I. INTRODUCTION

Shock is the clinical expression of circulatory failure that results in inadequate cellular oxygen utilization. Shock is a common condition in critical care, affecting about one third of patients in the intensive care unit (ICU), both over resuscitation and under resuscitation can adversely impact the outcomes. End point of resuscitation has always been a matter of debate, initially continuous SCvO2 monitoring as introduced by Rivers et al had the obvious limitation that normal/high values cannot discriminate whether delivery is adequate or in excess to demand. High ScvO2 profiles have even been shown to be related to elevated blood lactate concentration and poor survival rates.

Lactate cannot differentiate between different etiologies of shock and it can get elevated in various other conditions. Carbon dioxide (Co2) is highly diffusible and can be a marker of adequacy of venous return, the central venous and arterial CO2 gap, as an easily available clinical monitoring tool. Observational study has shown that Persistence of such a large pCO2 gap after 24 hours of treatment was predictive of higher mortality.

In conclusion, determining the PCo2 gap during resuscitation of critically ill patients is useful in deciding when to stop resuscitation. Central venous-arterial carbon dioxide difference (PCO2 gap) can be a marker of cardiac output adequacy in global metabolic conditions that are less affected by the impairment of oxygen extraction capacity. Assessing the adequacy of oxygen delivery with oxygen requirements is one of the key-goal of hemodynamic resuscitation. Clinical examination, lactate and central or mixed venous oxygen saturation (SvO2 and ScvO2, respectively) all have their limitations. Many of them may be overcome by the use of the carbon dioxide (CO2)-derived variables. The venoarterial difference in CO2 tension ("ΔPCO2" or "PCO2 gap") is not an indicator of anaerobic metabolism since it is influenced by the oxygen consumption. By contrast, it reliably indicates whether blood flow is sufficient to carry CO2 from the peripheral tissue to the lungs in view of its clearance: it, thus, reflects the adequacy of cardiac output with the metabolic condition. We investigate the relation between the PCO2 gap and serum lactate and its role in resuscitation of patients with septic shock.

II. REVIEW OF LITERATURE

Shock is defined as inability to maintain MAP which is refractory to fluid resuscitation. It has a guarded prognosis, there are many upstream and downstream markers for resuscitation, septic shock guidelines endorses Lactate as a prognostic marker; has got its own limitations as it can be elevated in other clinical conditions9 and it cannot differentiate the cause of shock9. With enough evidence coming up about over resuscitation and positive balance being one of the predictor of mortality there is a need for ideal resuscitation marker which can be easily employed bedside with present day equipment used on day to day basis.

CO2 is the end product of aerobic metabolism, PCO2 in the venous blood reflects the global tissue blood flow relative to metabolic demand. CO2 is about 20 times more soluble than O2 so it more reliably diffuses out of ischemic tissues into the venous effluent making it a sensitive marker of hypoperfusion in situations where an O2 diffusion barrier exists (e.g. non-functional and obliterated capillaries), "masking" poor O2 extraction (O2ER) and increased tissue O2 debt, CO2 still diffuses to the venous effluent, "unmasking" the low perfusion state for the clinician when venous-toarterial CO2 difference is evaluated the gap is a marker of adequacy of venous blood flow to remove CO2 produced rather than a marker of tissue hypoxia or dysoxia ${}^{11}$

As illustrated in table 1, Lactate is high in all types of shock, PCO2 Gap is high in cardiogenic and distributive shock which is amenable to fluid resuscitation and inotropic support and low in hypoxemic and cytopathic shock where fluid resuscitation has no role thus it can be concluded that PCO2 gap is useful in determining when to start and stop fluid resuscitation. Co2 gap is a marker of adequacy of venous blood rather than marker of tissue hypoxia or dysoxia as shown by Vallet et al in an experimental model of isolated limb in which ischemic hypoxia (IH) and hypoxic hypoxia (HH). The authors demonstrated that when DO2 was reduced beyond its critical threshold in IH (dysoxia), this was associated with an increased limb venous-to-arterial PCO2gap.

Conversely, in HH, pCO2 gap did not increase in spite of a marked VO2 and VCO2 reduction. ${}^{12}$ There is a good correlation between Mixed CO2 and Central CO2 difference with Arterial CO2 as demonstrated by Van Beest et al in severe sepsis and septic shock patients, hence Central CO2 can be substituted for mixed CO2 for determining the CO2 gap which acts as surrogate marker for Cardiac Index. ${}^{10}$

Cushieri J et al conducted study in ICU patients to see the correlation between Central Venous and Arterial CO2 gap and Cardiac index determined by thermodilution technique and showed statistically significant correlation. ${}^{13}$

Hence CO2 gap can be used as a marker of Cardiac output.

a) Role in Sepsis

In sepsis although Cardiac output may be normal but regional compromise of circulation is well documented phenomenon which may lead to increase in CO2 secondary to micro-circulation compromise. P(cv-a)CO2 could be considered as a better indirect assessment of systemic blood flow than ScvO2 in resuscitated-septic shock patients.[14]

A cutoff value for pCO2 gap of 0.8 kPa (6mmHg) discriminated between high and low lactate clearance and Cl. ${}^{15,16}$ In study done by Vallee et al done in septic shock patients compared When the $70\mathrm{\%}$ ScvO2 goal value is reached, the presence of a P(cv-a)CO2 larger than 6 mmHg shown to be an useful tool to identify patients who still remain inadequately resuscitated. ${}^{14}$

We hypothesize that CO2 gap is non inferior to lactate clearance in resuscitation of critically ill patients.

III. RESEARCH QUESTION

Would pCO2 gap serve as an ideal bedside marker to predict the outcome of resuscitation in a patient with shock?

IV. AIMS AND OBJECTIVES

Aim of the Project: To study the association between PCO2 gap and outcome of resuscitation in patients with shock.

Objectives of the Project: The Objectives of the project are as follows:

• Primary objectives- To study the association between PCO2 gap and in-hospital mortality in patients admitted with shock.
• Secondary objectives
• To study the correlation between PCO2 gap and lactate clearance.
• To study the role of PCO2 gap as a marker for endpoint of resuscitation in patients with shock.

V. METHODS AND METHODOLOGY

Study population:

• Inclusion Criteria
• All adult patients (more than 18 years of age) in shock requiring vasopressor to maintain MAP of $65\mathrm{mmHg}$, having a central venous access and arterial line.
• Exclusion Criteria
• Patient Refusal
• Pregnancy
• Advance directive with consensus against active resuscitation
• Disseminated Malignancy

Sample size: 71

Study design: Prospective observational study.

Study intervention: No interventions

Study duration: One Year

VI. METHODOLOGY

• All shock patients were resuscitated according to the standard protocol with fluid bolus of $30\text{ml/kg}$ over 1 hour and guided therapy with fluid challenges targeting heart rate, base deficit, urine output and pulmonary congestion as per routine clinical practice.

• Lactate clearance was documented every 2nd hourly and VBG from Central line and ABG from Radial Line was analyzed at the same time and CO2 gap was checked every 2nd hourly.

• $\diamond$ Screening 2D-echocardiography was done at the emergency department and inotropic agent was decided based on heart contractility.

• $\iff$ Patient demographic details, diagnosis, SOFA Score, was done in the first 6 hours of resuscitation (two hours apart) and the data was collected. Lactate and Co2 Gap were captured and documented after 24 hours of resuscitation.

• Aim of resuscitation was to target MAP of $65\mathrm{mm}\mathrm{Hg}$ and two stable lactate values 2 hours apart. If lactates had not improved then further fluid boluses were decided upon reviewing pulmonary congestion in ultrasound (M mode of lung will be done and if B lines are more than 4 then it is indicative of pulmonary congestion). The corresponding CO2 Gap was noted.

• First choice of vasopressor was nor-adrenaline as per the standard infusion dose. If patient requires vasopressor support despite fluid boluses then steroid in the form of injection Hydrocortisone $50\mathrm{mg}$ IV every 6th hourly was administered.

• Antimicrobial administration and further management was decided by clinical examination and supportive investigations as per clinician's judgement.

Data collection methods: Proforma

Data collection forms: Attached

VII. STATISTICAL METHODS

a) Sample Size Calculation

• Sample size was calculated using nMaster software v2.0
• In a study done by Beest PV et al, the mortality of patients with sepsis was $24.5\mathrm{\%}$ (13 out of 53) and risk of mortality for those with high PCO2 gap ranged from 1.6 to 5.3
• Keeping a conservative value in odds ratio as 2.5, with power of $80\mathrm{\%}$ and $5\mathrm{\%}$ alpha error the minimum required sample size is 71.

b) Statistical Analysis Plan

• Data was analyzed using R software. Continuous variable were described using mean and standard deviation. Categorical variables were described using frequency and percentage. Patients were categorized based on PCO2 difference and logistic regression was done to analyze various factors associated with mortality. Correlation between PCO2 difference and lactate was done using appropriate statistical methods. P value less than 0.05 was considered statistically significant.

c) Ethical consideration

Ethical clearance was obtained prior to the study from the ethics committee of the institution. Informed consent was obtained from the patient or guardian before the onset of study. Confidentiality of patient details are and will be maintained. It was explained to the patient that the study is purely descriptive and merely for data collection. There is no intervention required specifically for the study. Management of these patients were along the standard international guidelines. As the study did not involve any extra procedure, no compensation was offered during and after the study.

VIII. RESULTS

A total of 71 patients were enrolled in the study. 7 patients died from the 48 to 72 hours time period. Their samples were collected and analyzed till the 24th hour of admission. The mean age of the patients was 54 years (SD 16.2; range 18-81 years).

The primary outcome of the study was the correlation between the PCO2 gap and the in hospital mortality at each of the sampling time points. The correlation between the PCO2 gap and the in hospital mortality was positive at 0, 2, 4, 6 and 24 hours. The correlation was statistically significant at 0 and 2 hours. (Table 2)

There was a statistically significant negative correlation between end point of resuscitation and pCO2 gap at 2h,4h, 6h and 24 hours as implied by the Pearson's correlation in Table 3.

It was also observed that the pco2 gap at 0h,2h,4h, 6hours had a statistically significant positive correlation with lactate clearance.(Table 4)

IX. DISCUSSION

The association of lactate accumulation and oxygen debt during shock states has been described for decades 15. Throughout the years, there has been continued interest in refining resuscitation triggers, and response to therapy. Lactate clearance as an endpoint of resuscitation is supported by at least two multi-center studie ${}^{16,17}$. However, lactate clearance has disadvantages as lactates can sometimes be normal in septic shock ${}^{18}$, lactate elevation not solely due to oxygen delivery- consumption mismatch and it has different prognostic implications based on the initial value.

It was recognized in sepsis that pCO2 gap (or its mathematical derivatives) outperformed other markers in detecting tissue hypoperfusion ${}^{13,19-21}$. The arterial carbon dioxide is dependent on the pulmonary gas exchange and the venous carbon dioxide is dependent on the blood flow to the tissue ${}^{22}$. So, when the flow reduces in low cardiac output states like shock, the difference between the venous and arterial carbon dioxide increases. It has been demonstrated that the pCO2 gap increases in various types of shock. ${}^2$

In our study we found a statistically significant correlation of pCO2 gap at 0 hour and and 2nd hour of resuscitation and mortality in patients. It shows that high pCO2 gap on initial presentation can be used as a predictor of outcomes in patients with shock. Ospina-Tascon, G.A. et al.,[24] found that the persistence of high PCO2gap during the early resuscitation of septic shock was associated with higher 28 day mortality.

We also found that there was a statistically significant correlation between end point of resuscitation and pCO2 gap at 2h,4h, 6h and 24 hours. Hence, pco2 gap can be used as an endpoint of resuscitation in patients with shock. This was similar to the findings of Vallet B et al.,[11] who found that determining the gap during resuscitation of critically ill patients is useful when deciding when to stop resuscitation.

Our analysis also showed that PCO2 gap at various time points had positive correlation with lactate clearance. This was similar to a study done by Shyam M et al.,[25] who showed that the PcvCO2-PaCO2/CaO2-CcvO2 ratio and lactate are positively correlated during the first 24 hours of active resuscitation from sepsis-induced hypotension,

Pco2 gap is not inferior to lactate levels as a hemodynamic marker. It can be substituted in place of lactate levels to predict outcomes in patients presenting with shock. It can also be used as a guide for therapy to achieve endpoint of resuscitation.

X. LIMITATIONS

Our study has its limitations. It is a descriptive study without randomization of the patients. Also some technical aspects should be kept in mind when these indices are used in clinical practice. First, some errors in the PCO2 gap measurements may occur when sampling the venous blood: incorrect sample container, contaminated sample by air or venous blood or catheter fluid. Second, a too long delay of transport of blood sampling may significantly change the blood gas content at the venous and the arterial site.

XI. SUMMARY AND CONCLUSION

The PCO2 gap can be used as a marker of the adequacy of the cardiac output in patients with shock. Using pCO2 gap has potential to avoid administration of unnecessary fluids and inotropes in patients, who have lactate elevated in the absence of tissue hypo perfusion. We suggest using pCO2 gap as a complementary tool to evaluate the adequacy of blood flow to global metabolic demand. A high pCO2 gap on initial presentation was associated with high mortality rates. So it can be used as a predictor of outcomes in patients with shock.

List of abbreviations

ICU - Intensive care unit

MAP- Mean arterial pressure

CO2- carbon dioxide

PCO2- Partial pressure of carbon dioxide

EtCO2- End tidal concentration of carbon dioxide

CVP- Central venous pressure

SCVO2- Central venous oxygen saturation

VO2- Oxygen consumption

VCO2- Carbon dioxide output

CaCO2- Carbon dioxide content in the blood

K pa- Kilo pascal

SOFA- Sequential organ failure assessment

Mm Hg- millimeters of mercury.

VBG- Venous blood gas

ABG- Arterial blood gas.

1. Vincent JL, De Backer D Circulatory shock, N Engl J Med, 2013; 369: 1726-34

2. Acheampong A, Vincent JL. A positive fluid balance is an independent prognostic factor in patients with sepsis. Crit Care 2015; 19: 251 - 257.

3. Boyd JH, Forbes J, Nakada T et al. Fluid resuscitation in septic shock: a positive fluid balance and elevated central venous pressure are associated with increased mortality. Crit Care Med 2011; 39: 259 - 265;

4. Sakr Y, Birri PNR, Kotfis K et al. Higher fluid balance increases the risk of death from sepsis: results from a large international audit. Crit Care Medicine 2017; 45: 386 - 394.

5. Varpula M, Karlsson S, Ruokonen E, Pettila V (2006) Mixed venous oxygen saturation cannot be estimated by central venous oxygen saturation in septic shock. Intensive Care Med 32: 1336-1343.

6. van Beest P, Hofstra J, Schultz M, Boerma E, Spronk P, Kuiper M (2008) The incidence of low venous oxygen saturation on admission to the intensive care unit: a multi-center observational study in The Netherlands. Crit Care 12: R33.

7. Ince C, Sinaasappel M (1999) Microcirculatory oxygenation and shunting in sepsis and shock. Crit Care Med 27: 1369-1377.

8. Arnold RC, Shapiro NI, Jones AE, Schorr C, Pope J, Casner E, Parrillo JE, Dellinger RP, Trzeciak S. Multi-Center Study of Early Lactate Clearance as a Determinant of Survival in Patients with Presumed Sepsis. Shock.

10. Kraut JA, Madias NE. Lactic acidosis. N Engl JMed. 2014; 371(24): 2309-2319.

11. Van Beest PA, Lont MC, Holman ND, Loef B, Kuiper MA, Boerma EC (2013) Central venous-arterial pCO2 difference as a tool in resuscitation of septic patients. Intensive Care Med 39: 1034-103.

12. Vallet B, Pinsky MR, Cecconi M (2013) Resuscitation of patients with septic shock: please "mind the gap"! Intensive Care Med 39:1653-1655.

13. Vallet B, Teboul JL, Cain S, Curtis S (2000) Venoarterial CO2 difference during regional ischemic or hypoxic hypoxia. J Appl Physiol 89: 1317-1321.

14. Cuschieri J, Rivers EP, Donnino MW, Katilius M, Jacobsen G, Nguyen HB, Pamukov N, Horst HM (2005) Central venous-arterial carbon dioxide difference as an indicator of cardiac index. Intensive Care Med 31: 818-822.

15. Vallee F, Vallet B, Mathe O. Central venous-toarterial carbon dioxide difference: an additional target for goal-directed therapy in septic shock? Intensive care medicine. 34(12): 2218-25.

17. Weil M, Afifi AA. Experimental and Clinical Studies on Lactate and Pyruvate as Indicators of the

• Severity of Acute Circulatory Failure (Shock) Circulation. 1970; 41: 989-1001.

1. Jansen TC, van Bommel J, Schoonderbeek FJ, Sleeswijk Visser SJ, van der Klooster JM, Lima AP, Willemsen SP, Bakker J. Early lactate-guided therapy in intensive care unit patients: a multicenter, open-label, randomized controlled trial. Am J Respir Crit Care Med. 2010; 182(6): 752-761.

2. Jones AE, Shapiro N, Trzeciak S, et al. Lactate clearance versus central venous oxygen saturation as goals of early sepsis therapy. JAMA. 2010; 303(8): 739-746.

3. Hernandez G, Castro R, Romero C, et al. Persistent sepsis-induced hypotension without hyperlactatemia: Is it really septic shock? Journal of Critical Care. 2011; 26: 435. e439-435. e414.

4. Mallat J., Lemyze M., Meddour M., et al. Ratios of central venous-to-arterial carbon dioxide content or tension to arteriovenous oxygen content are better markers of global anaerobic metabolism than lactate in septic shock patients. Annals of Intensive Care. 2016; 6(1): 1-9. doi: 10.1186/s13613-016-0110-3.

5. West J. B. Gas transport to the periphery: how gases are moved to the peripheral tissues? In: West J. B., editor. Respiratory Physiology: The Essentials. 4th. Seattle, WA, USA: Amazon;

6. pp. 69-85.

7. Sun X.-G., Hansen J. E., Ting H., et al. Comparison of exercise cardiac output by the fuck principle using oxygen and carbon dioxide. Chest. 2000; 118(3): 631-640. doi: 10.1378/chest.118.3.631.

8. Weil MH, Rackow EC, Trevino R, Grundler W, Falk JL, Griffel MI. Difference in acid-base state between venous and arterial blood during cardiopulmonary resuscitation. New England Journal of Medicine. 1986 Jul 17; 315(3): 153-6.

9. Ducey JP, Lamiell JM, Gueller GE. Arterial-venous carbon dioxide tension difference during severe hemorrhage and resuscitation. Critical care medicine. 1992 Apr 1; 20(4): 518-22.

10. Ospina-Tascón, G.A., Bautista-Rincón, D.F., Umana, M. et al. Persistently high venous-to-arterial carbon dioxide differences during early resuscitation are associated with poor outcomes in septic shock. Crit Care 17, R294 (2013).

11. Madabhushi S, Trikha A, Anand RK, Ramachandran R, Singh PM, Rewari V. Temporal Evolution of the PcvCO2-PaCO2/CaO2-CcvO2 Ratio vs Serum Lactate during Resuscitation in Septic Shock. Indian J Crit Care Med. 2021 Dec; 25(12): 1370-1376. doi: 10.5005/jp-journals-10071-24044. PMID: 35027796; PMCID: PMC8693105.

APPENDICES

Proforma

PCO2 Gap - AS AN ENDPOINT OF RESUSCITATION AND PREDICTOR OF MORTALITY IN PATIENTS WITH SHOCK.

1. DATE OF ADMISSION
2. AGE: YEARS
3. SEX: MALE/FEMALE
4. COMORBIDITIES: DIABETES/HYPERTENSION/ IHD/ CKD/THYROID DISORDERS/ OTHERS
5. PROVISIONAL DIAGNOSIS
6. TYPE OF SHOCK: CARDIOGENIC/HYPOVOLEMIC/DISTRIBUTIVE/ANEMIC OR HYPOXEMIC/CYTOPATHIC
7. SOFA SCORE
8. MEAN ARTERIAL PRESSURE (ON ARRIVAL TO ER):
9. FLUID BOLUS: YES/ NO SPECIFY DETAILS -
10. VASOPRESSOR: YES/ NO, if YES specify the drug
11. DOBUTAMINE SUPPORT: YES/ NO
12. ENDPOINT OF RESUSCITATION:
13. FINAL OUTCOME OF PATIENT:

Dr. Prabhu,

Narayana health.

This Informed Consent Form is for men and women who come to the emergency department in state of shock- with low blood pressure not responding to IV fluids, and who we are inviting to participate in research. The title of our research project is PCO2 Gap - AS AN ENDPOINT OF RESUSCITATION AND PREDICTOR OF MORTALITY IN PATIENTS WITH SHOCK: A PROSPECTIVE OBSERVATIONAL STUDY.

This Informed Consent Form has two parts:

Information Sheet (to share information about the research with you)

Certificate of Consent (for signatures if you agree to take part)

PART I: Information Sheet

Introduction

I am Dr. Prabhu. We are doing research on patients presenting with shock to the emergency room, which can occur due to various causes like blood loss, cardiac failure, infection, anemia. I am going to give you information and invite you to be part of this research. Before you decide, you can talk to anyone you feel comfortable with about the research.

There may be some words that you do not understand. Please ask me to stop as we go through the information and I will take time to explain. If you have questions later, you can ask them of me, or the staff.

pCO2 gap is the difference between the venous and arterial carbon dioxide. When a patient presents with shock, they will be treated with IV fluids or medication to increase blood pressure (inotropes) by constriction of blood vessels depending upon the cause of the shock. To know when the shock has resolved, we are going to compare pCO2 gap to other parameters which have been previously established.

Purpose of the research To evaluate if pCO2 gap can be used to predict mortality and marker for end point of resuscitation

Participant selection

We are inviting all adults with shock to participate in the research on pCO2 gap.

Voluntary Participation

Your participation in this research is entirely voluntary. It is your choice whether to participate or not. Whether you choose to participate or not, all the services you receive at the hospital will continue and nothing will change. You may change your mind later and stop participating even if you agreed earlier.

Procedures and Protocol

Once you understand the study and give consent, your pCO2 gap will be measured on presentation, 2nd hour, 4th hour, 6th hour and at 24th hour. Patients presenting with shock will have an arterial line for invasive blood pressure measurement and a central line for administration of inotropes to treat the shock. Blood samples from these lines will help us to measure pCO2 gap. Treatment will be given for the shock as per standard guidelines and hospital protocol according to the patient's condition. Other parameters such as mean arterial pressure, IVC collapsibility, lactates will be compared to find out if pCO2 gap has a good correlation for endpoint of resuscitation (resolution of shock)

Duration

The research takes place over the course of 1 year. You will be followed up for 12 to 24 hours depending upon your clinical condition.

Side Effects

No new intervention or procedure is done for the study. You will already have lines from which blood samples will be taken. Hence there are no side effects for the study.

Risks

No additional risks and discomfort will be caused during this study.

Benefits

The findings of this study can change the views of using pCO2 gap as an endpoint of resuscitation.

Confidentiality

The information that we collect from this research project will be kept confidential. Information about you that will be collected during the research will be put away and no-one but the researchers will be able to see it. Any information about you will have a number on it instead of your name. Only the researchers will know what your number is and we will lock that information up with a lock and key.

Right to Refuse or Withdraw

You do not have to take part in this research if you do not wish to do so and refusing to participate will not affect your treatment at this hospital in any way. You may stop participating in the research at any time that you wish without losing any of your rights as a patient here. Your treatment at this hospital will not be affected in any way.

Whom to contact

If you have any questions you may ask them now or later, even after the study has started. If you wish to ask questions later, you may contact any of the following:

Contact the principal investigator

Name: Dr. Prabhu

Address: Narayana Health City, Bangalore

Contact No. 7358248887

This proposal has been reviewed and approved by Narayana Health Academic ethical committee, which is a committee whose task it is to make sure that research participants are protected from harm. If you wish to find about more about the IRB, contact Narayana Health Academic Ethics Committee. Name: Dr. Sanjay Rao

Designation: Member Secretary

Contact No. 9538008940;

PART II: Certificate of Consent

I have read the foregoing information, or it has been read to me. I have had the opportunity to ask questions about it and any questions that I have asked have been answered to my satisfaction. I consent voluntarily to participate as a participant in this research.

Print Name of Participant

Signature of Participant

Date Day/month/year

Statement by the researcher/person taking consent

I have accurately read out the information sheet to the potential participant, and to the best of my ability made sure that the participant understands the objectives of the research.

I confirm that the participant was given an opportunity to ask questions about the study, and all the questions asked by the participant have been answered correctly and to the best of my ability. I confirm that the individual has not been coerced into giving consent, and the consent has been given freely and voluntarily.

A copy of this ICF has been provided to the participant.

Print Name of Researcher/person taking the consent

Signature of Researcher /person taking the consent

Date Day/month/year

Print name of the impartial witness in capitals

Signature of impartial witness

Deferred Consent for Research Participation

Title of Project: PCO2 Gap - AS AN ENDPOINT OF RESUSCITATION AND PREDICTOR OF MORTALITY IN PATIENTS WITH SHOCK: A PROSPECTIVE OBSERVATIONAL STUDY.

Principal Investigator: Dr. Prabhu

Narayana health,Phone Number: 7358248887

The patient named below is being enrolled in this research study by deferred consent. The process of obtaining written informed consent will be deferred until after the patient is able to understand and has capacity to give consent. Written informed consent will be obtained to continue data collection after resuscitation from the patient or, if the patient lacked capacity, a legal representative.

Patient's Name:

Date/time assessed for enrolment: / / (dd/mm/yyyy) at: (time)

Reason(s) deferred consent process is used (check all that apply):

The patient is unconscious or lacks capacity to understand the risks, methods and purposes of the research study.

No next of kin/substitute decision maker is available to provide consent, or attempts to contact them have been unsuccessful despite diligent and documented efforts.

A substitute decision maker ________ (name and relationship) has been contacted by telephone, and the purpose, methods and risks of participation in this study have been explained to the third party. While the substitute decision maker has given verbal consent for participation, written consent must be still be obtained.

No relevant prior directive by the patient is known to exist.

Other:

Signature of investigator

Date and Time

ANNEXURE 1

NHH/AEC-CL-2020-506

Date: 2nd Feb 2021

Dr. Prabhu S

Narayana Hrudayalaya Hospitals, Bommasandra

Bangalore-560099

Study Title: PCO2 Gap - As An Endpoint Of Resuscitation And Predictor Of Mortality In

Patients With Shock: A Prospective Observational Study

Subject: Approval letter for above mentioned study

Dear Dr. Prabhu S.

We have received soft copy of the study documents vide your letter dated $9^{\text{th}}$ April 2020. The study protocol was reviewed by Scientific Research Committee (SRC) in its meeting on ${15}^{\text{th}}$ April 2020 and approved for Scientific content. The following Scientific Research Committee members were present during the meeting held on ${15}^{\text{th}}$ April 2020 at $2.00\text{pm}$

The study was further reviewed in NHAEC meeting held on 24th April 2020 and approved, pending some clarification from principal investigator. The clarification provided were reviewed by Ethics Committee and the NHAEC has decided to approve this study for scientific and ethical content. You are hereby permitted to conduct this study at Mazumdar Shaw Medical Centre, a unit of Narayana Hrudayalaya Ltd.

Documents Reviewed:

• Protocol, Version 1.2, Dated $5^{\text{th}}$ June 2020
• Informed consent form & Patient information sheet, Version 1.0 Dated 14 Sept 2018
• Informed consent form & Patient information sheet for relative participation

Dated 14th Sept 2020

Deferred consent for research participation version 2.0 dated 14 Sept 2020

Narayana Hrudayalaya Ltd.

Tel: +91 80 7122 2222, Extn: 2689, Direct: 080-27836966

Fax: 080-27835208 Web: narayanahealth.org

ANNEXURE II

Narayana Health Academic Ethics Committee

Study Proforma, Version 1.0 Dated ${13}^{\mathrm{th}}$ April 2020 The following members of the Eithers Group

2020 at 1:30 pm at Narayana Hrudayalaya Ltd, Narayana Health City, No. 258/A Bommasandra Industrial Area, Hosur Road, Bangalore-560099, Karnataka -India.

Neither the principal investigator Dr. Prabhu S nor any of her study team members were present during the decision - Making process.

The NHAEC is organized & operates according to the requirements of ICH-GCP, Indian Council of Medical Research guidelines & New Drugs and Clinical Trial Rules, 2019.

This approval is given for entire duration of the project subjected to the Principal investigator submitting 6 monthly progress report signed by the guide. Failure to submit 2 consecutive report will automatically revoke the approval.

The NHAEC is registered under DCGI with the EC Registration No. ECR/772/Inst/KA/2016/RR-19 valid till date 27 February 2022 issued under Rules 122DD of the Indian Drugs and Cosmetics Rules 1945 and also under DHR with Provisional number EC/NEW/INST/2020/561.

Yours Sincerely,

Date: 3.2.21

Dr. Sanjay Rao

Member Secretary

Narayana Health Academic Ethics Committee

Member Secretary

Narayana Health

Academic Ethics Committee

No.258/A Bommasandra Industrial A

Hosur Road, Bangalore - 56003.

A

080-71222222

Masandra Industrial Area, Hosur Road, Bangalore 560 099

Tel: +91 80 7122 2222, Extn: 2689, Direct: 080-27836966