Pathophysiological effects of abdominal CO2 insufflation on cerebral and splanchnic oxygenation in neonates and infants undergoing laparoscopy remain poorly investigated. We investigated laparoscopic pyloromyotomy as a paradigm to determine such changes in this specific population.Single-center, prospective cohort of 28 infants undergoing laparoscopic pyloromyotomy at the mean age of 30.9 ± 10.6 days. The pneumoperitoneum was set at 6 to 8 mmHg. Regional cerebral oxygen saturation (cSO2) and splanchnic oxygen saturation (sSO2) were measured by near-infrared spectroscopy. End-tidal carbon dioxide (EtCO2) levels, heart rate, body temperature, systemic blood pressure, and urine output were also recorded. Data (mean ± SD) were collected intraoperatively at 0, 15, and 30 minutes and compared to baseline values for each patient using the t-test.A significant decrease in cSO2 was recorded only at the beginning of surgery, while sSO2 significantly decreased from 15 intraoperative minutes (-7.1% ± 7.2; p = 0.0009) until the end of insufflation, followed by an increasing trend, although still below the baseline values (-6.5% ± 11.2; p = 0.01). EtCO2 increased significantly from the initial 15 intraoperative minutes, reaching a maximum of 42.6 ± 8.9 mmHg at 30-minute intervals. Urine output significantly decreased within the first 4 postoperative hours.Laparoscopic pyloromyotomy using low-pressure CO2 insufflation (6-8 mmHg) maintains stable cerebral oxygenation in neonates and infants, while splanchnic oxygenation and urine output experience temporary, reversible reductions. These findings suggest that low-pressure pneumoperitoneum is a safe and effective approach in neonatal laparoscopy, with minimal oxygenation and metabolic risks.

Retroperitoneal robotic-assisted laparoscopic pyeloplasty (R-RALP) is the commonest urologic procedure performed in children, entailing retroperitoneal CO2 insufflation and lateral decubitus, whose effects on cardiopulmonary variables are poorly known. We, therefore, studied hemodynamic and respiratory changes due to CO2 insufflation and lateral decubitus in children undergoing R-RALP and their effects on regional tissue oxygenation. Between 1/2021 and 7/2024, children affected by ureteropelvic joint obstruction (UPJO) underwent a pyeloplasty by R-RALP at Necker Enfants Malades Hospital (Paris, France), using a standardized surgical technique and a lung-protecting anesthetic protocol aimed to prevent hypercarbia. Cerebral and renal Near InfraRed Spectroscopy (NIRS) were added to standard monitoring. Mean monitoring parameters and NIRS values were derived from the prospectively kept continuous reading at eight preset points and analyzed. 37 patients were prospectively included (21 males), with a mean age of 6.0 ± 3.9 years, and mean body weight of 22.5 ± 11.3 kg; 15 patients were operated on in Left Lateral Decubitus (LLD) and 22  in Right Lateral Decubitus (RLD). No different LLD/RLD time trends were observed for standard monitoring parameters and NIRS measurements. Conversely, EtCO2 was higher in the RLD group at trocars insertion (T4, + 3.3 mmHg), beginning of CO2 insufflation (T5, + 2.9), and 45 min after the start of the procedure (T6, + 3.1). At the same time points, Pplat was higher in the LLD group at T4 (+ 3.0 cmH2O); T5, (+ 3.4) and T6 (+ 4.7). During R-RALP, the combination of RLD and CO2 insufflation promotes hypercarbia, while LLD requires increasing Pplat pressures, potentially favoring lung injury and hemodynamic instability during prolonged procedures.

Little is known about the effects of CO2 insufflation (CDI) on cerebral oxygen saturation (CrSO2) during laparoscopy in the pediatric population. In children undergoing robotic-assisted laparoscopic pyeloplasty (RALP), we prospectively assessed the effects of CDI using standard monitoring and cerebral near-infrared spectroscopy (NIRS). We also explored whether a correlation existed between CrSO2 and parameters known to affect cerebral blood flow. Between January 2021 and September 2023, a cohort of consecutive children older than 2 years underwent RALP at Necker-Enfants Malades Hospital in Paris. A ventilation protocol aimed to prevent hypercarbia was implemented. Data collected included standard monitoring parameters and CrSO2 by NIRS. Thirty patients (16 females), mean age 5.5 ± 3.9 (2.0-9.5) years, were included. Twenty-three patients underwent a retroperitoneal approach. The mean baseline CrSO2 value was 83.0 ± 9.8. Mean CrSO2 decreased during progressive CDI, never below baseline values, while standard-monitoring parameters did not significantly change. No significant correlation was detected between CrSO2 and end tidal CO2, or between CrSO2 and mean arterial pressure, at any operative time. During RALP, a gradual CDI doesn't cause pathological derangements of CrSO2. The lack of correlation between CrSO2 and standard parameters affecting cerebral blood flow suggests the likely presence of cerebral autoregulation in our population.

Transoral endoscopic resections in treating upper gastrointestinal submucosal lesions have the advantages of maintaining the integrity of the gastrointestinal lumen, avoiding perforation and reducing gastrointestinal fistulae. They are becoming more widely used in clinical practice, but, they may also present a variety of complications. Gas-related complications are one of the most common, which can be left untreated if the symptoms are mild, but in severe cases, they can lead to rapid changes in the respiratory and circulatory systems in a short period, which can be life-threatening. Therefore, it is important to predict the occurrence of gas-related complications early and take preventive measures actively. Based on the authors' results in the prepublication of the article "Nomogram to predict gas-related complications during transoral endoscopic resection of upper gastrointestinal submucosal lesions," and in conjunction with our evaluation and additions to the relevant content, radiographs may help screen patients at high risk for gas-related complications. Controlling blood glucose levels, shortening the duration of surgery, and choosing the most appropriate surgical resection may positively impact the prognosis of patients at high risk for gas-related complications during transoral endoscopic resection of upper gastrointestinal submucosal lesions.

Background: Thoracoscopic resection is the standard of care for congenital lung malformations (CLMs) in infants. However, there is rising concern that capnothorax may affect cerebral perfusion and oxygenation, carrying potential long-term effects on neurodevelopmental behavior. The aim of our study was to investigate, using near-infrared spectroscopy (NIRS), the regional cerebral oxygenation (CrSO₂) in infants undergoing thoracoscopic lung resection; the secondary aim was to assess the relationship between rSO₂ and standard monitoring. Methods: In this retrospective study, we reviewed all infants (<1 year old, ASA II) who underwent thoracoscopic CLM resection in double-lung ventilation under fixed capnothorax parameters (5 mmHg of pressure, 1 L/minute flow), standardized anesthetic protocol, standard monitoring, and multisite NIRS in our center. We focused our attention on 8 anesthetic and surgical maneuvers, potentially affecting tissue oxygen saturation. Results: Ten infants met the inclusion criteria. At surgery, median age was 5.5 (4-7) months, median weight 7.2 (6.6-8) kg, median operative time 110 (55-180) minutes, and median capnothorax duration 79 (34-168) minutes. No conversion to open surgery occurred. CrSO₂ values remained within clinically accepted values during thoracoscopy, beside a CrSO₂ drop >20% of basal value in 1 patient, during capnothorax induction. Renal NIRS added very little to standard monitoring, which appeared generally inadequate to consistently appraise end-organ perfusion. ETCO₂ best correlated with CrSO₂ variations, suggesting to be able to realistically predict them. Conclusions: The thoracoscopic treatment of CLMs under the given conditions appears well tolerated in infants, pending the continuous adjustment of ventilator settings by an experienced anesthetist, confident with NIRS technology.

Capnoperitoneum provides a ventilatory challenge due to reduction in end-expiratory lung volume and peritoneal carbon dioxide absorption in both children and adults. The primary aim of this controlled interventional trial was to determine the positive end-expiratory pressure (PEEP) level needed to ensure for adequate carbon dioxide clearance and preservation of carbon dioxide homeostasis in an experimental model of infant laparoscopy. The secondary aim was to evaluate potential effects on cardiac output of PEEP and abdominal pressure level variations in the same setting.

Eight chinchilla bastard rabbits were anesthetized and mechanically ventilated. Intra-abdominal pressures were randomly set to 0, 6, and 12 mm Hg by carbon dioxide insufflation. Carbon dioxide clearance using volumetric capnography, arterial blood gas data, and cardiac output was recorded, while PEEP 3, 6, and 9 cmH₂ O were applied in a random order.

A PEEP of 9 cmH₂ O showed restoration of carbon dioxide clearance without causing changes in arterial partial pressure of carbon dioxide and bicarbonate and with no associated deterioration in cardiac output.

The results promote a PEEP level of 9 cmH₂ O in this model of infant capnoperitoneum to allow for adequate carbon dioxide removal with subsequent preservation of carbon dioxide homeostasis. The use of high PEEP was not associated with any decrease in cardiac output.

Intraoperative hypercapnia and acidosis have been associated with thoracoscopic repair of both congenital diaphragmatic hernia and esophageal atresia/tracheoesophageal fistula.

The aim of the present study was to investigate whether thoracoscopic repair of congenital diaphragmatic hernia or esophageal atresia/tracheoesophageal fistula was associated with acidosis and hypercapnia in a large group of neonates, and to analyze the effects of acidosis and hypercapnia on early postoperative outcomes.

We reviewed the charts of neonates who underwent open or thoracoscopic congenital diaphragmatic hernia or esophageal atresia/tracheoesophageal fistula repair (2004-2014). Patients with available intraoperative arterial gas values were included. Data (PaCO₂ : mm Hg) were compared using paired/unpaired tests and are reported as difference [95% confidence interval].

Congenital diaphragmatic hernia: 187 neonates underwent open (n=153) or thoracoscopic (n=34) repair. Intraoperative arterial gas values were recorded in 96 open and in 23 thoracoscopic operations. Both groups had similar preoperative pH and PaCO₂ , and developed intraoperative acidosis (open -0.08 [-0.11, -0.05] P<.001, thoracoscopic -0.14 [-0.24, -0.04] P=.01) and hypercapnia (open: 7.8 [3.2, 12.4], P=.002; thoracoscopic: 20.2 [-2.5, 43, P=.07). Intraoperatively, neonates undergoing thoracoscopic repair developed lower pH than those having open surgery (-0.06 [-0.01, -0.10] P=.018), but maintained similar levels of PaCO₂ (-4.0 [-9.0, 4.4] P=.39). Esophageal atresia/tracheoesophageal fistula: 205 neonates underwent open (n=180) or thoracoscopic (n=25) repair. Intraoperative arterial gas values were recorded in 62 open and in 14 thoracoscopic operations. Both groups had similar preoperative pH and PaCO₂ , and developed intraoperative acidosis (open: -0.09 [-0.14, -0.04], P<.001; thoracoscopic: 0.21 [-0.28, -0.14], P<.001) and hypercapnia (open: 9.2 [2.6, 15.7] P=.008; thoracoscopic: 15.2 [1.6, 28.7], P=.03). Intraoperatively, neonates undergoing thoracoscopic repair developed lower pH than those having open surgery (difference 0.08 [0.01, 0.15], P=.02) but maintained similar levels of PaCO₂ (difference -1 [-9, 3], P=.35).

Neonates undergoing operative repair of congenital diaphragmatic hernia and esophageal atresia/tracheoesophageal fistula develop intraoperative acidosis and hypercapnia, regardless of the approach used. However, this phenomenon is more severe during thoracoscopic repair. Novel modalities to reduce intraoperative gas derangements, particularly during thoracoscopic repair, need to be established.

Congenital diaphragmatic hernia (CDH) in the newborn poses challenges to the multi-disciplinary teams involved in its management. Mortality remains significantly high, despite growing understanding and treatment options. Early intubation of antenatally diagnosed cases is crucial in preventing deterioration and persistent pulmonary hypertension. Early recognition of cases not diagnosed on antenatal scan, with appreciation of differential diagnosis, requires an index of suspicion and imaging. Increasing options and modalities are available, with only modest, if any, survival advantage. Permissive hypercapnea and minimal ventilation have made the most significant impact on survival in modern era. High-frequency oscillatory ventilation (HFOV), inhaled nitric oxide (iNO), treatment of pulmonary hypertension, and ECMO are used in a somewhat stepwise manner for stabilisation. Delayed surgery has become established later in management plan. The impact of individual therapies (e.g. HFOV, iNO, ECMO) on outcome is difficult to ascertain. Little level 1 or 2 evidence exists. Randomised studies and reviews on the role of ECMO have not yet proven any long-term survival benefit. One pilot randomised study of thoracoscopic repair suggests increased acidosis; intraoperative blood gases and CO2 levels should be closely monitored. Monitoring tissue oxygenation should be considered. There is no evidence to suggest the best patch material.

Thoracoscopic operations in neonates, such as repair of oesophageal atresia and tracheooesophageal fistula or congenital diaphragmatic hernia, can be associated with intraoperative acidosis and hypercapnia in the absence of hypoxia. These derangements in intraoperative gas exchanges seem to be related to the insufflation and absorption of medical CO2. The effects on the developing brain are unknown, and further prospective investigations are needed to elucidate whether different strategies should be implemented to avoid these intraoperative problems.

There is a paucity of level 1 and level 2 evidence for best practice in surgical management of CDH. Antenatal imaging and prognostication is developing. Observed to expected lung-to-head ratio on ultrasound allows better predictive value over simple lung-to-head ratio. Based on 2 randomised studies, the verdict is still out in terms the best group and indication for antenatal intervention and their outcome. Tracheal occlusion is best suited for prospective randomised studies of benefit and outcome. Only one pilot randomised controlled study of thoracoscopic repair exists, suggesting increased acidosis; blood gases and CO2 levels should be closely monitored. Only poorly controlled retrospective studies suggest higher recurrence rates. Randomised studies on the outcome of thoracoscopic repair are needed. Careful selection, anaesthetic vigilance, monitoring and follow-up of these cases are required. There is no evidence to suggest the best patch material to decrease recurrences. Evidence suggests no benefit from routine fundoplication based on the one randomised study. Multi-disciplinary follow-up is required. This can be visits to different specialities, but may be best served by a multi-disciplinary one-stop clinic.

We aimed to evaluate the effect of thoracoscopy in neonates on intraoperative arterial blood gases, compared with open surgery.

Congenital diaphragmatic hernia (CDH) and esophageal atresia with tracheoesophageal fistula (EA/TEF) can be repaired thoracoscopically, but this may cause hypercapnia and acidosis, which are potentially harmful.

This was a pilot randomized controlled trial. The target number of 20 neonates (weight > 1.6 kg) were randomized to either open (5 CDH, 5 EA/TEF) or thoracoscopic (5 CDH, 5 EA/TEF) repair. Arterial blood gases were measured every 30 minutes intraoperatively, and compared by multilevel modeling, presented as mean and difference (95% confidence interval) from these predictions.

Overall, the intraoperative PaCO2 was 61 mm Hg in open and 83 mm Hg [difference 22 mm Hg (2 to 42); P = 0.036] in thoracoscopy and the pH was 7.24 in open and 7.13 [difference -0.11 (-0.20 to -0.01); P = 0.025] in thoracoscopy. The duration of hypercapnia and acidosis was longer in thoracoscopy compared with that in open. For patients with CDH, thoracoscopy was associated with a significant increase in intraoperative hypercapnia [open 68 mm Hg; thoracoscopy 96 mm Hg; difference 28 mm Hg (8 to 48); P = 0.008] and severe acidosis [open 7.21; thoracoscopy 7.08; difference -0.13 (-0.24 to -0.02); P = 0.018]. No significant difference in PaCO2, pH, or PaO2 was observed in patients undergoing thoracoscopic repair of EA/TEF.

This pilot randomized controlled trial shows that thoracoscopic repair of CDH is associated with prolonged and severe intraoperative hypercapnia and acidosis, compared with open surgery. These findings do not support the use of thoracoscopy with CO2 insufflation and conventional ventilation for the repair of CDH, calling into question the safety of this practice. The effect of thoracoscopy on blood gases during repair of EA/TEF in neonates requires further evaluation. (ClinicalTrials.gov Identifier: NCT01467245).

To compare open repair (OR) with thoracoscopic repair (TR) for congenital diaphragmatic hernia (CDH) in neonates.

Twenty-four neonatal CDH cases diagnosed prenatally or within 6 h of birth at our institute from 2002 to 2012 with mild pulmonary hypertension managed without inhaled nitric oxide, were studied. OR was routine until 2006 (n = 14; L:R = 12:2) and TR became routine in 2007 (n = 10; L:R = 10:0). All subjects had identical management.

Gestational age at birth: OR 37.4 ± 1.6 vs. TR: 38.3 ± 1.1 weeks (p = 0.10); birth weight 2,636 ± 490 vs. 2,887 ± 429 grams (p = 0.20); preoperative A-aDO(2): 308 ± 200 vs. 331 ± 195 mmHg (p = 0.79); and operating time (min): 161 ± 42 vs. 194 ± 76 (p = 0.27). In TR, intraoperative cardiopulmonary status was stable, intraoperative hemorrhage was significantly less (4.8 ± 6.0 vs. 1.1 ± 0.1 grams; p = 0.038), wound cosmesis was excellent without surgical site infections, while, maximum postoperative CRP (2.0 ± 1.5 vs. 1.5 ± 1.1 mg/dL; p = 0.30), commencement of enteral feeding (6.9 ± 2.8 vs. 5.6 ± 2.8 days; p = 0.27), and length of postoperative hospitalization (36 ± 22 vs. 34 ± 12 days; p = 0.66) were improved, but not significantly. One OR case required surgery for intestinal obstruction.

Thoracoscopic repair appears to be as effective as OR for treating selected cases of CDH in neonates, with excellent wound cosmesis.

This article discusses the potential benefits and challenges of minimally invasive surgery for infants and small children, and discusses why pediatric minimally invasive surgery is not yet the surgical default or standard of care. Minimally invasive methods offer advantages such as smaller incisions, decreased risk of infection, greater surgical precision, decreased cost of care, reduced length of stay, and better clinical information. But none of these benefits comes without cost, and these costs, both monetary and risk-based, rise disproportionately with the declining size of the patient. In this review, we describe recent progress in minimally invasive surgery for infants and children. The evidence for the large benefits to the patient will be presented, as well as the considerable, sometimes surprising, mechanical and physiological challenges surgeons must manage.

Surgical management of congenital diaphragmatic hernia (CDH) remains a challenge for all clinicians. While the treatment strategies for CDH have evolved from emergent surgical intervention to initial hemodynamic stabilization with delayed surgical repair, surgical innovations have remained limited in the last 20 years. Advances in surgical approaches, such as minimally invasive surgery and alternatives to diaphragmatic replacement, have focused on improvements in surgical morbidity.

Funded knowledge about the physiological impact of laparoscopic surgery in children is sparse. Although there are data on hemodynamic compromise after creation of a pneumoperitoneum in children, little is known about microcirculatory changes at the mucosa level. Therefore, the aim of this study was to assess gastric microcirculation by continuous gastric air tonometry in the setting of laparoscopic versus open appendectomy.

Twenty children 5-17 years old undergoing laparoscopic and 7 children undergoing open appendectomy were included in the study. Gastric intramucosal CO(2) pressure (pCO(2)i) was measured under standardized flow and intraperitoneal pressure using continuous air tonometry (TONOCAP(®), Datex Ohmeda), and ΔpCO(2) (pCO(2)i - end-expiratory CO(2) pressure [pCO(2)e]) was obtained for the time course of surgery.

ΔpCO(2) increased significantly from the baseline value not only in the laparoscopic group but also in the open surgery group. Even though ΔpCO(2) was higher in the laparoscopic group at all time points, the overall increase in ΔpCO(2) for both groups was uniform. The largest differences were observed during the initial 20 minutes of the operation. The changes observed were exclusively due to an increase of pCO(2)i in relation to a constant pCO(2)e.

In the setting of a standardized, simple operation in an otherwise healthy child above the age of 5 years, our data suggest that the effect of a pneumoperitoneum on splanchnic perfusion is comparable to the compromise caused by open surgery. Further research must be obtained when evaluating the full impact of laparoscopy in children.

Congenital diaphragmatic hernia (CDH) and esophageal atresia with tracheoesophageal fistula (EA/TOF) can be repaired thoracoscopically, but this may cause hypercapnia, acidosis, and reduced cerebral oxygenation. We evaluated the effect of thoracoscopy in infants on cerebral oxygen saturation (cSO(2)), arterial blood gases, and carbon dioxide (CO(2)) absorption.

Eight infants underwent thoracoscopy (6 CDH and 2 EA/TOF). Serial arterial blood gases were taken. Regional cSO(2) was measured using near-infrared spectroscopy. Absorption of insufflated CO(2) was calculated from exhaled (13)CO(2)/(12)CO(2) ratio measured by mass spectrometry.

CO(2) absorption increased during thoracoscopy with a maximum 29% ± 6% of exhaled CO(2) originating from the pneumothorax. Paco(2) increased from 9.4 ± 1.3 kPa at the start to 12.4 ± 1.0 intraoperatively and then decreased to 7.6 ± 1.2 kPa at end of operation. Arterial pH decreased from 7.19 ± 0.04 at the start to 7.05 ± 0.04 intraoperatively and then recovered to 7.28 ± 0.06 at end of operation. Cerebral hemoglobin oxygen saturation decreased from 87% ± 4% at the start to 75% ± 5% at end of operation. This had not recovered by 12 (74% ± 4%) or 24 hours (73% ± 3%) postoperatively.

This preliminary study suggests that thoracoscopic repair of CDH and EA/TOF may be associated with acidosis and decreased cSO(2). The effects of these phenomena on future brain development are unknown.

In recent years minimally invasive surgical techniques in children have made substantial progress. The feasibility and safety of a wide spectrum of laparoscopic and thoracoscopic procedures have been confirmed in numerous studies. Moreover, it was reported that minimally invasive pediatric surgery is associated with lower morbidity, a shorter hospital stay, lower costs, better cosmetics and clinical results similar to those achieved by open surgery. The present article reviews information on established as well as feasible but not yet established surgical procedures. The discussion of potential hemodynamic, respiratory and organ perfusion effects of the CO(2) pneumoperitoneum and the notation of special logistic aspects should support the reader in the process of decision-making to schedule infants and children for minimally invasive surgery.

Thoracoscopic repair of congenital diaphragmatic hernia (CDH) has been described, but its efficacy and safety have not been validated. The aim was to compare our experience of thoracoscopy with laparotomy repair.

After ethics approval, we reviewed the notes of neonates with CDH operated in our institution between 2003 and 2008. Two historical groups were compared: infants who underwent laparotomy (2003-2008) or thoracoscopy (2007-2008). Data were compared by t test or Mann-Whitney tests.

Thirty-five children had open repair of CDH, and 13 had thoracoscopic repair. Groups were homogeneous for age and weight. Five (38%) neonates who had thoracoscopy were converted to open for surgical difficulties (n = 4) and O(2) desaturation (n = 1). Patch repair was used in 12 (34%) open and 6 (46%) thoracoscopic repairs. End-tidal CO(2) was significantly elevated during thoracoscopy, but this was not reflected in arterial CO(2) or pH. There were 3 (8%) recurrences after open repair and 2 (25%) after thoracoscopy (P = .19).

Thoracoscopic repair of CDH is feasible. Arterial blood gases should be closely monitored. Despite higher EtCO(2), conversion to open was mainly because of difficult repair. A randomized trial is necessary to assess the effect of thoracoscopy on ventilation and recurrences.

The aim of this paper is to review the factors which may affect breath (13)CO(2)/(12)CO(2) natural abundance in patients undergoing surgery or intensive care. Intravenous glucose administration is a major determinant of the (13)CO(2)/(12)CO(2) of breath as intravenous glucose preparations are almost all derived from cornstarch. In addition, the oxidation of endogenous substrates can affect the (13)CO(2)/(12)CO(2) ratio. During many endoscopic procedures, such as laparoscopic surgery, carbon dioxide insufflation is used to provide a working space. As medical CO(2) is relatively depleted in (13)CO(2) compared with endogenous and exogenous metabolic CO(2) sources, breath (13)CO(2)/(12)CO(2) measurements can be used to estimate CO(2) absorption during these procedures. However, all these factors may also be affected by the bicarbonate pool, making a definitive attribution of changes in breath (13)CO(2)/(12)CO(2) to a single factor problematic.

The knowledge on the physiological impact of endoscopic surgery in infants and children is limited. Cardiovascular effects of pneumoperitoneum are mainly the result of an increase in intraabdominal pressure, absorption of carbon dioxide, and a stimulation of the neurohumoral vasoactive system. In infants, pneumoperitoneum alters the heart rate, mean arterial pressure, left ventricular endsystolic and end-diastolic volume, and meridional wall stress. Urine production is significantly reduced, and cerebral oxygenation and blood flow are altered. However, postoperative immune function is preserved or restored faster, and specific physiological responses to endoscopic surgery are well tolerated by otherwise healthy infants and children. The effects in children with specific conditions, such as sepsis, cancer, or organ dysfunction, remain to be investigated.