Glad you got it working.

I feel I should mention that I specifically told you to just that 2 days ago ... quoted here:

You're cloning the source message inside the While loop that is iterating over segments within the message. That's not doing anything useful.

Clone the message, then iterate over its OBX segments, making whatever changes are necessary. Before sending it with SendRequestAsync(), do a pOutput.%Save().
This snippet below is completely untested and there are other enhancements I would make to it, but I'm not going to be available for a while, so here's something to play with. It's a cleaned up version of the code snippet you provided above. Note that there is not a single call to GetSegmentAt() ... it's an unnecessary extra step.

    // Message Subtype
    Set tMessageSubType = pRequest.GetValueAt("ORCgrp(1).ORC:1")
    //
    // Check if OBR:19 contains "Implant Usage (PSAS)" OR "Issued in Clinic (PSAS)"
    Set tOrderType = pRequest.GetValueAt("ORCgrp(1).OBRuniongrp.OBRunion.OBR:19(1).1")
    If ((tOrderType["Implant Usage (PSAS)") || (tOrderType["Issued in Clinic (PSAS)")) {
        // First loop: Count occurrences of "Item Number:"
        Set i = 1
        Set tItemNumberCount = 0
        While (pRequest.GetValueAt("ORCgrp(1).OBRuniongrp.OBXgrp("_i_").OBX")'="") {
            Set tOBXText = pRequest.GetValueAt("ORCgrp(1).OBRuniongrp.OBXgrp("_i_").OBX.5", .tStatus)
            //
            If (tOBXText [ "Item Number:") {
                Set tItemNumberCount = tItemNumberCount + 1
            }
            //
            If (tOBXText[ "Total Cost:") {
                Set tTotalCostSegment = i
                //$$$LOGINFO(tTotalCostSegment_" ------ "tTotalCostSegment check Total Cost")
            }
            Set i = i + 1
        }
        // Second loop: Modify OBX segments if necessary
        Set i = 1
        Set tItemNumberProcessed = 0
        Set pOutput = pRequest.%ConstructClone(1) // moved here because %ConstructClone() need only be done at the message object level.
        While (pOutput.GetValueAt("ORCgrp(1).OBRuniongrp.OBXgrp("_i_").OBX")'="") {
            Set tOBXText = pOutput.GetValueAt("ORCgrp(1).OBRuniongrp.OBXgrp("_i_").OBX.5", .tStatus) // using pOutput instead of pRequest
            If (tOBXText [ "Item Number:") {
                Set tItemNumberProcessed = tItemNumberProcessed + 1
            }
            If (tItemNumberCount > 1) && (tOBXText [ "REASON FOR REQUEST:") {
                set tOBXKey = i
                Set tOBXText=$p(tOBXText,":",2,5) /// OBX 5 text parsed to replace in OBX 5 later
                // Start replacement process
                Do pOutput.SetValueAt(tOBXText,"ORCgrp(1).OBRuniongrp.OBXgrp("_i_").OBX.5")
                $$$LOGINFO(tOBXText_" ---- OBX 5 parsed to be saved in new OBX 5") /// works
                Set tOBXTextChanged = pOutput.GetValueAt("ORCgrp(1).OBRuniongrp.OBXgrp("_i_").OBX.5")
                $$$LOGINFO(i_tOBXTextChanged_" --- i --- tOBXTextChanged, Is OBX 5 changed???")
            }
            Set i = i + 1
        }
    }
    Do pOutput.%Save()

%ConstructClone() need only be done at the message object level.

And I'm not sure why you're extracting segments to update them; you can use SetValueAt() against the message object instead a segment object ... 

For example this code:

Set tOBXSegmentpOutput = pOutput.GetSegmentAt("ORCgrp(1).OBRuniongrp.OBXgrp("_i_").OBX", .tStatus)
Do tOBXSegmentpOutput.SetValueAt(tOBXText, 5)

Is functionally identical to:

Do pOutput.SetValueAt(tOBXText,"ORCgrp(1).OBRuniongrp.OBXgrp("_i_").OBX.5")

That should help simplify the code.

You shouldn't need to do a "deep clone" for this, so the "1" argument to %ConstructClone() is optional.

Somewhere between the %ContstructClone() call and the SetValueAt() call, you'll be using the GetSegmentAt() method of the clone to get the segment object into tOBXSegmentpOutput.

The syntax of the SetValueAt() call should have the string to store as the first argument rather than the pOutput message object.

tOBXSegmentpOutput is a reference to the segment in the clone message. It should not need to be explicitly saved, and I'm pretty sure SaveData() doesn't do what you think it does anyway.

There are a few issues with this code, but the biggest one is that you've created a clone and should be modifying the clone (pOutput) exclusively. However, you're still calling SetValueAt() against a segment pulled from pRequest.

The above notwithstanding, you're still sending the original unchanged message object (pRequest) to the target operation with the SendRequestAsync() call.

Fundamentally, you should:

1. Create a clone of the request object pRequest (i.e. pOutput)
2. Modify the clone, which is a mutable copy of the original message
3. Send the modified clone (pOutput) to the target operation

Here's how I would approach this using a DTL ...

1. Create a counter variable to hold the number of occurrences of "Item Number:"
2. Use a for each action to iterate over the OBX segments
3. In the for each, create an if action that checks for the presence of "Item Number:" in OBX:5 (using ..Contains())
4. If the action is true, increment the counter variable

Example:

On completion of the for each, you should have a value that indicates the presence of more than one "Item Number." Next, update the OBXs:

1. Create another counter variable to track occurrences of "Item Number" to be used for comparison
2. Add another for each action to perform the modifications to the OBX segments
3. Use the $REPLACE() or ..Replace() functions to replace "REASON FOR REQUEST:" in each OBX:5 with an empty string
4. Add an if action to check the OBX:5 field for "Item Number:"; increment the new counter variable if found
5. Add an if action to evaluate the new counter variable against the original; if it's less than the original, add a line break (not actual $C(13)/$C(10) characters, but escaped representation such as \.br\ or \X0D\\X0A\; likely vendor-dependent)

Example: