric stenosis, pyloromyotomy, metabolic alkalosis, apnea, and respiratory insufficiency. For the detailed search, see Appendix 1.

| Eligibility criteria
All relevant studies were included regardless of study design, publication date, or language. Inclusion criteria were infants (age < 1 year) with (hypochloremic, hypokalemic) metabolic alkalosis, respiratory problems, and hypertrophic pyloric stenosis. Infants with metabolic alkalosis caused by diseases other than pyloric stenosis and infants with apnea or respiratory problems with another objectivated cause, such as congenital anomalies, idiopathic respiratory distress syndrome, infectious disease, or aspiration, were excluded from analysis.

| Study selection and methodological quality assessment
Studies were included according to the criteria listed above. Two reviewers (FvdB and LvW) independently screened title and abstract of the studies retrieved using the search strategy. After first selection, full text was screened for final selection. Disagreements were judged by an independent third reviewer (JD). The Joanna Briggs Institute (JBI) critical appraisal checklists for case reports and casecontrol studies were used to independently assess the methodological quality of the included studies. 17 The JBI bias tools are often used for case series and based on the internationally used case report (CARE) guidelines. 18

| Data extraction and analysis
For all eligible studies, we extracted the patient characteristics, the pre-and postoperative clinical course, blood gas values, serum electrolyte values, additional medical examination, used anesthetics, and surgical procedure. Respiratory problems and corresponding interventions were recorded as well. Data were extracted by two reviewers (FvdB and LvW). If incomplete, we attempted to contact the authors to obtain additional data.
The primary endpoint of this study is to examine the incidence of perioperative apnea in infants with IHPS and secondary to verify the possible association between apnea and (hypochloremic, hypokalemic) metabolic alkalosis. We conducted a descriptive synthesis of the findings of the included studies. It was not possible to perform a meta-analysis due to the limited number of patients.

| Literature search
The literature search initially provided 1048 potentially suitable studies. After exclusion of duplication articles, 799 studies remained, of which 741 studies were excluded subsequent to first screening.
One study was added after examination of reference lists and hand searching. After full-text screening, 46 more studies were excluded. Furthermore, one potentially eligible study was excluded because the article could not be traced, leaving twelve eligible studies that were included. See Figure 1 for the detailed PRISMA chart.

| Methodological quality
An overview of the quality assessment is presented in the Appendix S1. The overall risk of bias of the case reports is low to moderate for all case studies, except for the case report by Bennett et al, which scored high due to lack of detailed information. 9,14,15,[19][20][21] Most case studies did not specify the type and volume of resuscitation fluids nor the duration of oxygen treatment or the presence or absence of hypothermia.
The overall risk of bias of the case-control study by Abreu et al 22 is also qualified as low to moderate. Irrespective of the low to moderate risk of bias, the level of evidence of these studies is low due to the study design. The risk of bias of the study by Chipps et al was considered as high. Because the primary outcomes of all other cohort studies and the RCT were different from our intended endpoint, it was hard to define the risk of bias. Apart from Galinkin et al, none described the patient characteristics of the infants with perioperative apnea,nor the method which was used for respiratory monitoring and diagnosis of apnea. [23][24][25][26] Furthermore, it is unknown whether all infants of these studies received respiratory monitoring and thus whether other infants experienced (milder) apneas as well. Therefore, we indicated the risk of bias in these studies high.

TA B L E 3 Overview of cases of infants with IHPS and postoperative apnea
Two infants had prolonged attacks of central apneas (>15 seconds) in both active and quiet sleep, and four infants had prolonged attacks of obstructive apnea (>6 seconds) in active sleep. Prolonged apneas were no longer observed after recovery or in healthy controls. The second case presented with bradypnea (12 breaths/min) and oxygen saturation of 88% while breathing room air and showed three episodes of apnea. 14 Cases 2, 3, and 4 required intubation due to severe respiratory problems (Table 2). 9,19,20 Case 2 showed bradypnea (10-12 breaths/min) and apnea of 20 seconds. 19 He responded well to high-flow nasal cannula, but when asleep his respiratory rate decreased below 10 breath/min and invasive mechanical ventilation was necessary. Cases 3 and 4 had poor respiratory drive and bradycardia associated with apnea. 9,20 Case 5 describes an infant with gasping respiration and shock due to severe hypovolemia, but any further details were lacking. 7 We found only five descriptive cases of infants with IHPS and postoperative apnea (Table 3). 15

| Apnea and metabolic alkalosis
All described infants with preoperative apnea, including the infant with both pre-and postoperative apnea (Table 3; case 3), had hypochloremic metabolic alkalosis. 9,14,15,19,20,22 An exception to this was case 5 (Table 2) who presented with metabolic acidosis and shock. 7 Median preoperative serum values of all infants with preoperative apnea are shown in Table 4. In most infants, other causes of preoperative apnea were excluded based on clinical judgment and by the use of additional diagnostics including complete blood workup, urine analysis, chest X-ray, ECG, and cerebrospinal fluid analysis (

TA B L E 4
Median laboratory values of infants with preoperative respiratory problems.
Only one of five infants with postoperative apnea had noted hypochloremic metabolic alkalosis. 15 Exact laboratory values at presentation of infants with postoperative apnea were often not available. Other factors, which could induce postoperative apnea as anemia, hypoglycemia, sepsis, and neurological disorders, were ruled out.

| D ISCUSS I ON
We performed this systematic review to identify the incidence of perioperative apnea in infants with IHPS and to study the association between apnea and metabolic alkalosis. We identified thirteen articles describing infants with IHPS who experienced perioperative apnea, but all studies were of low quality or had other research questions. Although it is generally assumed that metabolic derangements should be corrected prior to surgery to prevent apnea, we found only one study which primarily investigated the incidence of perioperative apnea in infants with IHPS and no studies investigating the potential association of severe metabolic alkalosis with perioperative apnea.
Since most included studies were case series, we were unable to assess the incidence of perioperative apnea in infants with IHPS. Only one relatively small study addressed the exact incidence of preoperative apnea in infants with IHPS. 25 In this study, 27% of the infants All described infants with preoperative apnea, except one, had moderate to severe hypochloremic metabolic alkalosis. Several dated human and animal studies have shown compensatory hypoventilation in metabolic alkalosis. 12,13,[28][29][30] This in line with more recent reports of infants with apnea caused by severe metabolic alkalosis due to (pseudo-) Bartter syndrome, peritoneal dialysis with bicarbonate containing solutions, and consumption of gripe water, containing an high concentration of sodium bicarbonate by a previously healthy infant. [31][32][33][34] In infants with postoperative apnea, it was unclear whether the infants presented with metabolic alkalosis or not and whether this may have led to postoperative apnea. 22,23 Moreover, one infant had hypothermia and one an abnormal response to 17% inspired oxygen challenge 9 days after surgery. 13 Although the authors stated that these conditions did not contribute to the apneic episodes and that they have ruled out other contributing factors, in our view this might have played a role.
In all studies, it was unclear when metabolic and electrolyte derangements were considered as corrected and infants underwent surgery. In case of insufficient correction of metabolic derangements, it could be still possible that metabolic alkalosis influenced the respiratory drive.
It has been suggested that cerebrospinal fluid pH may be still elevated after rapid correction of serum electrolytes, which could continuously influence the respiratory drive. 13  In spite of its limitations, the current study suggests that infants with IHPS may have a risk to develop perioperative apnea. We found an reported incidence of 27% of preoperative and 0.2%-16% of postoperative apnea, respectively. The majority of these apneas seems to be benign and self-limiting. However, the incidence rates should be interpreted with caution because of the low quality and quantity of the studies. Today, with the universal availability of ultrasound, the diagnosis of IHPS is made earlier and infants may present with less severe metabolic derangements. For this reason, the incidence of perioperative apnea may be decreased. Further cohort studies are required to determine the current incidence of perioperative apnea in infants with IHPS and whether it is necessary to conduct respiratory monitoring. The precise underlying mechanism of apnea in these infants is still unknown, and the role of metabolic alkalosis should be further evaluated. Depending 1 exp pylorus stenosis/or stomach obstruction/ or pyloromyotomy/or exp alkalosis/or (hypertrophic pyloric stenosis or pylorus stenos* or pyloric stenos* or pylorostenos* or pyloromyotom* or hypokalemia* or hypokalaemia* or hypopotassemia* or hypochloremia or hypochloraemia or metabolic derangement* or alkalosis or metabolic alkanization or metabolic disturbance* or metabolic disorder*).ti,ab,kw.