The pathophysiological impact of intra-abdominal hypertension in pigs

Robert Wise; Reitze Rodseth; Ester Párraga-Ros; Rafael Latorre; Octavio López Albors; Laura Correa-Martín; Francisco M Sánchez-Margallo; Irma Eugenia Candanosa-Aranda; Jan Poelaert; Gregorio Castellanos; Manu L N G Malbrain

doi:10.1371/journal.pone.0290451

. 2023 Aug 28;18(8):e0290451. doi: 10.1371/journal.pone.0290451

The pathophysiological impact of intra-abdominal hypertension in pigs

Robert Wise ^1,^2,^3,^*, Reitze Rodseth ², Ester Párraga-Ros ⁴, Rafael Latorre ⁴, Octavio López Albors ⁴, Laura Correa-Martín ⁵, Francisco M Sánchez-Margallo ⁵, Irma Eugenia Candanosa-Aranda ⁶, Jan Poelaert ¹, Gregorio Castellanos ⁷, Manu L N G Malbrain ^8,^9,¹⁰

Editor: Nataša Kovač¹¹

¹Faculty Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Brussels, Belgium

²Discipline of Anaesthesiology, and Critical Care, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa

³Adult Intensive Care Unit, John Radcliffe Hospital, Oxford University Hospitals Trust, Oxford, United Kingdom

⁴Department of Anatomy and Comparative Pathology, Veterinary Faculty, University of Murcia, Murcia, Spain

⁵Laparoscopy Department Jesus Uson Minimally Invasive Surgery Centre, Caceres, Spain

⁶Highlands Teaching and Research Farm, Faculty of Veterinary Medicine, National Autonomous University of Mexico, Queretaro. Mexico

⁷Department of General Surgery, Virgen de la Arrixaca General University Hospital, Murcia, Spain

⁸First Department of Anaesthesiology and Intensive Care Medicine, Medical University of Lublin, Lublin, Poland

⁹Medical Director (CMO), Medical Data Management, Medaman, Geel, Belgium

¹⁰International Fluid Academy, Lovenjoel, Belgium

¹¹UHC, CROATIA

Competing Interests: Robert Wise: Dr. Wise declares that he has no financial or personal relationships that may have inappropriately influenced him in writing this paper. He is currently a member of the WSACS. Reitze Rodseth: Prof. Rodseth declares that he has no financial or personal relationships that may have inappropriately influenced him in writing this paper. He is supported in part by the National Research Foundation of South Africa. Ester Párraga-Ros: Prof. Párraga-Ros declares that she has no financial or personal relationships that may have inappropriately influenced him in writing this paper. Rafael Latorre: Prof. Latorre declares that he has no financial or personal relationships that may have inappropriately influenced him in writing this paper. Octavio López Albors: Prof. Lopez Albors declares that he has no financial or personal relationships that may have inappropriately influenced him in writing this paper. Laura Correa-Martín: Prof. Correa-Martín declares that he has no financial or personal relationships that may have inappropriately influenced him in writing this paper. Francisco M. Sánchez-Margallo: Prof. Sánchez-Margallo declares that he has no financial or personal relationships that may have inappropriately influenced him in writing this paper. Irma Eugenia Candanosa-Aranda: Prof. Candanosa-Aranda declares that he has no financial or personal relationships that may have inappropriately influenced him in writing this paper. Jan Poelaert: Prof. Poelaert declares that he has no financial or personal relationships that may have inappropriately influenced him in writing this paper. Gregorio Castellanos: Prof. Castellanos declares that he has no financial or personal relationships that may have inappropriately influenced him in writing this paper. Manu L. N. G. Malbrain: MLNGM is Professor of Critical Care Research at the 1st Department of Anaesthesiology and Intensive Therapy, Medical University of Lublin, Poland. He is co-founder, past-President and current Treasurer of WSACS (The Abdominal Compartment Society, http://www.wsacs.org). He is member of the medical advisory Board of Pulsion Medical Systems (part of Getinge group, Solna, Sweden), Serenno Medical, Potrero Medical, Sentinel Medical Technologies and Baxter. He consults for BBraun, Becton Dickinson, ConvaTec, Spiegelberg, and Holtech Medical, and received speaker’s fees from PeerVoice. He holds stock options for Serenno and Potrero. He is co-founder and President of the International Fluid Academy (IFA). The IFA (http://www.fluidacademy.org) is integrated within the not-for-profit charitable organization iMERiT, International Medical Education and Research Initiative, under Belgian law.

^✉

* E-mail: robwiseICU@gmail.com

Roles

Robert Wise: Formal analysis, Validation, Writing – original draft, Writing – review & editing

Reitze Rodseth: Formal analysis, Validation, Writing – original draft, Writing – review & editing

Ester Párraga-Ros: Investigation, Methodology, Writing – review & editing

Rafael Latorre: Investigation, Methodology, Writing – review & editing

Octavio López Albors: Investigation, Methodology, Writing – review & editing

Laura Correa-Martín: Investigation, Methodology, Writing – review & editing

Francisco M Sánchez-Margallo: Investigation, Methodology, Writing – review & editing

Irma Eugenia Candanosa-Aranda: Investigation, Methodology, Writing – review & editing

Jan Poelaert: Formal analysis, Validation, Writing – original draft, Writing – review & editing

Gregorio Castellanos: Conceptualization, Funding acquisition, Investigation, Methodology, Writing – review & editing

Manu L N G Malbrain: Formal analysis, Validation, Writing – original draft, Writing – review & editing

Nataša Kovač: Editor

PMCID: PMC10461824 PMID: 37639437

Abstract

Background

Intra-abdominal hypertension and abdominal compartment syndrome are common with clinically significant consequences. We investigated the pathophysiological effects of raised IAP as part of a more extensive exploratory animal study. The study design included both pneumoperitoneum and mechanical intestinal obstruction models.

Methods

Forty-nine female swine were divided into six groups: a control group (Cr; n = 5), three pneumoperitoneum groups with IAPs of 20mmHg (Pn20; n = 10), 30mmHg (Pn30; n = 10), 40mmHg (Pn40; n = 10), and two mechanical intestinal occlusion groups with IAPs of 20mmHg (MIO20; n = 9) and 30mmHg (MIO30; n = 5).

Results

There were significant changes (p<0.05) noted in all organ systems, most notably systolic blood pressure (SBP) (p<0.001), cardiac index (CI) (p = 0.003), stroke volume index (SVI) (p<0.001), mean pulmonary airway pressure (MPP) (p<0.001), compliance (p<0.001), pO2 (p = 0.003), bicarbonate (p = 0.041), hemoglobin (p = 0.012), lipase (p = 0.041), total bilirubin (p = 0.041), gastric pH (p<0.001), calculated glomerular filtration rate (GFR) (p<0.001), and urine output (p<0.001). SVV increased progressively as the IAP increased with no obvious changes in intravascular volume status. There were no significant differences between the models regarding their impact on cardiovascular, respiratory, renal and gastrointestinal systems. However, significant differences were noted between the two models at 30mmHg, with MIO30 showing worse metabolic and hematological parameters, and Pn30 and Pn40 showing a more rapid rise in creatinine.

Conclusions

This study identified and quantified the impact of intra-abdominal hypertension at different pressures on several organ systems and highlighted the significance of even short-lived elevations. Two models of intra-abdominal pressure were used, with a mechanical obstruction model showing more rapid changes in metabolic and haematological changes. These may represent different underlying cellular and vascular pathophysiological processes, but this remains unclear.

Introduction

Intra-abdominal hypertension (IAH) is present in 25–30% of critically ill patients on admission and causes profound systemic physiological derangement [1–10]. The consequences include renal dysfunction, prolonged intensive care and hospital stays, increased morbidity, multi-organ failure, and mortality [11]. Increased pressure within the intra-abdominal compartment reduces abdominal perfusion pressure (calculated as mean arterial pressure minus intra-abdominal pressure (IAP)), [12] thereby impairing perfusion to the intra- and extra-abdominal organs and, in particular, watershed areas such as the intestinal mucosa. Venous compression increases venous pressure resulting in congestion, intestinal edema, and gastrointestinal bacterial translocation [13].

The interaction between different organ systems within neighbouring anatomical compartments has been described as polycompartment syndrome [14, 15]. It is for this reason we have studied multiple organ systems together. This study includes two models of raised intraabdominal pressure, a pneumoperitoneum and a mechanical intestinal obstruction model [16]. We have previously demonstrated that intestinal vascular occlusion may differ between a pneumoperitoneum versus a mechanically obstructed model [16]. This may affect organ systems differently. Lactate increased substantially in a mechanically obstructed model which may reflect increased anaerobic metabolism because of imbalances in cardiorespiratory dynamics. This may in turn promote an inflammatory state but has yet to be proven, and probably requires a longer period of sustained elevated IAP.

The primary aim was to study the systemic effects of raised IAP on various organ systems. We used both the pneumoperitoneum and mechanical obstruction models to generate elevated intra-abdominal pressure. Data from all pigs, regardless of the model used, were included in the analysis for the primary outcome. We felt it important to study these effects across various IAP levels, as this has not been well documented previously. The secondary aim was to describe the effects between the two different models. We hypothesised that there would be no conceivable difference between the two models because of the relatively short duration of raised IAP.

Methods

Regulatory issues

The study was performed in accordance with the recommendations in the Royal Decree 1201/2005 of 10 October 2005 on the protection of animals used for experimentation and other scientific purposes. All experimental protocols were approved by the Committee on the Ethics of Animal Experiments of Minimally Invasive Surgery Centre Jesús Usón and by the Council of Agriculture and Rural Development of the Regional Government of Extremadura (No. ES100370001499), Spain.

Animal study population

Forty-nine white female pigs (24.1 kg; range 17.3–33 kg) were fasted for 24 hours before receiving premedication with intramuscular atropine (0.04 mg/kg), diazepam (0.4 mg/kg) and ketamine (10 mg/kg). Induction and anesthesia were the same as described previously by Correa-Martin et al. [16]. The animals were pre-oxygenated with fractional inspired oxygen of 1.0 (fresh gas flow of 3–5 l/min), before propofol 1% (3 mg/kg) was administered. They were intubated, mechanically ventilated, and anesthesia was maintained with isoflurane (MAC of 1.25). Intravenous 0.9% sodium chloride fluid (2 ml/kg/h) and a remifentanil infusion (0.3 mcg/kg/min) for analgesia was provided intraoperatively. The animals were euthanised using potassium chloride (1–2 mmol/kg) on completion of the study, as per the American Veterinary Medical Association Panel on Euthanasia guidelines.

Study design

The swine were consecutively allocated into six groups: a single control group (Cr; n = 5), three pneumoperitoneum groups with IAPs of 20 mmHg (Pn20; n = 10), 30 mmHg (Pn30; n = 10), and 40 mmHg (Pn40; n = 10), and two mechanical intestinal occlusion groups with IAPs of 20 mmHg (MIO20; n = 9) and 30 mmHg (MIO30; n = 5). Each group was studied for three and five hours, except the MIO30 that was only studied for 3 hours. A laparoscopic insufflation technique was used for the pneumoperitoneum model. The mechanical intestinal obstruction model, which was previously published, was achieved by placing a laparoscopic suture at the ileocaecal valve and infusing 0.9% saline into the bowel (16).

All the swine were positioned supine. IAP was measured using three methods simultaneously, with the direct intraperitoneal measurement technique used as the method to achieve the IAP target [16]. Gastric and bladder pressures were measured using the same methods as those described for humans in the WSACS consensus guidelines [16–18]. Multiple physiological parameters, together with blood samples, were measured every 30 minutes. Once IAP was stabilised, measurements were initiated and designated as T1. The control group did not have any intervention to increase IAP and received the same anesthetic and 30-minute physiological measurements as the experimental groups.

Data collection

IAP was measured simultaneously at 30 minutes intervals in each pig using the three methods (i.e., transperitoneal [TP], transvesical [TV], and transgastric [TG]). The direct TP technique was considered the gold standard as it was a direct measure of IAP. A Jackson-Pratt catheter was inserted laparoscopically into the abdominal cavity and placed on the liver to perform TP IAP measurements [16]. A Foley catheter in the bladder and urine drainage bag were used for TV IAP measurements together with a manual manometer system (Holtech Medical, Charlottenlund, Denmark). An endoscopically placed gastric balloon-tipped catheter was connected to an electronic pressure transducer (Spiegelberg, Hamburg, Germany) to measure TG IAP. Transgastric measurements were graphically recorded in real time. The results of these comparisons have been previously reported [19].

Physiological signs and laboratory tests were collected every 30 minutes. Cardiovascular parameters measured included heart rate, blood pressure, cardiac output parameters (cardiac output, pulse pressure variation (PPV), stroke volume variation (SVV), assessed with continuous electrocardiogram, pulse oximetry (with hemodynamic E-modulus PRESTN anesthesia monitor S/5TM General Electric Datex-Ohmeda®), invasive arterial blood pressure measurement and pulse contour cardiac output (PiCCO, Getinge, Sölna, Sweden) device. Respiratory parameters measured included respiratory rate, arterial oxygen saturation (SpO₂), partial pressure of carbon dioxide (pCO₂), mean pulmonary artery pressure (MPP), and ventilation parameters (tidal volumes (Vt), compliance, plateau pressure (PP), minute volume). These measurements came from the anesthetic monitor, ventilator, and arterial blood gases. Ventilation was provided with an FiO₂ of 1.0, a tidal volume of 10-15ml/kg, positive end-expiratory pressure of 2cmH₂O, at a rate set (14 breaths/minute) to obtain an end-expiratory CO₂ partial pressure of 35-40mmHg. Metabolic and hematological parameters from blood samples included pH, base excess, bicarbonate, lactate, APTT, INR, and platelets. Gastrointestinal parameters from blood samples included ALT, ALP, GGT, LDH, total bilirubin, and lipase. An endoscopically inserted monitor connected to the anesthesia monitor (S/5TM General Electric Datex-Ohmeda, Helsinki, Finland) measured continuous gastric mucosal pH via tonometry. Renal function was assessed via a calculated glomerular filtration, urine output, and blood samples for urea and creatinine.

Statistical analysis

We performed a statistical power analysis for sample size estimation from data analysing hemodynamic parameters from previous pig studies with an alpha of 0.05 and power equal to 0.80 [20–22]. With an alpha of 0.05 and power of 80%, the projected sample size needed with this effect size for the primary endpoints was 4 (Appendix A in S2 File supplementary electronic media). The proposed sample size, both in groups and combined by model, was adequate for the objectives of this study.

Categorical variables were described as proportions (%) and compared using Chi-square or Fisher exact test. Continuous variables are presented as means with standard deviations when normally distributed, and as medians with interquartile ranges when non-normal distribution occurred. Normality was evaluated with the Kolmogorov-Smirnov test. One-way ANOVA or Kruskal-Wallis tests were used to compare continuous variables as appropriate.

Physiological parameters were clustered into six groups: cardiovascular, respiratory, metabolic, hematological, gastrointestinal, and renal. These parameters were considered dependent variables. The interdependencies between the physiological parameters were explored for completeness. A linear mixed model was used to estimate changes in the physiological parameters over time, with measurements every 30 minutes. The mixed model accounted for the dependencies over time and the imbalanced nature of the data with a random intercept for the pig-specific averages and a random slope for the pig-specific changes over time. Pig-specific variances were also allowed. Not all combinations of treatment and pressure were present in the dataset. Therefore, specific comparisons were created to analyse the appropriate subgroups of observations. Various variables were highly correlated. Some were on an interval scale, while others were binary.

As a result, a combination of Pearson, polyserial, and polychoric correlations was performed. Data evolution over time was plotted to represent the relationship between pressure, IAP model, and duration. To assist in interpretation, all data were rescaled by a factor of 10. Rank 10 refers to subtracting each time point by ten so that ten becomes zero, and five becomes minus five. The advantage is that the value of the intercept can be interpreted. This value is the expected value if all predictors in the model were zero, and this is now true for a time equal to ten.

A linear mixed model was used to analyse the physiological parameters to explain the observed scores while incorporating changes over time. We used the Shaffer p-value correction for multiple comparisons. All analyses were performed using R version 3.5.3 (R Core Team (2017). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL https://www.R-project.org/).

This is a secondary, but more complete analysis, of a study previously published by the same group (16).

Results

The pathophysiological effects of elevated intra-abdominal pressure on various organ systems are shown in the following tables: cardiovascular (Table 1), respiratory (Table 2), metabolic and hematological (Table 3), gastrointestinal (Table 4), and renal systems (Table 5).

Table 1. Cardiovascular parameters regardless of IAP model presented as median values with interquartile ranges and significance.

	Control	IAP 20mmHg	IAP 30mmHg	IAP 40mmHg	p-value
	n = 5	n = 19	n = 15	n = 10	p-value
*Heart rate (beats/min)*	104 (14)	92 (41.0)	113.0 (42.5)	117 (58.5)	<0.001
*Systolic BP (mmHg)*	86.0 (17.0)	57.0 (20.0)	61.0 (15.0)	64.0 (16.0)	<0.007
*Cardiac index (L/min/m* ² )	4.2 (1.3)	2.03 (0.86)	2.28 (0.83)	2.31 (0.82)	<0.001
*SVI (mL/m* ² )	39.0 (13.2)	21.0 (6.8)	20.0 (6.0)	17.0 (9.5)	<0.001
*PPV (%)*	17.0 (5.8)	26.0 (7.0)	25.0 (7.0)	28.0 (3.0)	<0.001
*SVV (%)*	19.5 (7.0)	26.0 (8.0)	30.0 (7.0)	30.0 (5.0)	<0.001

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BP = blood pressure; SVI = stroke volume index; PPV = pulse pressure variation; SVV = stroke volume variation

Table 2. Respiratory parameters regardless of IAP model, presented as median values with interquartile ranges and significance.

	Control	IAP 20mmHg	IAP 30mmHg	IAP 40mmHg	p-value
	n = 5	n = 19	n = 15	n = 10	p-value
*MPP (mmHg)*	5.0 (0.0)	6.0 (0.0)	7.0 (1.0)	8.0 (1.8)	<0.001
*Compliance (mL/cmH* ₂ 0)	18.0 (2.5)	8.4 (1.9)	6.3 (2.0)	6.5 (1.4)	<0.001
pO₂ *(mmHg)*	355.5 (70.1)	407.0 (113.0)	489.0 (187.3)	371.0 (83.0)	0.003
VT_E *(ml)*	290.0 (75.0)	210.0 (50.0)	240.0 (50.0)	275.0 (40.0)	<0.002
*pCO₂ (mmHg)*	42.2 (5.0)	47.8 (17.3)	46.1 (11.5)	37.0 (11.6)	0.091
*Plateau pressure (cmH* ₂ 0)	18.0 (3.0)	27.0 (6.0)	34.0 (6.8)	43.0 (10.0)	<0.001
*Driving pressure (cmH* ₂ 0)	17.0 (3.0)	26.0 (5.0)	32.0 (7.0)	42.0 (11.0)	<0.001

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MPP = mean pulmonary airway pressure; pO₂ = arterial partial pressure of oxygen; VT_E = expiratory minute volume; pCO₂ = arterial partial pressure of carbon dioxide

Table 3. Metabolic and hematological parameters regardless of IAP model, presented as median values with interquartile ranges and significance.

	Control	IAP 20mmHg	IAP 30mmHg	IAP 40mmHg	p-value
	n = 5	n = 19	n = 15	n = 10	p-value
Base excess (mmol/L)	4.0 (3.0)	2.6 (7.0)	-1.0 (8.3)	-6.0 (8.5)	0.088
Bicarbonate (mmol/L)	28.5 (4.5)	27.7 (7.1)	24.7 (7.3)	20.1 (8.6)	0.038
Haemoglobin (g/dL)	7.6 (0.8)	8.6 (0.8)	9.3 (1.5)	10.0 (1.5)	0.021
Platelets (x10 ⁹ /L)	412.0 (140.0)	429.0 (144.0)	436.0 (248.8)	397.0 (98.5)	<0.001
APTT (sec)	14.3 (6.2)	24.0 (40.0)	29.0 (46.4)	55.0 (65.3)	0.124
INR	0.8 (0.2)	1.2 (0.21)	1.14 (0.30)	1.07 (0.24)	0.652

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APTT = activated partial thromboplastin time; INR = international normalised ratio

Table 4. Gastrointestinal parameters regardless of IAP model, presented as median values with interquartile ranges and significance.

	Control	IAP 20mmHg	IAP 30mmHg	IAP 40mmHg	p-value
	n = 5	n = 19	n = 15	n = 10	p-value
LDH (U/L)	1046.0 (153.5)	903.0 (406.0)	1100.0 (338.0)	1032.0 (349.0)	0.834
Lipase (U/L)	3.6 (0.8)	6.5 (1.9)	8.7 (5.95)	8.5 (4.5)	0.032
ALT (IU/L)	38.5 (7.8)	30.0 (10.3)	37.5 (17.4)	27.0 (13.5)	0.001
GGT (IU/L)	30.0 (13.5)	30.0 (10.5)	34.0 (16.0)	35.0 (12.0)	0.798
ALP (U/L)	368.5 (217.5)	339.0 (138.0)	321.0 (93.0)	383.9 (163.8)	0.023
Total bilirubin (mg/dL)	0.3 (0.2)	0.15 (0.14)	0.30 (0.18)	0.42 (0.38)	0.037
Gastric tonometry (pH)	7.24 (0.06)	7.13 (0.14)	6.91 (0.28)	6.68 (0.37)	<0.001
pCO₂ gap (mmHg)	3.00 (1.36)	11.20 (12.72)	11.40 (17.84)	25.0 (10.0)	<0.001

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LDH = lactate dehydrogenase; ALT = alanine aminotransferase; GGT = Gamma-glutamyl transferase; ALP = alkaline phosphatase

Table 5. Renal parameters regardless of IAP model, presented as median values with interquartile ranges and significance.

	Control	IAP 20mmHg	IAP 30mmHg	IAP 40mmHg	p-value
	n = 5	n = 19	n = 15	n = 10	p-value
Calculated GF (mmHg)	59.0 (17.5)	10.0 (24.0)	-14.5 (18.5)	-34.0 (15.0)	<0.001
Urine output (ml/kg/hr)	2.8 (1.0)	0.39 (0.95)	0.36 (0.15)	0.23 (0.18)	<0.001
Urea (mg/dL)	20.7 (9.4)	24.5 (11.1)	25.1 (9.1)	26.3 (9.2)	0.349
Creatinine (mg/dL)	2.3 (0.6)	2.69 (1.14)	2.73 (0.79)	2.33 (0.44)	0.283

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GF = glomerular filtration

1. Cardiovascular system

Blood pressure

There was a decrease in both systolic and diastolic pressure as IAP increased and as time progressed. The most significant changes occurred at the highest pressures. A strong intra-class correlation was present.

For systolic blood pressure, the downward evolution occurred in all models but was more substantial at higher pressures. Diastolic pressure changes and relationships were similar to systolic pressure changes, only less significant (S3 Fig in S2 File).

Cardiac output parameters

IAH lowered the cardiac output and stroke volume index in all models (S4 Fig in S2 File). The most significant changes occurred in the MIO models.

Stroke volume index decreased significantly (61.1%), with the greatest changes seen as the pressure increased. Stroke volume variation (SVV) and pulse pressure variation (PPV) increased (100.9% and 93.5% respectively, p<0.001) across all groups and in both models compared to the control group.

2. Respiratory system

Mean pulmonary airway pressure (MPP)

MPP increased (62.5%, p<0.001) across all group, with the highest pressures corresponding to the highest IAP. There were almost no differences for MPP between the groups except for Pn30 and Pn40, which differed significantly (p<0.001) (S7 Fig in S2 File). There seemed to be an inverse relationship between MPP and weight.

Compliance

Dynamic compliance [calculated as tidal volume divided by (plateau pressure minus PEEP)] was reduced (60.2%, p<0.001) in all IAH models, with moderate intra-class correlation (S8 Fig in S2 File).

Partial pressure of oxygen (pO₂)

The partial pressure of oxygen differed in all the IAH models compared to the control. A strong intra-class correlation was present.

Expiratory minute volume (MVE)

Expiratory minute volume was decreased (33.6%, p<0.002) for all models compared to the control group (S10 Fig in S2 File).

Partial pressure of carbon dioxide (pCO₂)

None of the comparisons suggested any difference in pC0₂ readings. Lower pCO₂ readings were seen in heavier pigs (S11 Fig in S2 File).

Plateau pressure (PP) and driving pressure

Driving pressure and PP (125.6%, p<0.001) increased with IAP, with the highest values being reached in the P40 and MIO30 groups (Fig 1). Especially noticeable were some extreme increases in the MIO30 and Pn40 groups (p<0.001).

3. Metabolic and hematological systems

Base excess (BE)

The base excess decreased (102.1%, p = 0.088) in nearly all models compared to the control group (S14 Fig in S2 File). The Pn20 group differed the least when compared to the control.

Bicarbonate (HCO₃)

Bicarbonate responded similarly to base excess, with readings decreasing (12.5%, p = 0.038) more rapidly in all groups when compared to the control group (except in the Pn20 group) (S15 Fig in S2 File).

Hematology

Hematological parameters mainly showed a positive correlation in both models and at all pressures. Platelet levels revealed an increasing trend from lower IAPs to the higher IAPs in both models (25.7% increase regardless of model) and were significant (p<0.001). Activated partial thromboplastin time (APTT) had an upwards trend (517.3% increase regardless of model, p = 0.124) and was significant in the MIO group. The international normalised ratio (INR) was relatively consistent across both models and at all pressures.

4. Gastrointestinal system

Lactate dehydrogenase (LDH)

LDH increased (14.4% increase, p = 0.834) as IAP increased, however, the changes were not significant. The Pn20 model increased more rapidly than in the control group (S17 Fig in S2 File). There were outliers in each group. The pigs with the highest LDH showed higher mortality.

Lipase

The increase in lipase (147.3%, p = 0.032) was seen across all groups, with the higher values corresponding to higher IAP. Some pigs in the PN30 and Pn40 groups showed the greatest increases in lipase.

Liver tests

Alanine aminotransferase (ALT) increased over the 20mmHg and 30mmHg groups, regardless of the pressures. ALT unexpectantly decreased in the PN40 group.

Gamma-glutamyl transferase (GGT) decreased (6.9% decrease, p = 0.798) and showed a difference in evolution between Pn20 and Pn30. There was also a difference between the control and each of the 20mmHg conditions (p = 0.038 and 0.044 respectively). There were significant differences observed for all groups at rank 10 (p<0.001).

Alkaline phosphatase (ALP) and total bilirubin (totBil) both showed gradual, yet significant changes (31.2% decrease, p = 0.023 and 50% increase, p = 0.037, respectively) as IAP rose. There were significant differences observed for all groups at rank 10 for ALP (p<0.001).

Gastric tonometry

There was a significant and progressive decrease in pH for gastric tonometry as the intra-abdominal pressure increased. The decline was this most marked when the IAP reached 40mmHg (a 4% reduction). The pCO₂ gap (a surrogate marker for cardiac output) increased significantly as the IAP rose.

5. Renal system

Calculated glomerular filtration

Glomerular filtration was calculated using the formula: filtration gradient = MAP–(2 x IAP). IAP measures were obtained transvesically, transperitoneally, and transgastrically. As time progressed, there was a downward trend for all groups (104.6%, p<0.001). The most significant changes were seen with the highest pressures (Fig 2). A strong intra-class correlation was noted.

Urine output

Urine output was significantly greater in the control group when compared to each of the groups. Urine output decreased with the increasing IAP (S20 Fig in S2 File). At worst, this reduction was 74.6% (p<0.001).

Urea

Urea increased (20.1%, p = 0.349) in the IAH models compared to the control (S21 Fig in S2 File). Moderate intra-class correlation was identified.

Creatinine

Creatinine increased (5.7%, p = 0.283) as time progressed in all IAH models compared to the control group (S22 Fig in S2 File). There was a strong intra-class correlation.

Secondary objectives (refer to supplementary data)

The comparison between the pneumoperitoneum model and the mechanical obstruction model did not show any significant differences in the cardiovascular or respiratory parameters measured. The changes were at times more rapid when the abdominal pressures were higher. There were minor differences observed between groups.

Metabolic parameters showed a decreased base excess across both models. The Pn20 group differed the least when compared to the control. Bicarbonate decreased in both models but was more marked in the MIO model compared to the PN group at 20mmHg (S15 Fig in S2 File). Haematological changes were consistent across the models and groups, however, the MIO30 group showed greater changes in INR, platelets and APTT.

The gastrointestinal system revealed unexpected results. The bilirubin and ALT decreased or only marginally increased in both 20mmHg models. Bilirubin rose the most when pressures increased, especially at 40mmHg. There were no significant differences between models for GGT and ALP.

The evolution of increase for LDH was greater in the Pn compared to the MIO models (S17 Fig in S2 File).

The opposite occurred for lipase, where lipase increased across both models and at all pressures (S18 Fig in S2 File). The evolution of increase for lipase and ALT were strongest in the MIO30 group.

Renal parameters reflected similar trends independent of the model of intra-abdominal pressure used. The creatinine increased more sharply in the pneumoperitoneum groups, especially Pn30 and Pn40 (S22 Fig in S2 File).

Discussion

Several previous studies aimed to investigate aspects of the pathophysiological consequences of IAP. This study found worsening cardiorespiratory function and a predictable effect on renal function. The metabolic, hematological, and gastrointestinal effects are significant for some, but not all, parameters studied. This may be a result of the short duration of the implemented models, with insufficient time to reach significance. Alternatively, it may represent more complicated pathophysiology or protective mechanisms in early IAH. Metabolic changes showed a positive correlation in the Pn model, but a negative correlation in the MIO group. The reason for this is uncertain but may represent different underlying pathophysiology related to the effects of mechanical obstruction. The results are discussed according to organ system.

Cardiovascular system

The cardiovascular changes observed were as expected following the rise in IAP with a subsequent increased afterload, a decreased preload, and thereby decreased cardiac output. Additionally, as the stroke volume is determined by a combination of preload, contractility, afterload, and heart rate, there were significant increases in heart rate to compensate for a reduced stroke volume (heart rate increased by 40.2% regardless of model). This was particularly noticeable when IAP was 30mmHg or more.

An important finding was the relationship between elevated intra-abdominal pressure and markers of fluid responsiveness. SVV and PPV have been helpful in volume status assessment; however, the impact of intra-abdominal pressure appears to make these measurements difficult to interpret [21, 23]. Previous research has published conflicting results. Deloya et al. found an IAP greater than 15mmHg to cause significant changes in SVV despite the subjects being normovolaemic.

Contrary to this, Jacques et al. concluded that SVV was still helpful in the face of elevated IAP, but different thresholds may apply. These two previous studies were pig models; however, Liu et al. examined the same question in patients undergoing laparoscopic cholecystectomy [23]. The findings showed SVV increased progressively as the IAP was raised with no changes in volume status. In our study, the pigs were presumed to have been kept euvolemic with a constant infusion of IV crystalloids and only insensible losses. Despite this, IAP lowered the cardiac output in all models and increased PPV and SVV across all groups and in both models. This supports previous findings of the difficulty in using cardiovascular markers of volume status that use respiratory variation in subjects with elevated IAP. Measurement of IAP should be considered when using SVV or PPV, and for the utility of SVV should be determined in patients with IAP.

Interestingly, the systolic BP and cardiac index were closer to the control group values in the animals with higher IAP (40mmHg) versus lower IAP (20mmHg). Theoretically, these haemodynamic findings may be the consequence of the mechanical and neurohormonal responses to extremely elevated intra-abdominal pressure. These are related to inferior vena cava compression, aortic compression, decreased splanchnic blood flow, decreased renal blood flow, and diaphragmatic displacement. The overall result of these effects includes increased right atrial pressure, increased systemic vascular resistance, countered by a possible decrease in cardiac output. However, a slightly elevated systolic BP may be seen with a higher cardiac index at higher IAP if the effects on SVR and RAP are greater than the effects on cardiac output. Another explanation might be the mathematical coupling between high levels of IAP and AP due to the mechanical transmission of pressures from one compartment to another as is seen in the polycompartment syndrome.

Respiratory system

The pressure exerted on the diaphragm by high IAP causes decreased tidal volumes, compliance, functional residual capacity, and increased respiratory and airway pressures [24–29]. Previous animal and human studies have demonstrated a non-uniform decrease in lung volume and functional residual capacity with abdominal distension and elevated IAP. Most studies are conducted over hours, and hypothetically, we expect these findings to worsen as time progresses. Both chest wall and lung compliance are affected. The progressive decrease in compliance across both models and at each IAH pressure, with significant negative correlation, was in keeping with previous studies [26, 28, 30]. MPP and plateau pressure) measurements increased with a significant positive correlation in most groups, the exception being the MIO20 group. IAH appears to increase both inspiratory airway and pleural pressures, and thus does not seem to affect transpulmonary pressures significantly.

The pO₂ decreased in the Pn40 model, but the apparent increase in pO₂ in the other models requires further exploration. Ventilation-perfusion relationships have been studied in animals and humans [27, 31–33]. There appears to be a redistribution of blood flow from atelectatic and dependent areas of the lung when IAP is raised. This causes a redistribution of blood flow to improve the ventilation-perfusion mismatch. This compensatory mechanism may account for the increases in pO₂ in some groups. These changes may occur rapidly, but how and when it is overwhelmed requires further research. The partial pressure of carbon dioxide responded as predicted.

PEEP was not adjusted during the study despite increasing IAP. This was done to assess the effects of the rising IAP. Previous animal studies have investigated the effects of PEEP and demonstrated an improvement in end-expiratory lung volumes, shunt fraction, dead space, and oxygenation when matching PEEP levels with IAP. This study did not intend to describe the effects of PEEP [27, 28, 34]. The importance of recognising increased IAP and its potential influence on the chest wall and lung compliance, tidal volumes, and functional residual capacity, should be a focus of ventilation teaching. Incorporation of IAP measurement into ventilator setting decision pathways should be considered.

Metabolic and hematological systems

Interestingly, the metabolic findings showed varying results between the models, but overall, values decreased in nearly all models compared to the control group. These changes were relatively rapid for base excess and serum bicarbonate, and highlight the importance of early identification of IAH.

The increasing platelet trend was unexpected. Mean platelet volume (MPV) has been studied in response to elevated IAP in patients undergoing laparoscopic cholecystectomy as a model for IAH [35–41]. Interestingly, there was a significant increase in MPV on insufflation and a decrease with deflation, confirming a platelet response to elevated IAP. There are several theories about platelet response to elevated IAP. MPV has previously been linked as a marker of inflammation to several different pathologies, including septicemia, cardiac, respiratory and intra-abdominal pathologies [42–44]. The platelet response may be driven by the secretion of free oxygen radicals and inflammatory mediators in response to poor abdominal perfusion. This in turn promotes the production of platelets through the stimulation of megakaryocytes [45]. Other theories suggest hormonal action on megakaryocytes, the retention of small platelets in ischaemic organs, and platelet swelling in response to thrombopoietin [46–48]. However, the increase in platelets over a relatively short time (maximum 5 hours), despite the long average lifespan of platelets (8–10 days), suggests a relatively rapid process that requires further investigation.

Gastrointestinal system

In this study, GGT, alkaline phosphatase, and LDH all showed progressive change as the IAP increased in both models. There was a progressive increase in the lipase measurements, most marked in the Pn and MIO30 groups, with corresponding statistical significance. Total bilirubin increased significantly between the control group and IAP 40mmHg.

The pCO₂ (pCO₂ gap = PcvCO₂ –PaCO₂) has previously been identified as a surrogate marker for cardiac output and used in various settings [49–53]. A pCO₂ gap >6mmHg suggests a persistent shock state. All groups of raised IAP had a pCO₂ gap of >6mmHg and rose significantly with the IAP increase.

Renal system

Renal dysfunction occurs with elevated intra-abdominal pressure because of venous congestion, increased left ventricular afterload and decreased renal perfusion, and a systemic inflammatory response [54–57]. The compression of renal veins will result in venous congestion and a decrease in glomerular filtration with an increase in renin release. Diminished renal perfusion and salt and water retention may contribute to a vicious cycle of fluid accumulation and increasing IAP [58, 59].

Creatinine, urea, glomerular filtration and urine output all demonstrated changes that were expected as a consequence of the pathophysiology described above. The lack of statistically significant changes, for all but glomerular filtration, may be due to the short duration of the raised IAP.

Comparison between raised IAP models

The lack of differences between the two models in the cardiorespiratory parameters may be expected when both models had the same IAP, and the inflammatory responses may not have had enough time to influence contractility through inflammatory mediated negative inotropy.

The metabolic effects of IAP appear to be influenced by the mechanism of intra-abdominal hypertension [16]. The explanation may be linked to the impact on bowel mucosa and underlying tissue that was ligated as part of the model (like that which occurs in bowel obstruction). This may result in a perfusion deficit, as shown by the decrease in pHi.

Lipase appears to be a useful marker to monitor, regardless of the model of IAH. In comparison, total bilirubin increased significantly between the control group and IAP 40mmHg but did not reveal any trends or consistent statistically significant correlation between the two models.

Glomerular filtration was shown to be a useful marker of renal decline and showed a statistically significant correlation in both models and at all pressures (Pn20 vs. MIO20 and Pn30 vs. MIO30).

Limitations

Although care was taken to control and standardise all interventions, there may have been a difference in each animal’s underlying physiology. While this was a relatively large animal study, there were only five or fewer animals in each group. Due to funding limitations, one group had four, which still satisfied our sample size requirements. The implications of this include a limited ability to identify statistically significant changes, especially when parameters are measured over only a few hours. Set pressures were used versus gradually increasing pressures over time which may have been closer to clinical situations. However, we chose this design to define the size of the groups, as pigs may not have survived raised pressures for long periods, thus missing out on observing what happens at 30mmHg and 40mmHg. We did not measure readings beyond 5 hours, and there was not a 40mmHg intervention for the mechanical obstruction group. Consequently, changes that take longer to manifest, such as elevation of creatinine and urea, would not be identified. The effect of PEEP could not be removed completely because a PEEP of zero was not possible on the anaesthetic machine used. Unfortunately, lactate readings, global end-diastolic volume, and extravascular lung water could not be reported because of incomplete data.

Conclusion

Supporting information

S1 Data

(PDF)

Click here for additional data file.^{(413.1KB, pdf)}

S1 File

(PDF)

Click here for additional data file.^{(6.1MB, pdf)}

S2 File. Electronic supplementary media.

The file contains S1-S22 Figs, S1, S2 Tables, and Appendix A.

(PDF)

Click here for additional data file.^{(1.8MB, pdf)}

Acknowledgments

We would like to acknowledge Wilfried Cools from the Interfaculty Center Data processing and Statistics at the Vrije Universiteit Brussel (VUB), for his statistical analysis contribution.

Data Availability

All relevant data are within the paper and its Supporting information files.

Funding Statement

This work was supported by one grant from Extremadura Regional Government through the Plan Regional de Investigación de Extremadura, Spain (PRI09A161 to Minimally Invasive Surgery Center Jesus Usón) to FSM and GCE. The funder had no role in study design, data collection, analysis, decision to publish, or preparation of the manuscript. The funders of the grant did not play any role in the study.

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PLoS One. doi: 10.1371/journal.pone.0290451.r001

Decision Letter 0

Alexander Wolf

31 Jan 2023

PONE-D-22-32095Pathophysiological impact of different models of intra-abdominal hypertension in pigsPLOS ONE

Dear Dr. Wise,

Your work on experimental IAH is very comprehensive and provides a lot of data. Nevertheless, your manuscript should be revised for publication. Regarding the revision, I refer to the reviews listed below.

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PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

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Reviewer #1: Partly

Reviewer #2: Partly

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

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Reviewer #1: Yes

Reviewer #2: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

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Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Wise et al have investigated the impact of elevated intra-abdominal pressure (IAP) on physiological variables in two different experimental models in pigs. The study represents original research describing in details the changes in cardiovascular, respiratory, renal, gastrointestinal and hematological function and metabolism response elevated IAP. Albeit the same group or other authors have previously reported similar findings, the manuscript is comprehensive summary of the pathophysiological alterations that may be observed in experimental setting of intra-abdominal hypertension (IAH). As such, it is valuable information for researchers in the field. As an additional value, the authors compare the impact of two different models, pneumoperitoneum and intestinal obstruction model, respectively.

The manuscript contains extensive amount of data. My first main concern is the way the data are presented. The main aim of the study remains unclear, and this makes the manuscript vague. Was the main aim to describe the physiological changes in response to increased IAP or was it to compare the two models of IAH? If it was the latter (as it noted in introduction and in title), then the data should be presented accordingly, demonstrating the presence or absence of differences between these two as a first priority. At present, Tables 1 to 5 refer to physiological variables regardless of IAP model, while the data of two separate models are find in supplement. This is inconsistent with study title and hypothesis.

My second main concern is the length of discussion. With 8 pages (!) in total it resembles PhD thesis rather than single scientific report. The discussion should shortened considerably, to max of 4 pages, with reduction of repeated description of your own findings, and replacing this with discussion on comparative findings from other relevant studies.

Other comments:

Abstract:

- Prolonged intensive care and hospital stay are not relevant in context of present study. Renal dysfunction, morbidity, multi-organ failure are unnecessary repetition.

- Please rephrase the results section. Choose the most relevant indices, report their numerical values.

- Conclusions: last sentence is speculative, not precisely in context of present study. Consider rephrasing.

Introduction

- Many of the references 1-10 are out of date. More recent data are available. For example Reintam Blaser A, et al. Crit Care Med. 2019; 47(4):535-542

- Paragraph on polycompartment syndrome is not necessary. Instead, please open more your hypothesis. Why the two models of IAP should have different impact on physiological variables and organ function? Elaborate on the inflammatory response to mechanical obstruction. Is it proven in pig model?

Study design

- As I understand, the animals were immediately in the start of experiment exposed to either 20, 30 or 40 mmHg of IAP. One may argue that such high pressures (especially of 30 and 40 mmHg) very unlikely would develop quickly, in minutes. Rather, the gradual increase to 20, and then to 30, and 40 mmHg would more to resemble the real life clinical scenario. Please explain your considerations for choosing the study design.

- Please elaborate the similarities and differences between pigs and humans in respect to IAP-s. Is 20 mmHg in pigs’ similar severity as in humans? Forty mmHg would be rather exceptional in humans, quickly leading to an catastrophic deterioration. What is the rationale to test this value in pig model?

- Page 9, first paragraph. WSACS guidelines do not describe the bladder pressure measurements in experimental animals. Please correct.

Statistical analysis

- What was the primary endpoint for sample size calculation? Please indicate it in main text, not in supplementary materials.

- Please confirm the data in Tables 1 to 5 are all normally distributed, and mean (SD) is correct way of data presentation. Please avoid using ± in mean (SD) presentation. Please check the decimals after comma, unify through the Tables.

- Pig-specific variances were allowed (Page 11, first paragraph). Please explain what that means.

- This is secondary, but more complete analysis, of a study previously published by the same group (16). How much of data exactly have been published previously? How many experiments out of 49 animals were included in the previous report?

Results

- Restructure the data presentation according to the main hypothesis

- Calculated glomerular filtration. What you mean with: “Analysis of calculated glomerular filtration was performed using data collected from transvesical, transperitoneal, and transgastric measures.“ Please explain, consider rephrasing.

Discussion

- The first sentence: This study quantified the impact of two different models on physiological parameters in pigs. This is vague. Above all, the results in present form (the Tables and Figures, which attract the first attention) demonstrate the effect of IAP on organ systems, regardless of the IAP model. Either restructure the results, or change the introduction and discussion.

- For most of cardiovascular indices, no differences between the models were observed. What that shows? I am not sure we should expect the differences here; I am in doubt with the hypothesis that these models have different impact on physiology. In opposite, I would put forward the hypothesis that the impact is similar for both models.

- The discussion is far too detailed in many aspects. This is not necessary, please shorten, generalize, underline the most important findings and compare them with existing knowledge.

- In your preliminary study (ref 16) it is concluded that the most relevant parameters to evaluate the deleterious effects of IAH are monitoring of APP, Cdyn, pHi and lactate. Does your current study confirms the preliminary data? Please discuss.

- Please avoid repeated presentation of results!

Conclusions

- Second sentence: „Using SVV or PPV in the presence of IAH is an unreliable way of assessing volume status.” How did you come to this? The volume status (fluid responsiveness, for example) was not specifically assessed; these indices were not compared to others in that respect. Please stick precisely only on observed findings while making the conclusions.

Reviewer #2: The authors studied the pathophysiological effects of elevated IAP in animal models of pneumoperitoneum (Pn) and mechanical intestinal obstruction (MIO) as part of a complex, exploratory animal study.

Based on the experiments conducted and the results presented, the authors have performed a very comprehensive, detailed and thorough comparative data analysis with a high level of statistical support. The value of the study is that the observed changes are discussed by organ system.

However, the scientific value of this huge study, the ability to pick out the truly relevant pathophysiological variations is not an easy task for the reader. Therefore, the reviewer's main suggestion is that, instead of a meaningless and general conclusion, either in the Conclusion or in the Potential clinical implications chapter, the authors should emphatically summarise the important differences found in the two models when comparing the damage to different organ systems.

Additional comments:

1. The element numbers (n) reported in the Study design description on page 8 do not match the element number data reported in the first row of Tables 1-5 of the Results.

2. Why Table 1-5 only shows the data for the Pn groups and the significance value detected compared to the control group. Why do we not see the data and statistical differences of the MIO groups compared to the control or PN groups?

3. In line 4 of the Study design, the information reads "Each group was divided in half and studied for three and five hours". This raises the question of whether the tables present data for the 3 or 5 hour study?

4. On page 26, in the Limitations, do not refer to "insufficient grant money" when there were deaths of pigs in several study groups during the trial (Figures S2, S7, S11, S12).

5. The 5-hour study is sufficient to analyse correlations between IAP and the other parameters tested. However, the 5 h is not sufficient to explain the pathophysiological difference between the two models in terms of inflammatory responses, as hypothesized. This would have required longer study time and the determination of more inflammatory markers.

**********

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Reviewer #1: No

Reviewer #2: No

**********

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PLoS One. 2023 Aug 28;18(8):e0290451. doi: 10.1371/journal.pone.0290451.r002

Author response to Decision Letter 0

23 May 2023

Dear Editor of PLOS One

We are grateful for the comprehensive review with advice and suggestions from the reviewers. We have amended the manuscript according to their reviews, with significant changes to the clarity of the introduction and objectives, presentation of the results, and shortening of the discussion (focussing on the primary objective). We have tried to explain those statistical areas and design of the study that wasn’t clear. We have made corrections as advised by the reviewers and attempted to answer all of their questions below.

Thank you for your time to look at the manuscript again and we look forward to hearing back.

Reviewer #1:

Wise et al have investigated the impact of elevated intra-abdominal pressure (IAP) on physiological variables in two different experimental models in pigs. The study represents original research describing in detail the changes in cardiovascular, respiratory, renal, gastrointestinal and hematological function and metabolism response elevated IAP. Albeit the same group or other authors have previously reported similar findings, the manuscript is comprehensive summary of the pathophysiological alterations that may be observed in experimental setting of intra-abdominal hypertension (IAH). As such, it is valuable information for researchers in the field. As an additional value, the authors compare the impact of two different models, pneumoperitoneum and intestinal obstruction model, respectively.

The manuscript contains extensive amount of data. My first main concern is the way the data are presented.

1. The main aim of the study remains unclear, and this makes the manuscript vague. Was the main aim to describe the physiological changes in response to increased IAP or was it to compare the two models of IAH? If it was the latter (as it noted in introduction and in title), then the data should be presented accordingly, demonstrating the presence or absence of differences between these two as a first priority.

We understand that our aims were not stated clearly enough. We thank the reviewer for highlighting this and have altered the text to better describe what our objectives were. The primary aim was a description of the physiological effects of IAP, and the secondary objective was a comparison of these effects between the 2 models used against a control group. We have amended the text to make it clearer to the reader.

The amended text reads as follows:

“The primary aim was to study the systemic effects of raised IAP on various organ systems. We used both the pneumoperitoneum and mechanical obstruction models to generate elevated intra-abdominal pressure. Data from all pigs, regardless of the model used, were included in the analysis for the primary outcome. We felt it important to study these effects across various IAP levels, as this has not been well documented previously. The secondary aim was to describe the effects between the two different models. We hypothesised that there would be no conceivable difference between the two models because of the relatively short duration of raised IAP.

2. At present, Tables 1 to 5 refer to physiological variables regardless of IAP model, while the data of two separate models are find in supplement. This is inconsistent with study title and hypothesis.

We agree with the reviewer, and we have changed the title to better fit our objectives:

“The pathophysiological impact of intra-abdominal hypertension in pigs”

3. My second main concern is the length of discussion. With 8 pages (!) in total it resembles PhD thesis rather than single scientific report. The discussion should shorten considerably, to max of 4 pages, with reduction of repeated description of your own findings, and replacing this with discussion on comparative findings from other relevant studies.

We have shortened the discussion considerably and removed repeated findings. We have focussed on the primary objective with reference to the secondary objective findings in the supplementary material, otherwise there is simply too much information.

Other comments:

Abstract:

4. Prolonged intensive care and hospital stay are not relevant in context of present study. Renal dysfunction, morbidity, multi-organ failure is unnecessary repetition.

Thank you for this suggestion, we have amended the text accordingly:

“Intra-abdominal hypertension and abdominal compartment syndrome are common with clinically significant consequences.”

5. Please rephrase the results section. Choose the most relevant indices, report their numerical values.

We agree that this section required clarity and have made changes as per the reviewer’s request.

“There were significant changes (p<0.05) noted in all organ systems, most notably systolic blood pressure (SBP) (p<0.001), cardiac index (CI) (p=0.003), stroke volume index (SVI) (p<0.001), mean pulmonary airway pressure (MPP) (p<0.001), compliance (p<0.001), pO2 (p=0.003), bicarbonate (p=0.041), hemoglobin (p=0.012), lipase (p=0.041), total bilirubin (p=0.041), gastric pH (p<0.001), calculated glomerular filtration rate (GFR) (p<0.001), and urine output (p<0.001). SVV increased progressively as the IAP increased with no obvious changes in intravascular volume status. When describing the two models, there were no significant differences between the models regarding their impact on cardiovascular, respiratory, renal and gastrointestinal systems. However, significant differences were noted between the two models at 30mmHg, with MIO30 showing worse metabolic and hematological parameters, and Pn30 and Pn40 showing a more rapid rise in creatinine.”

6. Conclusions: last sentence is speculative, not precisely in context of present study. Consider rephrasing.

We agree and thank the reviewer for the suggestion and have amended the text in accordance with the comment.

“This study identified and quantified the impact of intra-abdominal hypertension at different pressures on several organ systems and highlighted the significance of even short-lived elevations. Two models of intra-abdominal pressure were used, with a mechanical obstruction model showing more rapid changes in metabolic and haematological changes. Differences between the two models may represent different underlying cellular and vascular pathophysiological processes, but this remains unclear”.

Introduction

7. Many of the references 1-10 are out of date. More recent data are available. For example, Reintam Blaser A, et al. Crit Care Med. 2019; 47(4):535-542

Thank you for the suggestion, we have updated the references, accordingly, having removed those that were published before 2010.

Smit, M., Koopman, B., Dieperink, W. et al. Intra-abdominal hypertension and abdominal compartment syndrome in patients admitted to the ICU. Ann. Intensive Care 10, 130 (2020). https://doi.org/10.1186/s13613-020-00746-9

Reintam Blaser, Annika MD, PhD1,2; Regli, Adrian MD3,4,5; De Keulenaer, Bart MD3,6; Kimball, Edward J. MD7; Starkopf, Liis MSc8; Davis, Wendy A. MPH, PhD4; Greiffenstein, Patrick MD, FACS9; Starkopf, Joel MD, PhD1,10; the Incidence, Risk Factors, and Outcomes of Intra-Abdominal (IROI) Study Investigators. Incidence, Risk Factors, and Outcomes of Intra-Abdominal Hypertension in Critically Ill Patients—A Prospective Multicenter Study (IROI Study). Critical Care Medicine 47(4):p 535-542, April 2019. | DOI: 10.1097/CCM.0000000000003623

Muturi, A., Ndaguatha, P., Ojuka, D. et al. Prevalence and predictors of intra-abdominal hypertension and compartment syndrome in surgical patients in critical care units at Kenyatta National Hospital. BMC Emerg Med 17, 10 (2016). https://doi.org/10.1186/s12873-017-0120-y

8. Paragraph on polycompartment syndrome is not necessary. Instead, please open more your hypothesis. Why the two models of IAP should have different impact on physiological variables and organ function? Elaborate on the inflammatory response to mechanical obstruction. Is it proven in pig model?

We are grateful for this suggestion and have amended the text as suggested, discussing possible effects on gastrointestinal vasculature.

“The interaction between different organ systems within neighbouring anatomical compartments has been described as polycompartment syndrome (14, 15). It is for this reason we have studied multiple organ systems together. This study includes two models of raised intraabdominal pressure, a pneumoperitoneum and a mechanical intestinal obstruction model (16). We have previously demonstrated that intestinal vascular occlusion may differ between a pneumoperitoneum versus a mechanically obstructed model. This may affect organ systems differently. Lactate increased substantially in a mechanically obstructed model which may reflect increased anaerobic metabolism because of imbalances in cardiorespiratory dynamics. This may in turn promote an inflammatory state but has yet to be proven, and probably requires a longer period of sustained elevated IAP.”

Párraga Ros E, Correa-Martín L, Sánchez-Margallo FM, Candanosa-Aranda IE, Malbrain MLNG, Wise R, Latorre R, López Albors O, Castellanos G. Intestinal histopathological changes in a porcine model of pneumoperitoneum-induced intra-abdominal hypertension. Surg Endosc. 2018 Sep;32(9):3989-4002. doi: 10.1007/s00464-018-6142-z. Epub 2018 May 17. PMID: 29777353.

Correa-Martín L, Párraga E, Sánchez-Margallo FM, Latorre R, López-Albors O, Wise R et al (2016) Mechanical intestinal obstruction in a porcine model: effects of intra-abdominal hyper- tension. A preliminary study. PLoS ONE 11(2):e0148058

Study design

9. As I understand, the animals were immediately in the start of experiment exposed to either 20, 30 or 40 mmHg of IAP. One may argue that such high pressures (especially of 30 and 40 mmHg) very unlikely would develop quickly, in minutes. Rather, the gradual increase to 20, and then to 30, and 40 mmHg would more to resemble the real-life clinical scenario. Please explain your considerations for choosing the study design.

We agree with the reviewer’s comment, and a graduated increase in pressure would have simulated a closer to life scenario. However, we chose to study the pigs at separate pressures maintained for the specified time periods because of concerns that many of the pigs may not have survived to reach 40mmHg and we would then not have been able to observe what happens at this pressure. Also, the response of the pigs to pressures for so long would have been difficult to predict and resulted in the size of the groups changing as pigs died. Under these study conditions we were also able to study extreme pressures, like 40mmHg, which would not be possible in most clinical settings. We have added a comment to the limitations section in response to this useful suggestion.

“Set pressures were used versus gradually increasing pressures over time which may have been closer to clinical situations. However, we chose this design to define the size of the groups, as pigs may not have survived raised pressures for long periods, thus missing out on observing what happens at 30mmHg and 40mmHg.”

10. Please elaborate the similarities and differences between pigs and humans in respect to IAP-s. Is 20 mmHg in pigs’ similar severity as in humans? Forty mmHg would be rather exceptional in humans, quickly leading to a catastrophic deterioration. What is the rationale to test this value in pig model?

There are little data looking specifically at similarities between human and pigs with respect to intra-abdominal pressure. Our assumption is based on several previous studies that have suggested the utility in using pigs for the study of anatomical and pathological process due to the similarity in anatomical size and structure, physiology, and immunology. All animal models have inherent limitations, and we would not expect a 1 to 1 correlation from any animal model to human. As we have noted in our previous response, the use of these pressure allows unique insight into the physiological effects of these high pressures.

Very high IAPs are rarely studied. We decided it would be useful to study both commonly encountered pressures, as well as extremes in pressures, as this may highlight pathological processes not easily identified unless sustained at lower pressures for very long periods, which would be difficult to simulate in a laboratory.

Lunney JK, Van Goor A, Walker KE, Hailstock T, Franklin J, Dai C. Importance of the pig as a human biomedical model. Sci Transl Med. 2021 Nov 24;13(621):eabd5758. doi: 10.1126/scitranslmed.abd5758. Epub 2021 Nov 24. PMID: 34818055.

Hou N, Du X, Wu S. Advances in pig models of human diseases. Animal Model Exp Med. 2022 Apr;5(2):141-152. doi: 10.1002/ame2.12223. Epub 2022 Mar 27. PMID: 35343091; PMCID: PMC9043727.

11. Page 9, first paragraph. WSACS guidelines do not describe the bladder pressure measurements in experimental animals. Please correct.

Thank you, we realise this needed clarification. We worded it in this way to describe the method (and not have to go into detail) but have highlighted that this technique is the same gold standard technique from guidelines for humans.

“Gastric and bladder pressures were measured using the same methods as those described for humans in the WSACS consensus guidelines”

Statistical analysis

12. What was the primary endpoint for sample size calculation? Please indicate it in main text, not in supplementary materials.

Thank you, we have made the adjustment as you have suggested.

“We performed a statistical power analysis for sample size estimation from data analysing hemodynamic parameters from previous pig studies with an alpha of 0.05 and power equal to 0.80.”

13. Please confirm the data in Tables 1 to 5 are all normally distributed and mean (SD) is correct way of data presentation. Please avoid using ± in mean (SD) presentation. Please check the decimals after comma, unify through the Tables.

We have made the changes to the tables as requested with standard deviations in brackets, and the title of each table indicating that the mean is presented.

We can confirm that the data is normally distributed, and we have checked the correct decimal placement.

14. Pig-specific variances were allowed (Page 11, first paragraph). Please explain what that means.

The statistical analysis assumed that not all pigs were physiologically the same. This was accounted for in the linear mixed model.

For example, a LMM could include terms to account for variation within each pig measurements. Consider the model

Y = b0 + b1x1 + b2x2 + a1z1 + a2z2 + cisigmai^2 + some error

The terms x1 and x2 are fixed effects

The terms z1 and z2 are random effects

And they account for the pigs variation in sigmai^2.

15. This is secondary, but more complete analysis, of a study previously published by the same group (16). How much of data exactly have been published previously? How many experiments out of 49 animals were included in the previous report?

The initial publication was a much smaller sample from the initial experiment with only 15 pigs included, all of them in the mechanical obstruction model and only looking at 20mmHg pressure at 2 and 5 hours.

Results

16. Restructure the data presentation according to the main hypothesis

We agree with the reviewer in that the primary and secondary objectives were not clear enough to match the results. We also agree with other comments that the results section needs to be clearer and simplified for the reader. As such, we have focussed the results section on the primary objective findings. We have included a section after reporting the primary findings at the end of the results section as a short synopsis of the secondary objectives, with reference to the supplementary data with the reader wishes to delve into those findings. We have restructured and make extensive changes, hopefully meeting the expectations of the reviewers.

17. Calculated glomerular filtration. What you mean with: “Analysis of calculated glomerular filtration was performed using data collected from transvesical, transperitoneal, and transgastric measures. “ Please explain, consider rephrasing.

Glomerular filtration (not glomerular filtration rate) was calculated from MAP and IAP (Filtration gradient = MAP – [2 x IAP]). Estimation of GF is typical in porcine models where specific renal drug excretion (e.g., chromium-51 or technetium-99m) is not possible to measure a true GFR. At the time of the study design, it was felt that the short duration of the study may have led to an unpredictable measure of creatinine clearance.

We have changed the phrasing in the text to read as follows: Glomerular filtration was calculated using the formula: filtration gradient = MAP – (2 x IAP). IAP measures were obtained transvesically, transperitoneally, and transgastrically.

Discussion

18. The first sentence: This study quantified the impact of two different models on physiological parameters in pigs. This is vague. Above all, the results in present form (the Tables and Figures, which attract the first attention) demonstrate the effect of IAP on organ systems, regardless of the IAP model. Either restructure the results or change the introduction and discussion.

We would like to thank the reviewer for this advice. We have changed the title, restructured the results, and focused the introduction and discussion on the primary objective, which is hopefully clearer for the reader.

19. For most of cardiovascular indices, no differences between the models were observed. What that shows? I am not sure we should expect the differences here; I am in doubt with the hypothesis that these models have different impact on physiology. In opposite, I would put forward the hypothesis that the impact is similar for both models.

Thank you, we agree that we did not make our thoughts about this clear enough and have amended the manuscript accordingly. We agree with the reviewer’s thoughts and rephrased the hypothesis so that it is more clearly and links directly to our intended message.

20. The discussion is far too detailed in many aspects. This is not necessary, please shorten, generalize, underline the most important findings and compare them with existing knowledge.

Thank you for the suggestion. We have tried to do this with significant shortening of the discussion, focussing on salient points related mostly to the primary objective, and comparisons with published literature.

21. In your preliminary study (ref 16) it is concluded that the most relevant parameters to evaluate the deleterious effects of IAH are monitoring of APP, Cdyn, pHi and lactate. Does your current study confirm the preliminary data? Please discuss.

APP has previously been touted as a useful predictor of IAH injury and an early warning sign to hasten therapeutic intervention. However, our data showed several non-normally distributed data. This may have been because of the “mast-suit” type effect from early raised IAP in some pigs that tended to make it an unreliable marker and difficult to analyse and interpret. Added to this is the clinical scenario of the additional sue of inotropes which can create a higher APP, but where splanchnic perfusion may be much worse. As a result, we dd not report APP.

Dynamic compliance, pHi and lactate all remain relevant parameters in evaluating the deleterious effects of IAH. However, several other parameters from each organ system appear just as useful, including SVI, mean pulmonary pressure, driving pressure, pCO2 gap, and urine output.

However, this study did not aim to confirm this aspect of the first analysis, but rather to first describe the changes seen in the animals at the different pressure levels. We have not compared the utility of different parameters as this would further complicate the paper.

22. Please avoid repeated presentation of results!

Thank you for highlighting this error, we have corrected where needed.

Conclusions

23. Second sentence: „Using SVV or PPV in the presence of IAH is an unreliable way of assessing volume status.” How did you come to this? The volume status (fluid responsiveness, for example) was not specifically assessed; these indices were not compared to others in that respect. Please stick precisely only on observed findings while making the conclusions.

We thank the reviewer for this observation and have removed this statement from the conclusion and amended our discussion. Our findings support previous studies as opposed to directly identifying SVV and PVV as being an unreliable way of assessing volume status. Changes in SVV and PVV are supposed to predict volume status. In our model, animals’ volume status was not directly assessed, but equally, they did not lose any fluid and were given IV fluid throughout the study. Interstitial fluid loss was not accounted for hence we agree with the reviewer that this cannot be presented as a direct finding, but rather in support of previous studies which have found SVV and PPVV to be inaccurate in the cases of raised IAP.

Duperret S, Lhuillier F, Piriou V, Vivier E, Metton O, Branche P, et al. Increased intra-abdominal pressure affects respiratory variations in arterial pressure in normovolaemic and hypovolaemic mechanically ventilated healthy pigs. Intensive Care Med. 2007; 33(1):163–71. PMID: 17102964

Renner J, Gruenewald M, Quaden R, Hanss R, Meybohm P, Steinfath M, et al. Influence of increased intra-abdominal pressure on fluid responsiveness predicted by pulse pressure variation and stroke volume variation in a porcine model. Crit Care Med. 2009; 37(2):650–8. doi: 10.1097/CCM. 0b013e3181959864 PMID: 19114894

Jacques D, Bendjelid K, Duperret S, Colling J, Piriou V, Viale JP. Pulse pressure variation and stroke volume variation during increased intra-abdominal pressure: an experimental study. Crit Care. 2011; 15(1):R33. doi: 10.1186/cc9980 PMID: 21247472

Reviewer #2:

The authors studied the pathophysiological effects of elevated IAP in animal models of pneumoperitoneum (Pn) and mechanical intestinal obstruction (MIO) as part of a complex, exploratory animal study.

We are grateful for these comments and suggestions from the reviewer. We have worked on the discussion and made significant changes and hope that it now meets expectations. Our primary aim was to describe the pathophysiological changes, with the comparison of the 2 models being the secondary aim. We have tried to make this clearer.

Additional comments:

1. The element numbers (n) reported in the Study design description on page 8 do not match the element number data reported in the first row of Tables 1-5 of the Results.

We thank the reviewer for highlighting this section as being unclear. There were 49 pigs in total.

Control = 5

Pneumoperitoneum 20mmHg = 10

Pneumoperitoneum 30mmHg = 10

Pneumoperitoneum 40mmHg = 10

Mechanical Intestinal Obstruction 20mmHg = 9

Mechanical Intestinal Obstruction 30mmHg = 5

Making the following numbers for the table:

Control: = 5

IAP 20mmHg = 19

IAP 30mmHg = 15

IAP 40mmHg = 10

2. Why Table 1-5 only shows the data for the Pn groups, and the significance value detected compared to the control group. Why do we not see the data and statistical differences of the MIO groups compared to the control or PN groups?

We understand that this needed to be clearer. We have renamed the tables, explained the primary and secondary objectives more clearly, and reworded the start of the results section to hopefully bring clarity. The tables represent the pooled data from all groups regardless of IAP model and reflect our attempt to describe our primary objective, namely the physiological effects of raised IAP on the various organ systems. Hence the number of subjects as described above.

We thank the reviewer for this comment and have amended the wording so as not to cause confusion.

All pigs were included in the analysis for the primary objective. The assignment of pigs to the different treatments, combining condition, pressure and duration, were as follows: Not all combinations were present, implying “missingness” by design. Contrasts are therefore required to make the appropriate comparisons. Such comparisons typically only make use of a subset of the data. NOTE: It was assumed, that the duration conditions are completely equivalent except for those measurements at the end. In other words, it is assumed that there was no reason to expect that the evolution ran differently at the earlier stages, and the additional measurements in the longer duration only showed how the evolution continues. It was thus possible to compare the evolution for each physiological parameter and how it may differ depending on the model and the pressure. The control condition with 0 pressure compared to the obstruction and pneumoperitoneum conditions with increasing pressure (40mmHg only for pneumoperitoneum). The obstruction and pneumoperitoneum compared directly with a pressure of 20mmHg or 30mmHg.

We have attached the statical analysis for further review if required, but after consultation with the biostatistician, are confident of the linear mixed model created for analysis.

4. On page 26, in the Limitations, do not refer to "insufficient grant money" when there were deaths of pigs in several study groups during the trial (Figures S2, S7, S11, S12).

Thank you for this comment, which we have addressed. The deaths in those groups were considered as outcomes, however, the reviewer is correct in saying that we were not able to make the groups the same size because for the shortfall. However, we did meet appropriate sample size. We have reworded this sentence and are happy to change it again if recommended otherwise.

“Due to funding limitations, one group had four, which still satisfied our sample size requirements.”

Once again, we hank the reviewer for this comment and suggestion and have explored these concepts in the discussion.

Attachment

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PLoS One. doi: 10.1371/journal.pone.0290451.r003

Decision Letter 1

Alexander Wolf

4 Jul 2023

PONE-D-22-32095R1The pathophysiological impact of intra-abdominal hypertension in pigsPLOS ONE

Dear Dr. Wise,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please submit your revised manuscript by Aug 18 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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Additional Editor Comments:

Thank you for your revised manuscript, which has improved significantly. However, there are still objections from a reviewer regarding the statistics, which you should addres.

In this regard, I noticed that you use a one-way ANOVA for normal distribution. As a logical consequence, a Kruskal Wallis test should be done when the distribution is not normal.

I recommend to combine the one-way ANOVA and the Kruskal Wallis test in case of more than two groups to be compared with an appropriate post-hoc test.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Reviewer #1: The revion has siginficantly improved the manuscript. I found my critique adequately adressed. I have only one conern with respect of data presentation:

Authors describe in Statistical analysis section, that continuous variables are presented as means with standard deviations when normally distributed, and as medians with interquartile ranges when non-normal distribution occurred.

In Tables, all data are presented means(SD). Please confirm that all data are indeed normally distributed. With biological data with relatively low number of experiments per group, this would be unusual. Please correct, if needed. If some data are not normally distributed, then entire Table should be presented as medians and IQR.

Reviewer #2: The authors made significant changes to the manuscript text, thus, the quality of the study reached an adequate standard.

**********

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Reviewer #1: No

Reviewer #2: No

**********

PLoS One. 2023 Aug 28;18(8):e0290451. doi: 10.1371/journal.pone.0290451.r004

Author response to Decision Letter 1

19 Jul 2023

Dear Editor

Reviewer #1:

Question 1:

Please find our responses to the two remaining questions, the first from reviewer #1, and the second a comment and suggestion from the editor. The revision has significantly improved the manuscript. I found my critique adequately addressed. I have only one concern with respect of data presentation: Authors describe in Statistical analysis section, that continuous variables are presented as means with standard deviations when normally distributed, and as medians with interquartile ranges when non-normal distribution occurred. In Tables, all data are presented means (SD). Please confirm that all data are indeed normally distributed. With biological data with relatively low number of experiments per group, this would be unusual. Please correct, if needed. If some data are not normally distributed, then entire Table should be presented as medians and IQR.

Response: Thank you for this comment and correction of the analysis. Almost all data were not normally distributed. The tables have been corrected with medians and inter-quartile ranges.

Additional Editor Comments:

Question 2:

Thank you for your revised manuscript, which has improved significantly. However, there are still objections from a reviewer regarding the statistics, which you should address. In this regard, I noticed that you use a one-way ANOVA for normal distribution. As a logical consequence, a Kruskal Wallis test should be done when the distribution is not normal. I recommend to combine the one-way ANOVA and the Kruskal Wallis test in case of more than two groups to be compared with an appropriate post-hoc test.

Response: As the data were not normally distributed, we have corrected the tables and presented the data as median and inter-quartile ranges. We have repeated the analysis using a Kruskal Wallis test and corrected the p-values. The slight changes in the p values have not changed the findings. We have added the following to the text:

“... Normality was evaluated with the Kolmogorov-Smirnov test. One-way ANOVA or Kruskal-Wallis tests were used to compare conAnuous variables as appropriate.”

Kind regards

Attachment

Submitted filename: Response to reviewers.pdf

Click here for additional data file.^{(40.5KB, pdf)}

PLoS One. doi: 10.1371/journal.pone.0290451.r005

Decision Letter 2

Nataša Kovač

9 Aug 2023

The pathophysiological impact of intra-abdominal hypertension in pigs

PONE-D-22-32095R2

Dear Dr. Rober Wise,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Nataša Kovač, MD, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

Reviewer #3: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: I Don't Know

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: (No Response)

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Reviewer #1: (No Response)

Reviewer #2: The authors have addressed most of the reviewers comments by adding new data and/or rewriting the manuscript. Therefore, I do not have further comments.

Reviewer #3: The authors have stated: "A statistical power analysis was performed for sample size estimation, based on data from previous animal studies [1-5]. With an alpha of 0.05

and power = 0.80, the projected sample size needed with this effect size for the endpoint of heart rate was 2. This is based on a starting heart rate

of 105 ± 10 with a predicted increase of at least 20%."

Could you just provide additional info on other parameters used for the calculation of sample size, for example, which R package and which method? Was it some method for mixed effects model sample size calculation?

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

**********

PLoS One. doi: 10.1371/journal.pone.0290451.r006

Acceptance letter

Nataša Kovač

16 Aug 2023

PONE-D-22-32095R2

The pathophysiological impact of intra-abdominal hypertension in pigs

Dear Dr. Wise:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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on behalf of

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PLOS ONE

Associated Data

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Supplementary Materials

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Data Availability Statement

All relevant data are within the paper and its Supporting information files.

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PERMALINK

The pathophysiological impact of intra-abdominal hypertension in pigs

Robert Wise

Reitze Rodseth

Ester Párraga-Ros

Rafael Latorre

Octavio López Albors

Laura Correa-Martín

Francisco M Sánchez-Margallo

Irma Eugenia Candanosa-Aranda

Jan Poelaert

Gregorio Castellanos

Manu L N G Malbrain

Roles

Abstract

Background

Methods

Results

Conclusions

Introduction

Methods

Regulatory issues

Animal study population

Study design

Data collection

Statistical analysis

Results

Table 1. Cardiovascular parameters regardless of IAP model presented as median values with interquartile ranges and significance.

Table 2. Respiratory parameters regardless of IAP model, presented as median values with interquartile ranges and significance.

Table 3. Metabolic and hematological parameters regardless of IAP model, presented as median values with interquartile ranges and significance.

Table 4. Gastrointestinal parameters regardless of IAP model, presented as median values with interquartile ranges and significance.

Table 5. Renal parameters regardless of IAP model, presented as median values with interquartile ranges and significance.

1. Cardiovascular system

Blood pressure

Cardiac output parameters

2. Respiratory system

Mean pulmonary airway pressure (MPP)

Compliance

Partial pressure of oxygen (pO2)

Expiratory minute volume (MVE)

Partial pressure of carbon dioxide (pCO2)

Plateau pressure (PP) and driving pressure

Fig 1. Scatter plot of plateau pressure variables.

3. Metabolic and hematological systems

Base excess (BE)

Bicarbonate (HCO3)

Hematology

4. Gastrointestinal system

Lactate dehydrogenase (LDH)

Lipase

Liver tests

Gastric tonometry

5. Renal system

Calculated glomerular filtration

Fig 2. Scatter plot of calculated glomerular filtration variables.

Urine output

Urea

Creatinine

Secondary objectives (refer to supplementary data)

Discussion

Cardiovascular system

Respiratory system

Metabolic and hematological systems

Gastrointestinal system

Renal system

Comparison between raised IAP models

Limitations

Conclusion

Supporting information

Acknowledgments

Data Availability

Funding Statement

References

Decision Letter 0

Alexander Wolf

Roles

Author response to Decision Letter 0

Decision Letter 1

Alexander Wolf

Roles

Partial pressure of oxygen (pO₂)

Partial pressure of carbon dioxide (pCO₂)

Bicarbonate (HCO₃)