Clinical Characteristics of Pediatric Patients With Septic Shock Caused by Acute Appendicitis

A Case Series

Abstract

Objectives 

This study aimed to explore the clinical characteristics of septic shock in pediatric patients caused by acute appendicitis.

Methods 

This case series included patients with septic shock caused by acute appendicitis in Beijing Children's Hospital between January 2015 and December 2020.

Results 

Six patients with septic shock caused by acute appendicitis were enrolled. One patient was an infant with extremely low weight; 2 patients were obese. The diagnosis was delayed in 4 patients (the time from onset to diagnosis was 5 days in 3 children and 4 days in 1 child). All patients had abnormally raised inflammatory markers (C-reactive protein 119.17 ± 48.36 mg/L, procalcitonin 129.95 ± 86.09 ng/mL). Severe abdominal infection was found in all patients. There was appendix perforation in 4 patients and diffused peritonitis in 3 patients. Two patients had metabolic diseases (Wilson disease and decreased biotinase activity, respectively). Five patients had an appendectomy and 1 patient received conservative treatment. Five patients were discharged in stable condition, while 1 patient died.

Conclusions 

Children with delayed diagnosis, abnormal body weight, significant elevation in inflammatory markers, and underlying metabolic disease may be at greater risk of complicated appendicitis and septic shock.

Evidence-Based Medicine 

Level of Evidence: IV

Sepsis is defined as systemic inflammatory response syndrome (presence of 2 or more of the following: core temperature >38.5°C or <36°C, tachycardia, tachypnea, and leukocytosis) in the presence of documented infection.¹ A child is diagnosed with septic shock when there is sepsis and cardiovascular dysfunction.² Sepsis is a significant cause of morbidity and mortality in pediatric patients, particularly in the setting of shock.³ Lack of recognition and attention to septic shock often leads to delayed diagnosis and treatment. High-risk groups of septic shock include premature neonates and patients with immunosuppression or immunodeficiency syndrome, chronic diseases (cardiac, respiratory, neuromuscular), indwelling devices/access devices, or patients after a recent hospitalization.⁴ The respiratory system, abdominal cavity, urinary tract, and skin are the most common infection sources that lead to sepsis shock.⁴

Acute appendicitis is among the most common causes of emergency abdominal surgery in children.⁵ A few acute appendicitis patients may progress to life-threatening septic shock. However, the etiology is still unclear, and only a few cases have been reported. To improve the recognition and understanding of septic shock caused by acute appendicitis, this study retrospectively reported the clinical characteristics of pediatric patients treated for appendicitis-associated decompensated septic shock.

METHODS

Study Design and Patients

The case series collected patients with acute appendicitis and decompensated septic shock treated in Beijing Children's Hospital between January 2015 and December 2020. This retrospective observational study was approved by the ethics committee of Beijing Children's Hospital, and informed consent was waived because of the nature of retrospective studies. The diagnosis of septic shock was confirmed according to the guidelines of Chinese Children with Septic Shock and the American College of Critical Care Medicine.^1,6,7 Patients were excluded if the clinical data were incomplete or the septic shock was compensatory.

Data Collection

Clinical characteristics were collected from the hospital medical records, including age, sex, temperature, blood pressure, vasopressors, heart rate, skin and peripheral circulation, consciousness status on admission, blood lactic acid levels, serum C-reactive protein (CRP), capillary refill time (CRT), and body weight; the onset of septic shock to diagnosis time, antibiotics used, and blood markers of inflammation (white blood cells [WBCs], procalcitonin [PCT], neutrophils [NEUTs]); and the severity of abdominal infection, intraoperative appendix status, postoperative pathological types, concomitant diseases, previous diseases, duration of hospital stay, and discharge condition. The weight range was based on the standard growth curve of Chinese children.⁸

Statistical Analysis

Only descriptive analysis was performed in this study.

Results

Six patients with septic shock caused by acute appendicitis were enrolled (4 boys and 2 girls). Table 1 and 2 summarizes the clinical data of the 6 patients. Patient 4 was an infant (5.8 months old), and patient 5 was a preschool child (50 months old). Patients 1 and 6 were obese children and patient 4 had a very low body weight of 6 kg. Four patients had a long onset to diagnosis time: 5 days in 3 children and 4 days in 1 child. All the patients had abnormally high serum CRP and PCT levels; the average values were 119.17 ± 48.36 mg/L and 129.95 ± 86.09 ng/mL, respectively (normal: CRP < 8 mg/L, PCT ≤ 0.25 ng/mL). Intraoperative inspection revealed severe abdominal infection in the patients: 4 patients had an appendix perforation, 3 had diffused peritonitis, and 1 patient had a gangrenous appendix. Two patients had genetic and metabolic diseases (Wilson disease and decreased biotinase activity). Three patients had a previous history of diseases: patient 6 developed pneumonia 9 months before admission, patient 1 had recurrent respiratory tract infection, and patient 2 had febrile convulsion at 3 and 5 years of age. Five patients had appendectomy, and 1 patient received conservative treatment. Five patients were discharged in stable condition, while 1 patient died.

TABLE 1 - Diagnostic Basis of 6 Septic Shock Cases on Admission

	Sex	Age, mo	Temperature, °C	Blood Pressure, mm Hg	Vasoactive Drugs	Heart Rate, times/min	Skin and Peripheral Circulation	CRT, s	Consciousness	Blood Lactic Acid, mmol/L
Case 1	Boy	150	41	113/71, the lowest systolic pressure is 40	Dopamine, noradrenaline	182	Marbling skin, cool extremities	5	Unconsciousness	3.6
Case 2	Boy	129	41	102/20	Dopamine, noradrenaline	120	Pale complexion, cool extremities	3	Lethargy	7.1
Case 3	Girl	86	39.8	88/46	Noradrenaline	192	Cool lower extremities	3–4	Unconsciousness	7
Case 4	Boy	5.8	36.5	62/33	Noradrenaline	152	Cool lower extremities	3	Lethargy	0.7
Case 5	Girl	50	39.2	78/46	Noradrenaline	205	Cool extremities	4	Unconsciousness	2.7
Case 6	Boy	153	36.4	140/90	Noradrenaline	>170	Cyanosis and marbling skin	>5	Weak mental reaction	8

TABLE 2 - Clinical Features of the 6 Septic Shock Patients Caused by Acute Appendicitis

	Weight (kg, Percentile of the Same Age and Sex)	Previous/Combined Diseases	Onset to Diagnose, d	Standard Pathogen-Sensitive Antibiotic Treatment	CRP, mg/L	WBC, (×109/L	PCT, ng/mL
Case 1	70 kg, > 97th	Susceptible to respiratory infections	5	No	>160	4.4	>200
Case 2	46 kg, 75th–90th	Febrile convulsion at 3 and 5 y old	2	No	70	10.46	>200
Case 3	25 kg, 50th–75th	Wilson disease	5.2	No	83	0.28	124.1
Case 4	6 kg, 0th–3rd	Descending colon resection and anastomosis 2 mo before admission, decreased biotinase activity	5	No	185	8.56	0.91
Case 5	18 kg, 50th–75th	Autism	4	No	79	3.9	>200
Case 6	78 kg, >97th	Pneumonia 9 mo before admission	1.25	No	138	15.13	54.73
91.8	1000	Yes	Located behind ileum, perforation in the middle section, luminal fecal stone	Acute suppurative appendicitis	48 d	Rehabilitation and discharge
91.3	——	——	Retroperitoneal appendicitis, localized inflammation	——	10 d	Discharged after stable condition
3.5	None	No	Located in the anterior ileum, adhesions and curly, covering pus, the mesentery rotated 180 degrees counterclockwise	Multifocal necrosis of the mucous and submucous	12 h 50 min (0.54 d)	Died
38.6	20	Yes	Covering pus moss, root section perforated	Acute suppurative appendicitis	10 d	Discharged after stable condition
47.9	300	Yes	Located behind ileum, perforated, luminal fecal stone	Acute suppurative appendicitis	25 d	Discharged after stable condition
88.2	No detailed record	No	Located behind ileum, the largest outer diameter is 1.5 cm. gangrene and perforated on the mesangial side with mesangial swollen	Acute gangrenous appendicitis	11 d	Discharged after stable condition

Representative Cases

Case 1 is a 12 1/2-year-old boy weighing 70 kg. He was admitted to hospital primarily because of “intermittent abdominal pain for more than 5 days, vomiting for more than 4 days, and fever for more than 3 days”; the highest temperature was 41°C. On admission, he presented with convulsions (upward rolling of the eyes, bruising around the mouth, and leg weakness), with systolic blood pressure dropping to 40 to 50 mm Hg (Table 1). Physical examination showed abdominal guarding, tenderness and rebound tenderness, particularly in the right lower quadrant. B-scan ultrasonography of the abdomen showed swelling of the right lower quadrant appendix with an outer diameter of 1.2 cm, thickening of surrounding mesentery, and massive turbid free ascites in the peritoneal cavity. Blood analysis revealed an abnormal elevation in inflammatory markers (Table 2). Emergency exploratory laparotomy and appendectomy were performed under general anesthesia. During the operation, a large amount of yellow pus was found in the abdominal cavity, the intestinal tract was widely covered with pus, and the appendix was perforated. There were no intraoperative or postoperative complications, and the tracheal intubation was removed 5 days after the operation. He was discharged from the hospital 47 days after the surgery. Since discharge, he has been in good physical condition without complications.

Case 2 is an 11-year-old boy weighing 46 kg. He was admitted to the hospital with a history of “abdominal pain and vomiting for 2 days, fever and poor mental response for 20 hours.” Gastroenteritis was considered in a local hospital. Eight hours before admission, his temperature rose to 41°C, and he had a convulsion characterized by upward rolling of the eyes, tonic-clonic fits of the limbs, and failure to respond to stimuli. The fit lasted for about 10 minutes and then stopped spontaneously. Emergency monitoring showed a blood pressure of 102/20 mm Hg, decreased left ventricular ejection fraction (approximately 56%), troponin level of 0.763 ng/mL, brain natriuretic peptide of 694 ng/mL, abnormally increased inflammatory markers, a PH of 7.291, and serum lactic acid of 7.1 mmol/L (Table 1). The patient had a history of febrile convulsions at ages 3 and 5 years. Therefore, shock and convulsion of unknown origin were considered. Dopamine infusion (for maintaining blood pressure), sodium bicarbonate (for correcting acid imbalance), and antibiotics were administered. His blood pressure was stable and shock was corrected on the third day of admission. However, abdominal ultrasonography showed an edematous retrocecal appendix with an outer diameter of 0.9 cm, a wall thickness of 0.3 cm, and adhesions. Therefore, perforation of a retroperitoneal appendix with wrapping was considered. He was managed conservatively and discharged a week later with normal blood indices. Half a year later, he was readmitted with chronic appendicitis and underwent a laparoscopic appendectomy. Pathological examination of the surgical specimen showed chronic appendicitis with mild periappendicitis. He was discharged from the hospital 3 days after the surgery. There were no complications during the follow-up period.

Case 3 is a 7-year-old girl weighing 25 kg. She was admitted to the hospital with a history of “intermittent fever and abdominal pain for 5 days,” with the highest temperature of 39°C. She was managed as a case of fever of unknown origin by a local hospital and was treated with intravenous cefuroxime, anti-inflammatory, and antishock medications due to agranulocytosis and hepatolenticular degeneration. However, the symptomatic treatment was not effective. She presented to the emergency unit of our hospital with lethargy and apathy. On examination, she had generalized abdominal guarding, tenderness, and rebound tenderness, particularly in the right lower quadrant. A routine blood test showed derangement of CRP (83 mg/L), WBC (0.28 ×10⁹/L), NEUT% (3.5%), lymphocyte count (92.9%), and PCT (124.09 ng/mL; Table 2). Abdominal ultrasonography showed thickening of the right lower quadrant appendix with a maximum outer diameter of 1.2 cm and a wall thickness of 0.2 cm. Intracavitary effusion was seen, with a little surrounding exudation and mild swelling of the mesentery. The initial diagnosis was “acute appendicitis, neutropenia, and hepatolenticular degeneration (Wilson disease)”. Then, exploratory laparoscopy and appendectomy were performed under general anesthesia. Intraoperative exploration showed adhesion and curling of the appendix, which was externally coated with pus. After the operation, the patient developed refractory septic shock, which was difficult to correct despite active antishock treatment and 2 cardiopulmonary resuscitations. Combined with the possibility of extremely severe infection and 3-line reduction in blood count of unknown cause, poor stress response arising from hepatolenticular degeneration, and liver failure, the parents chose to give up treatment after our explaining of the condition. The patient died after returning home.

Case 4 is a 6-month-old male infant weighing 6 kg. He was admitted to the hospital primarily because of “vomiting for 5 days, fever and crying for 4 days,” with the highest temperature of 38.9°C. He was diagnosed with congenital genetic metabolic disease and underwent colectomy and anastomosis for “necrotizing enterocolitis, colon stricture” 2 months before admission (Table 2). He was then transferred to the emergency department of our hospital. Physical examination showed abdominal distention, guarding, tenderness, and rebound tenderness. Abdominal B-scan ultrasonography showed appendix abscess and free empyema in the peritoneal cavity. Inflammatory markers were increased significantly. The child was lethargic, and his blood pressure gradually dropped to 62/33 mm Hg; heart rate was 152 beats per minute, lower limbs were cool, and CRT was 3 seconds (Table 1). The blood pressure remained 63 to 68/33 to 40 mm Hg despite extracellular volume expansion with normal saline. Therefore, norepinephrine was infused at the rate of 0.2 ug/kg·min to raise the blood pressure to normal. A diagnosis of “septic shock, appendicular abscess, and secondary peritonitis” was made. Exploratory laparotomy was performed under general anesthesia, with intraoperative exploration revealing diffuse peritonitis and perforation at the root of the appendix. The surgery was successful, and the patient was discharged 10 days later with normal blood indices. Since discharge, he has been in good physical condition.

Case 5 is a 4-year-old girl weighing 18 kg. She was admitted to the hospital with a “poor mental response for 4 days, fever and vomiting for 3 days, and low temperature with cold limbs for 9 hours.” The highest recorded temperature was 39.2°C. She received antibiotic treatment in a nearby hospital a day before presentation. Eight days after birth, she underwent laparoscopic right oophorectomy for ovarian torsion. She was also diagnosed with autism 17 months before admission to our hospital. On admission, she had a poor mental response, a heart rate of 205 beats per minute, hypotensive with a blood pressure of 78/46 mm Hg, generalized abdominal guarding, tenderness, and rebound tenderness, particularly in the right lower quadrant (Table 1). B-scan ultrasonography of the acute abdomen showed perforation of an acute suppurative appendix, with multiple empyemas in the intestines and pelvis. An abnormal elevation in inflammatory markers was found (Table 2). Thus, a diagnosis of “perforated acute suppurative appendicitis, acute severe infection, and septic shock” was made. Exploratory laparoscopy was performed under general anesthesia, revealing a large amount of free pus in the abdominal cavity, diffuse peritonitis, and perforation of the appendix. She was stable after the surgery and was discharged on the 24th-day postop. Since discharge, he has been in good physical condition.

Case 6 is a 13-year-old boy weighing 78 kg. He was admitted to the hospital with “intermittent vomiting for 30 hours, migrating right lower abdominal pain for 25 hours, and chills for more than 1 hour.” Nine months before admission, he was locally hospitalized for pneumonia, during which a bronchoscopy was performed. On admission, physical examination showed generalized abdominal guarding, tenderness, and rebound tenderness, particularly in the right lower quadrant. B-scan ultrasonography of the acute abdomen showed a perforated acute suppurative appendix with an intracavitary bezoar. He had an abnormal increase in inflammatory markers. His heart rate and blood pressure were more than 170 beats per minute and 140/90 mm Hg, respectively (Table 1). The patient developed chills, cyanotic skin, and cold limbs. Capillary refill time was more than 5 seconds, and blood gas analysis revealed a lactic acid level of 8 mmol/L. Therefore, “acute suppurative appendicitis and septic shock” was considered. Active volume expansion and vasoactive drugs were used to maintain the blood pressure. Exploratory laparoscopy and appendectomy were performed under general anesthesia. There was swelling and gangrene in the middle and distal segments of the appendix covered with pus, perforation on the mesenteric side of the appendix, edema and empyema of the mesentery, and bezoar in the appendix cavity. The surgery was successful, and he was discharged in stable condition 10 days after the operation. Since discharge, he has been in good physical condition.

DISCUSSION

This case series reported the clinical characteristics of 6 children with complicated appendicitis that developed septic shock. All patients had complicated appendicitis (perforation in 4 cases, periappendicular abscess in 1 case, and generalized peritonitis in 3 patients), abnormally raised acute phase reactants, and circulatory collapse. This report indicated that pediatric patients with complicated appendicitis are susceptible to sepsis and circulatory compromise, and patients should be carefully monitored and treated promptly to avoid life-threatening complications.

The progression of acute appendicitis to septic shock in these patients can be attributed to 2 main reasons: the severity and quick progression of the disease and the relative weak immune systems of the patients. The possible specific influencing factors include age, weight, concomitant diseases, delay in diagnosis, peritonitis, and pathological types of the appendix.⁹

Infants and preschool children do not exhibit the typical clinical symptoms of acute appendicitis. Children at this age cannot communicate and express themselves, and the clinical symptoms often overlap with symptoms of acute gastroenteritis, mesenteric lymphadenitis, respiratory tract infection, constipation, and other abdominal diseases.⁹ Abdominal examination is often encountered with crying, resistance, and poor cooperation, which increases the possibility of delayed diagnosis. In addition, children at this stage often have omentum hypoplasia, which is unlikely to wrap and confine the inflamed appendix. Hence, diffuse peritonitis occurs easily, and a large amount of peritoneal toxin absorption leads to the rapid progression of infection.⁹ In our study, cases 4 and 5 belonged to this age group, and the time from onset to clear diagnosis exceeded 4 days. Patient 5 was a child with autism, making it more difficult to diagnose appendicitis. These factors favor the occurrence of septic shock. Thus, the patients had features of generalized peritonitis on examination, which was confirmed intraoperatively by diffuse peritonitis from perforated appendicitis, indicating the inability of the omentum to confine the spread of peritoneal infection.

Immune status is closely related to body weight and nutrition. The incidence and severity of infectious diseases for obese children are significantly higher than for nonobese children of the same age.¹⁰ Obesity is often accompanied by chronic low-grade inflammation and immune dysfunction and is a common underlying disease associated with sepsis.^10,11 Patients 1 and 6 were obese children, which may account for the progression of appendicitis and the spread of infection. Conversely, in a patient with serious infection, energy consumption is exceptionally high, and the lack of energy reserves seriously weakens the immunity.¹² Patient 4 was a child with very low body weight and poor nutritional status; severe abdominal infection is more likely to lead to sepsis and shock.

Common causes of perforation in acute appendicitis are the appendiceal wall lymphatic follicular hyperplasia caused by bacterial and viral infection and fecal stone obstruction of the appendiceal cavity.⁵ If the surrounding tissues or omentum cannot wrap and confine the perforation of the appendix promptly, free pus accumulates in the peritoneal cavity leading to diffuse peritonitis. The toxins are absorbed into the blood through the peritoneum, leading to septic shock. In the appendix located behind the cecum or in the retroperitoneum, the symptoms of inflammation may not be obvious,⁵ and this condition often delays diagnosis and treatment. In this study, case 2 had retroperitoneal appendicitis with close wrapping; because his symptoms were not obvious, the onset of the disease might have occurred earlier. On the third day after admission, his shock was corrected, and B-ultrasound made a clear diagnosis based on suspected right abdominal tenderness. Similarly, case 6 had gangrene and perforation on the mesenteric side of the appendix. After perforation, the appendix was sealed by the mesoappendix, rich in blood vessels, resulting in severe swelling of the mesentery and subsequent absorption of toxins into the systemic circulation through the mesenteric vessels. One similar adult case was reported by Man et al.¹³ In addition, gangrene of the appendix promotes bacterial growth, severe infection, and subsequent bacterial peritonitis, promoting sepsis and shock.

Biotin is a water-soluble sulfur-containing vitamin involved in the metabolism of carbohydrates, fat, and proteins. Children with biotinase deficiency have impaired mitochondrial energy synthesis, skin damage, and decreased immune function.¹⁴ The decrease of biotinase activity in patient 4 may be an important reason for the rapid progression of septic shock after acute infection. Wilson disease is an autosomal recessive disease due to the ATP7B gene mutation. The defect leads to excess deposition of free copper in the liver, leading to derangement of liver function.¹⁵ Patient 3 was diagnosed with Wilson disease 1 month before admission and had poor blood coagulation function (prothrombin time: 16.9 seconds, activated partial thromboplastin time: 35.6 seconds, international normalized ratio: 1.7) and albumin levels (25.5 g/L). Although septic shock in patient 3 was mainly related to severe infection and unexplained decrease of blood cells (WBC = 0.28 × 10⁹/L, RBC = 3.07 × 10¹²/L, PLT = 27.1 × 10⁹/L), poor liver function and poor hepatic response to stress might be one of the reasons for the rapid deterioration of her condition.

This study has some limitations. It is a single-center, retrospective study with a limited number of samples. Further large-sample, multicenter studies are needed to clarify the etiology of septic shock in children with acute appendicitis.

CONCLUSIONS

Children with delayed diagnosis, abnormal body weight, significant elevation in inflammatory markers, underlying metabolic disease, nonstandard, or nonpathogen-sensitive antibiotics therapy are at greater risk of complicated appendicitis, sepsis, and septic shock. Therefore, attention should be given to early detection and prompt treatment to avoid septic shock.