Anesthetic Implications of an Upper Respiratory Infection in Children

PEDIATRIC ANESTHESIA

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ANESTHETIC IMPLICATIONS OF AN UPPER RESPIRATORY INFECTION IN CHILDREN Lynn D. Martin, MD, FAAP

Viral upper respiratory infections (URI) are common throughout the population but are particularly frequent in children. In fact, normal children may suffer from an average of three to eight URI per year. Historically, it has been standard anesthetic practice to cancel elective surgery in children currently or recently suffering from a URI. This practice of postponing elective surgery for patients stems from the widely held belief that the risks of perioperative respiratory complications are increased in this population. 24 The frequent and recurrent nature of URI in children, however, makes scheduling of elective surgery in the small window of time in which the patient has been symptom-free for 4 to 6 weeks is problematic at best. Of course there are many causes of runny noses in children (allergic rhinitis, foreign object). Not all are acute viral URI. The first step is determining whether the child is at baseline or has a new infectious upper respiratory problem. Furthermore, the psychological stress to the patient and family as well as the inefficient use of the anesthesiologist, surgeon, and medical care facility must be considered. This article reviews the pathophysiologic changes in the respiratory system associated with URI, the published literature regarding the risks of perioperative complications in patients with URI, possible modifications of anesthetic practice to minimize the potential for these complications, and suggested guidelines to assist parents, pediatricians, anesthesiologists, and surgeons when confronted with this common clinical dilemma.

PATHOPHYSIOLOGIC CONSIDERATIONS

Studies investigating the respiratory pathophysiology of a URI have demonstrated a variety of abnormalities roughly divided into two broad categories,

From the Department of Pediatrics, Swedish Medical Center/Seattle, Seattle, Washington

PEDIATRIC CLINICS OF NORTH AMERICA VOLUME 41 • NUMBER 1 • FEBRUARY 1994

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peripheral airway abnormalities and airway hyperreactivity. Unfortunately, the technical difficulties associated with the performance of pulmonary function testing in children have limited most pathophysiologic studies to adults or animal models. Peripheral Airway Changes

Many studies have documented peripheral airway abnormalities in adults with acute viral URI. These alterations in respiratory function include diminished diffusion capacity/, 23 abnormal frequency dependence of compliance,>' 36 abnormal frequency dependence of resistance/o decrease in density-dependent flow rates,14 and increased closing volumes.14, 26 These peripheral airway changes, particularly the alterations in closing volumes, predispose the patient to intrapulmonary shunting and hypoxemia. The increase in closing volume secondary to the URI in combination with the decrease in functional residual capacity (FRC) that normally occurs with general anesthesia summate to a significant risk of hypoxemia. The effects of anesthesia on the distribution of ventilation, perfusion, shunt, and FRC have been studied using anesthetized sheep infected with parainfluenza virus." They found that the severity of hypoxemia due to the viral infection was greater than expected for the amount of measured intrapulmonary shunt. These authors concluded that the exaggerated hypoxemia was due to increased lung oxygen uptake, presumably secondary to the inflammatory response caused by the acute viral infection. The mechanisms of these alterations in peripheral airway function remain unknown. They may be related to changes in hypoxic pulmonary vasoconstriction in the infected lung, to changes in the volume and clearance of secretions in the infected airways, or to alterations in airflow and distribution, Regardless of the precise mechanisms, these findings are consistent with the frequent clinical observation that there is an increased risk of perioperative hypoxemia in patients with recent viral URI. Airway Hyperreactivity It has been recognized for many years that previously healthy patients without pre-existing lung disease may have temporary airway hyperreactivity for up to 6 weeks after a viral respiratory infection., ,13 The mechanisms involved in the viral-induced airway hyperreactivity are multifactorial (Fig. 1). Airway smooth muscle from animals with experimental viral infections responded normally to acetylcholine and beta-agonists, suggesting that intrinsic alterations in the smooth muscle are not responsible!' 25 A multitude of immunologic and inflammatory mediators such as histamine, bradykinin, and leukotrienes, are released during viral infections and may be associated with bronchoconstriction,5 Several studies suggest that a significant component of the airway hyperresponsiveness seems to be neurally mediated. ,,13 The neural abnormalities described with viralinduced hyperreactivity include increased vagal reflex bronchoconstriction,,4, 13-15 and increased response to tachykininsP' 25, 37, 39 The demonstration that atropine was able to block airway hyperresponsiveness in humans with viral infections suggests a primary role for the vagal reflexes in the pathogenesis. ' ,13 It was speculated that viral-induced epithelial damage exposed sensory nerve endings which could then be more easily stimulated, thereby increasing the afferent limb of the reflex 13 (see Fig. 1). Electrical stimula-

INFLAMMATORY CELLS

AIRWAY SMOOTH MUSCLE CELLS

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Figure 1. Proposed pathophysiologic mechanisms of viral-induced airway hyperreactivity. Viral injury to the epithelium increases the likelihood of stimulation of vagal irritant afferent fibers which increase vagal efferent release of acetylcholine acting upon smooth muscle M3 receptors. Viral release of neuraminidase impairs preganglionic M2 inhibitory muscarinic receptors on the vagus nerve, thereby potentiating the release of acetylcholine. Viral infections also promote inflammatory cell response with release of such mediators as histamine, bradykinin, and leukotrienes which act either directly on airway smooth muscle cells or stimulate the C-fiber release of tachykinins (TYK), both promoting smooth muscle contraction. Finally epithelial injury is associated with decrease in neutral endopeptidase (NEP) activity which is responsible for the degradation of the tachykinins.

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tion of vagal efferent fibers also caused greater airway smooth muscle contraction in parainfluenza infected guinea pigs compared with controls.' Exogenous acetylcholine did not result in increased bronchoconstriction in infected animals, thereby demonstrating that an increased release of acetylcholine from the vagus is responsible for these clinical findings. The discovery of structurally and functionally distinct muscarinic receptor subtypes greatly aided our understanding of viral-induced airway hyperreactivity. Stimulation of muscarinic receptors (M3) on airway smooth muscle results in constriction, whereas stimulation of muscarinic receptors (M2) on the vagal nerve endings inhibits the release of acetylcholine. '7 Thus, the M2 receptors on the vagus nerve form a negative feedback loop in which acetylcholine released by the nerves stimulates smooth muscle contraction, while at the same time inhibiting any further release of acetylcholine. Stimulators of the M2 receptor (pilocarpine) inhibit vagally mediated bronchoconstriction, whereas inhibitors (gallamine) potentiate this response up to tenfoldY Therefore, damage to this receptor subtype would be expected to increase the release of acetylcholine and potentiate vagal bronchoconstriction. There is also evidence of functional damage to M2 receptors in guinea pigs infected with parainfluenza virus. '6 In this study, electrical stimulation of the vagus in infected animals resulted in greater bronchoconstriction, which was neither potentiated by gallamine nor inhibited by pilocarpine. The loss of the inhibitory M2 receptors may be the result of mediators released by inflammatory cells's or direct viral damage of the receptors. 1S The M2 muscarinic receptors contain sialic acid residues, which are essential for agonist binding and are susceptible to cleavage by viral neuraminidase. Reduced agonist affinity has been demonstrated using in vitro ligand binding studies in parainfluenza-infected guinea pig lungs which can be completely blocked by a neuraminidase inhibitOr. '5 The lower agonist affinity to the M2 receptor would decrease the inhibitory feedback, thereby increasing the release of acetylcholine in virus-infected airways. Viral infections also may increase airway smooth muscle constriction in response to tachykininsp,25,39 Tachykinins are a family of sensory neuropeptides found in vagal afferent C-fibers in the airways.40 A wide variety of chemical and physical factors result in afferent neuronal conduction, which in tum elicits the local release of the neuropeptides through the axon reflex. 40 The neuropeptides promote airway smooth muscle contraction by both direct effects on bronchial smooth muscle and potentiation of cholinergic neurotransmission. Neutral endopeptidase (NEP) breaks down tachykinins into inactive metabolites, Inhibition of this enzyme by phosphoramidon increases the contractile response to both exogenous tachykinins and endogenous neuronal release by capsaicin or electrical stimulation, The potentiation of the response to tachykinins by viral infections is due to the loss of NEP activity in the airway tissueY' 25 By decreasing airway NEP activity by 50%, viral infections potentiate the bronchoconstrictor effect to a similar degree as pretreatment with phosphoramidon. Viral infections also may alter other components of the respiratory system, Respiratory muscle weakness has been demonstrated in adults suffering from URI which persisted for as long as 12 days,33 Under normal situations, both acetylcholine and tachykinins stimulate airway submucosal gland secretion, Although not formally studied, in view of the demonstrated abnormalities in acetylcholine and tachykinins' regulation associated with viral infections, it should be no surprise that the quality and quantity of airway secretions are altered.

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PERIOPERATIVE RISK

Although it is widely accepted that patients suffering from a recent URI have an increased perioperative risk of respiratory complications, there is a paucity of information regarding the nature of the morbidity that may result when an anesthetic is administered. A series of reports cite anecdotal cases of respiratory complications including bronchospasm, acute subglottic edema with stridor, hypoxia, and atelectasis. 6• B, 30, 32, 45 Several patients developed atelectasis severe enough to require bronchoscopy and postoperative mechanical ventilation. 32 Intubation was associated with each of these cases. In intubated patients, URI also increase the likelihood of intraoperative endotracheal tube obstruction from secretions. 32 In three prospective studies, patients with a history of current or recent URI had a tenfold higher risk of bronchospasm or laryngospasm. B• 34, 35 These potentially severe complications have been associated with perioperative mortality.30 Several studies have documented a higher incidence of perioperative hypoxemia in patients with a URI.IO, 27, 31 DeSoto and colleagues lo prospectively studied 50 children (25 with and 25 without URI) who underwent general anesthesia and found a statistically significant increased risk of postoperative hypoxemia in the infected group. Similar results were observed in another prospective study of 130 children. 31 Kinouchi and colleagues27 demonstrated that the time period of apnea required for hemoglobin saturation to decrease to 95% after ventilation with 100% oxygen was approximately 30% less in children with a URI. These authors state ~hat the decision to proceed with surgery in these children should follow careful evaluation of such factors as the nature and urgency of the proposed surgical procedure as well as the frequency and severity of the URI. Those anesthetized require close perioperative oxygen saturation monitoring and administration of supplemental oxygen during transport and in the postoperative recovery room. Many continue to question the wisdom of administering general anesthesia for an elective surgical procedure in patients with a recent history of URI.s, 19, 21, 24

In contrast, other investigators have reported several series of children anesthetized with a URI in which no significant respiratory complications were noted. 3s, 42, 43 In the first series, 3585 anesthetic events were retrospectively reviewed and divided into three groups: asymptomatic, asymptomatic with a history of symptoms within 2 weeks prior to surgery, and symptomatic. 43 Interestingly, there was no increase in complications of anesthesia in the symptomatic group, but there was a threefold increase in bronchospasm and laryngospasm in the asymptomatic patients with a recent history of URI symptoms. This study has been criticized for its retrospective design, patient categorization, and possible selection bias. 19, 24 The nonspecific symptoms associated with viral URI also may be seen with vasomotor or allergic rhinitis. If this were the case, patients with chronic symptoms of nonviral origin may be over-represented in the symptomatic group, whereas those with true viral symptoms may be over-represented in the asymptomatic group with recent symptoms. Thus, this study may actually support the hypothesis that viral infections increase the complications of anesthesia. These same authors subsequently published a prospective study in which children with and without symptoms of viral URI underwent myringotomy and tympanostomy under general anesthesia. 44 No complications were found in either group. None of these patients, however, underwent endotracheal intubation, which seems to be a major risk factor precipitating respiratory complications such as bronchospasm and atelectasis.lO. 32, 34 Finally, Rolf and Cote3B prospectively

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studied 402 children who were asymptomatic or had a nonpurulent URI and underwent general anesthesia for an elective procedure. They found a significant increase in the incidence of minor desaturation events (Sp02 of 95% or less for 60 seconds or more) and bronchospasm in intubated patients. They concluded that "children with mild URI may be safely anesthetized, because the problems encountered are generally easily treated and without long-term sequelae."38 Several studies have suggested that general anesthetics may actually decrease the severity of viral URI.28, 43, 44 Inhalational anesthetics either had no effect in ferrets 44 or decreased histologic changes and mortality in mice?8 Recently, halothane anesthesia has been shown to decrease the sequelae of influenza pneumonitis in mice by suppressing the local recruitment of alveolar inflammatory cells. 43 These results are supported by a clinical study in which patients had a less severe course of URI when randomly selected to receive anesthesia for surgery compared with matched controls that did not receive anesthesia or surgery.41 Some authorities criticize this finding because surgical drainage of the middle ear fluid also may have altered the natural history of the patient's URI. Thus, there seems to be no consensus regarding the safety of administering anesthesia to children with a recent history of URI. The majority of evidence suggests that recent viral infection is indeed a risk factor for pulmonary anesthetic complications, particularly when intubation is required. In addition, in children with underlying reactive airway disease, a recent URI increases the frequency and worsens the severity of bronchospasm, a dreaded intraoperative anesthetic complication. Thus, these considerations are even more germane in asthmatic children. All of these risks must be weighed against the physiological, psychological, and financial implications of delays in surgery. ANESTHETIC PRACTICE

Although an in-depth discussion of the anesthetic principles to be followed in a child with a recent URI are beyond the scope of this article, knowledge of several general guidelines may facilitate discussion between the respective medical specialists involved. When forced to provide anesthesia for a surgical procedure in a patient with recent URI, serious considerations should be given to a local or regional anesthetic technique. Unfortunately, sole use of these techniques is rarely possible in children due to their lack of cooperation. When performing a general anesthetic, every effort should be made to avoid endotracheal intubation if possible, because this procedure clearly escalates the risk of respiratory complication. Avoiding endotracheal intubation is frequently not possible, however, because of the specific surgical requirements for many of the common pediatric procedures. The general anesthetic agents used should be selected to minimize airway reactivity.22 A deep inhalational general anesthetic which blocks airway irritant receptors and directly bronchodilates the airways is preferable. The depth of anesthesia is particularly important during insertion and removal of the endotracheal tube. In view of the numerous reports of arterial hemoglobin oxygen desaturation, pulse oximetry should be closely monitored intraoperatively and postoperatively. The near universal finding of increased vagally mediated reflex bronchoconstriction suggests that the administration of anticholinergic medications (muscarinic receptor antagonist) prior to tracheal intubation may interrupt the reflex arc. 24 Because of its antisecretory and bronchodilatory properties22 as well as its ability to prevent irritant-induced airway constriction,13 many anesthesiologists routinely administer atropine prior to airway instrumentation. This practice, however, has yet to be shown of clinical

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benefit by a controlled study. Glucocorticoids have been shown to attenuate viral-stimulated tachykinin-induced airway edema formation. 37 This effect may be due to the stimulation of NEP, the principal enzymatic pathway of breakdown of the tachykinins, which has been demonstrated in cultured airway epithelial cells. 3 Thus, glucocorticoids potentially may ameliorate the tachykinin-induced airway hyperreactivity observed after viral infection. Future developments may include more effective antiviral medications or more selective muscarinic receptor antagonists. The ability to selectively block airway smooth muscle M3 receptors may be particularly desirable in patients with a viral-induced M2 receptor dysfunction. All current cholinergic antagonists available for use in humans are nonselective in nature. The nonselective antagonists will oppose the effect of acetylcholine on the smooth muscle itself, but it will also block the M2 inhibitory feedback, thereby increasing the release of acetylcholine by the vagus nerve. '7 A selective M3 antagonist would not have this undesired effect. Finally, another theoretic pOSSibility would be the administration of recombinant human NEP to replace the enzyme activity lost secondary to viral infections. In fact, this therapy decreased tachykinin-induced cough in animal models experimentally infected for up to 2 hours. 29 Even this short-term effect may prove beneficial when administered prior to the induction of anesthesia in patients at risk for airway hyperreactivity. GENERAL RECOMMENDATIONS

From the preceding discussion, it is possible to construct a suggested decision tree for use by clinicians facing the dilemma of possible perioperative complications versus the psychological and financial stresses associated with the delay of elective surgery (Fig. 2). It must be emphasized that these are only suggestions; the actual decisions must be left to the parents and the clinicians evaluating the patient and involved in the surgical procedure. The first branch point in the decision tree is relatively simple, quantifying the urgency of the proposed surgical procedure. Emergency surgery logically must proceed, whereas elective procedures will require further evaluation. The next consideration would be the severity of the URI. Patients with systemic manifestations, such as fever greater than 38.5°C, purulent nasal discharge, or lower respiratory symptoms (productive cough, crackles, positive chest radiograph findings), present greater risk for operative complications. Therefore, these patients should have the surgical procedure delayed for 4 to 6 weeks after the resolution of symptoms to allow airway hyperresponsiveness to resolve. Patients with mild URI symptoms, in which the surgical procedure can safely be completed with a regional anesthetic or general anesthesia without an endotracheal tube, may proceed with only minor additional risk. Finally, patients who require endotracheal intubation should be evaluated for other possible respiratory risk factors (e.g., chronic lung disease, reactive airway disease, airway abnormality) because these conditions are all exacerbated by URI. This group of patients with additional risks would likely benefit from a delay in surgery to allow resolution of this additional and temporary pulmonary risk factor. During this time, optimal therapy for the underlying respiratory disease (such as increased aerosols and steroids for an asthmatic child) can be instituted. The child and parents need to be involved in this decision-making process. The parents should be engaged in a complete discussion in which the additional risks of respiratory complications when anesthetizing a patient with a recent URI are described while obtaining the informed consent. The surgeon and anesthe-

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Figure 2. Suggested clinical decision tree for patients being evaluated for surgery with a recent history of upper respiratory infection.

siologist must be fully prepared to deal with any of the possible respiratory events intraoperatively and postoperatively. Finally, the parents must be informed that the procedure may need to be aborted without completion secondary to a complication, thereby necessitating a possible second anesthetic in the near future. CONCLUSION

The evaluation of a child scheduled for elective surgery with a recent upper respiratory infection is a very common clinical situation. Upper respiratory tract infections are associated with changes in respiratory function that predispose children to laryngospasm, hypoxemia, atelectasis, and vagally mediated airway hyperreactivity. These alterations in pulmonary function have been associated with up to a tenfold higher incidence of perioperative respiratory complications in patients receiving general anesthesia, particularly in association with endotracheal intubation. Modifications in anesthetic practice may decrease but will not eliminate the risk of these complications. When faced with this clinical situation, the patient and parents as well as the medical care team must all be involved in the difficult decision whether to proceed or delay surgery. When electing to delay surgery, the procedure should ideally be rescheduled 4 to 6 weeks after the resolution of symptoms, as the abnormalities associated with airway hyperresponsiveness may be present for that length of time. ACKNOWLEDGMENT I would like to thank our excellent support staff, Sunny Schlehr and Donna Bosworth, for their unending assistance in the preparation of the manuscript.

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Address reprint requests to Lynn D. Martin, MD, FAAP Department of Pediatrics Swedish Medical Center I Seattle 747 Summit Avenue Seattle, WA 98104-2196